Ligarda-Samanez, 2026

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Received: 7 December 2025
Revised: 23 December 2025
Accepted: 25 December 2025
Published: 27 December 2025
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Review
Innovations in the Delivery of Bioactive Compounds for
Cancer Prevention and Therapy: Advances, Challenges,
and Future Perspectives
Carlos A. Ligarda-Samanez 1,* , Mary L. Huamán-Carrión 1,* , Jackson M’coy Romero Plasencia 2 ,
Dante Fermín Calderón Huamaní 3, Bacilia Vivanco Garfias 4, Jenny C. Muñoz-Saenz 5,
Maria Magdalena Bautista Gómez 4, Jaime A. Martinez-Hernandez 3 and Wilber Cesar Calsina-Ponce 6
1 Nutraceuticals and Biomaterials Research Group, Universidad Nacional José María Arguedas,
Andahuaylas 03701, Peru
2 Department of Mathematics and Physics, Universidad Nacional de San Cristóbal de Huamanga,
Ayacucho 05000, Peru; jackson.romero@unsch.edu.pe
3 Department of Environmental Engineering, Universidad Nacional San Luis Gonzaga, Ica 11001, Peru;
dante.calderon@unica.edu.pe (D.F.C.H.); jaime.martinez@unica.edu.pe (J.A.M.-H.)
4 Department of Obstetrics, Universidad Nacional de San Cristóbal de Huamanga, Ayacucho 05000, Peru;
bacilia.vivanco@unsch.edu.pe (B.V.G.); maria.bautista@unsch.edu.pe (M.M.B.G.)
5 Environmental Engineering School, Universidad Continental, Huancayo 12006, Peru;
jmunoz@continental.edu.pe
6 Social Sciences Faculty, Universidad Nacional del Altiplano, Puno 21001, Peru; wcalsina@unap.edu.pe
* Correspondence: caligarda@unajma.edu.pe (C.A.L.-S.); huamancarrionmary@gmail.com (M.L.H.-C.);
Tel.: +51-985-822-085 (C.A.L.-S.); +51-921-919-905 (M.L.H.-C.)
Abstract
Naturally occurring bioactive compounds represent a promising option for cancer preven-
tion and therapy due to their ability to modulate apoptosis, angiogenesis, inflammation,
oxidative stress, and cell signaling. However, their clinical impact is limited by low
bioavailability, chemical instability, rapid metabolism, and poor tumor microenvironment
accumulation. Innovative delivery platforms, including lipid and polymeric nanoparti-
cles, liposomes, micelles, nanoemulsions, hydrogels, and stimulus-responsive systems,
have been developed to improve stability, absorption, tumor specificity, and therapeutic
efficacy. This review integrates molecular mechanisms, preclinical and clinical evidence,
and recent technological advances, highlighting both potential and limitations. Although
several compounds show encouraging results in cell and animal models, only a small
number have progressed to early clinical trials, where outcomes remain heterogeneous
and often fail to replicate preclinical magnitudes. Regulatory barriers, a lack of formu-
lation standardization, and the absence of predictive biomarkers persist. Sustainability
is also addressed through the valorization of agrifood by-products and green extraction
processes. This review provides an integrative framework linking molecular mechanisms,
advanced delivery technologies, clinical translation, and sustainability, offering a broader
perspective than conventional reviews. Future perspectives emphasize multicenter trials,
comparative designs, and the development of regulatory guidelines for nanoformulated
bioactive compounds.
Keywords: drug delivery; nanoformulations; tumor microenvironment; pharmacokinetics;
clinical translation; bioavailability
Pharmaceuticals 2026, 19, 60 https://doi.org/10.3390/ph19010060
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1. Introduction
Cancer continues to be one of the leading causes of death worldwide. The most
recent epidemiological reports show a steady increase in both incidence and mortality, with
marked variations across regions, age groups, and access to diagnosis and treatment [1–3].
This situation poses a significant health and social challenge, as the disease not only
compromises the health of millions of people but also has a significant economic impact. In
addition to the direct costs of care, there is the so-called “financial toxicity,” which affects
households and reduces labor productivity, factors that together increase pressure on health
systems and deepen existing inequalities [4–6].
On the other hand, conventional oncology treatments, such as chemotherapy, radiother-
apy, and immunotherapy, have documented limitations that limit their effectiveness. These
include primary and acquired tumor resistance, disease recurrence, and toxicity profiles that
affect patients’ quality of life, decrease adherence, and compromise clinical outcomes [7–9].
These limitations have spurred the search for innovative approaches that complement or
enhance current therapies, with an emphasis on less-toxic, more-selective strategies.
In this context, naturally occurring bioactive compounds have gained prominence in
cancer prevention and therapy. Among them are polyphenols, carotenoids, alkaloids, and
terpenes, known for modulating critical stages of carcinogenesis and acting as adjuvants
through proapoptotic, antiangiogenic, antimetastatic, epigenetic, and immunomodulatory
effects, among others [10–13]. Representative examples are curcumin, resveratrol, epigallo-
catechin gallate (EGCG), and lycopene, which have been extensively studied in preclinical
and clinical models. However, their low bioavailability, chemical instability, and rapid
metabolism limit their efficacy. Therefore, in recent years, innovative delivery systems,
such as liposomes, polymeric nanoparticles, and nanoemulsions, have been developed to
improve stability, absorption, and tumor selectivity [11–14].
Despite these advances, significant controversies remain. Several polyphenols exhibit
dual redox behavior: depending on the dose and context, they can act as protective antioxi-
dants or as pro-oxidants with antitumor potential. This ambivalence explains some of the
discrepancies observed between in vitro studies, in vivo trials, and clinical trials [15,16].
Furthermore, these variations depend on multiple factors, including concentration and
exposure time, formulation and vehicle used, individual metabolism, gut microbiota, and
the tumor microenvironment. In this regard, it is essential to standardize experimental
designs and reporting to achieve more rigorous comparisons and build stronger con-
sensus [12,14,17]. However, the breadth of existing studies, most reviews address these
aspects in isolation. Current literature rarely integrates molecular mechanisms, deliv-
ery innovations, biological limitations, clinical translation, and sustainability within a
single framework. This lack of synthesis prevents a comprehensive understanding of
how these components interact and limits the development of more effective and scalable
therapeutic strategies.
Likewise, the available literature reveals significant gaps. Most reviews maintain a
descriptive approach and fail to integrate molecular mechanisms with delivery platforms
or clinical outcomes in a critical way. Similarly, few evaluations report metrics on the
quality, safety, and traceability of formulations [10,12]. There is also limited literature
linking innovations in delivery systems to scalability and sustainability. Given that agri-
food by-products represent an alternative source of bioactive compounds and that green
extraction processes offer environmental and economic advantages, it is essential to connect
these perspectives with thechemoresistant cancer cell
models.
In vitro (bladder cancer
models).
The study identified specific resistance
mechanisms, including mutations in PIK3CA,
KRAS, and FGFR3, as well as alterations in
ABCB1 and SLC3A1 genes, enabling the
development of personalized therapeutic
strategies.
[240]
Vincristine
PCL/C-dots–based double
emulsion nanotheranostic
system.
In vitro (hepatoblastoma
and hepatocellular
carcinoma models).
The PCL-based nanotheranostic platform
(≈200 nm) demonstrated superior antitumor
efficacy compared with the free drug,
achieving enhanced cell growth inhibition
and optimal colloidal stability (PDIOpportunities
Bioactive compounds face significant challenges that have limited their progress to-
ward more established clinical stages. Among the most relevant obstacles are their low
bioavailability and rapid metabolism, characteristics widely documented for polyphenols,
terpenes, and carotenoids, which reduce their systemic half-life and make it difficult to
achieve stable therapeutic concentrations [140,160]. Likewise, the marked variability in
natural sources, associated with genetic differences, climate, post-harvest practices, and
phytochemical composition, complicates the standardization of extracts and affects the
reproducibility of results [25]. Added to this is the limited industrial scalability of advanced
delivery technologies, such as nanoencapsulation, hydrogels, and lipid-polymer hybrid
systems, whose processes require specialized equipment and high operating costs [159].
Finally, regulatory obstacles also pose a challenge: while nutraceuticals are often approved
under more flexible frameworks, nanopharmaceuticals derived from natural compounds
must meet strict safety, efficacy, and reproducibility requirements, which slows their transi-
tion to clinical applications [165].
Another critical challenge is the lack of methodological standardization across studies
evaluating nanoformulated bioactive compounds. Variations in pH conditions, particle size
determination, polydispersity index (PDI), zeta potential measurements, and encapsulation
efficiency protocols hinder the comparability of results and limit the reproducibility of
reported formulations. Moreover, the use of different analytical instruments, dispersants,
and sample-preparation procedures frequently leads to discrepancies in stability profiles
and release kinetics. Establishing harmonized characterization frameworks, aligned with
international standards for nanomaterials, would substantially improve the reliability of
preclinical data and facilitate regulatory assessment and clinical translation.
Clinically, biological variability and extract heterogeneity introduce additional bar-
riers. Despite these limitations, significant opportunities are emerging that strengthen
the position of bioactive compounds in oncology. One of the most notable is the use
of agri-food by-products, in line with the principles of the circular bioeconomy, which
enables the production of functional compounds in a sustainable manner with reduced
environmental impact [18,19,21]. At the same time, there is growing interest in integrating
these compounds with immunotherapy and targeted therapies, given their potential to
modulate inflammatory, epigenetic, and mitochondrial pathways in a manner comple-
mentary to conventional drugs [160]. Likewise, integrating omics technologies, including
genomics, transcriptomics, and metabolomics, with artificial intelligence tools enables the
identification of biomarkers, the optimization of formulations, and the prediction of clinical
responses with greater precision [25]. Taken together, these opportunities outline a promis-
ing scenario for the innovative application of bioactive compounds within contemporary
precision oncology.
Beyond these opportunities, several forward-looking directions are emerging that
could accelerate the translation of bioactive compounds into clinical practice. These include
the use of AI-driven predictive models to optimize encapsulation efficiency and release
profiles, surface-engineered nanocarriers designed to improve targeting of the tumor
microenvironment, and the development of computational tools to model dose–response
relationships and interindividual variability. Additionally, incorporating digital biomarkers
and adaptive clinical trial designs may help refine patient selection and enhance the
evaluation of nanoformulated bioactives in real-world settings.
Figure 2 visually summarizes this duality between current challenges and emerging
opportunities, integrating aspects of sustainability, advanced delivery technologies, and
therapeutic innovation.
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Figure 2. Integrative model of sustainability, innovative delivery systems, and precision oncology.
7. Future Perspectives
The clinical advancement of bioactive compounds in oncology will require coordinated
efforts to overcome current limitations and consolidate their therapeutic applications. An
immediate priority is the implementation of multicenter clinical trials, particularly those
involving nanoformulated bioactives, to obtain more robust, generalizable data on efficacy
and safety across diverse populations.
Likewise, validating efficacy biomarkers will be essential in both preventive and
therapeutic contexts. The identification of molecular, metabolomic, or immunological
markers will enable the selection of more responsive patient subgroups and facilitate
progress toward personalized medicine strategies.
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Another key direction involves comparative studies between bioactive compounds
and conventional drugs, or between bioactive–drug combinations. These analyses will help
elucidate potential synergies, optimize therapeutic regimens, and justify their integration
into standardized clinical protocols.
Finally, the field requires the development of specific regulatory guidelines for bioac-
tive compound delivery technologies, particularly nanoformulations, hydrogels, and hy-
brid systems. Such frameworks would support the harmonization of quality, reproducibil-
ity, and safety criteria, thereby accelerating their transition into advanced clinical stages
and eventual therapeutic consolidation.
Emerging technologies will further shape the future of this field. Artificial-intelligence
algorithms may assist in predicting encapsulation behavior, optimizing formulation param-
eters, and modeling complex pharmacokinetic–pharmacodynamic interactions. Surface-
engineered nanocarriers represent another promising avenue to enhance tumor specificity
and microenvironment responsiveness. Likewise, computational tools enabling virtual
screening, dose optimization, and patient stratification modeling could substantially im-
prove the design and success of early-phase clinical trials.
Figure 3 summarizes these progressive stages, from initial trials to the establishment
of specific regulatory frameworks.
 
Figure 3. Future perspectives for the delivery of bioactive compounds and their application in cancer
prevention and therapy.
8. Conclusions
Bioactive compounds represent one of the most promising frontiers in cancer pre-
vention and therapy, as they can modulate multiple pathways involved in carcinogenesis.
However, their clinical impact remains limited due to intrinsic factors, including low
bioavailability, chemical instability, rapid metabolism, and poor tumor microenvironment
accumulation. Innovative delivery platforms, including lipid and polymeric nanoparticles,
liposomes, micelles, nanoemulsions, hydrogels, stimuli-responsive systems, and hybrid
approaches, have demonstrated significant progress in improving the stability, absorp-
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tion, selectivity, and efficacy of these compounds. However, no single technology fully
overcomes all challenges.
Despite encouraging results in in vitro and in vivo studies, clinical translation remains
restricted, with early-phase trials predominating and outcomes varying widely. This gap
highlights the need to standardize formulations, optimize pharmacokinetic parameters,
identify response biomarkers, and design more robust multicenter clinical trials to validate
their actual effectiveness across diverse populations.
A critical priority moving forward is the harmonization of analytical and character-
ization protocols, particularly for nanoformulated bioactivesystems, where disparities
in particle size measurements, PDI values, zeta potential, and encapsulation efficiency
methods hinder cross-study comparability. Establishing unified methodological standards
aligned with international nanomaterials guidelines will strengthen reproducibility, im-
prove regulatory assessment, and accelerate the transition of bioactive compounds toward
clinically meaningful applications.
Sustainability has also emerged as a key component. The valorization of agri-food
by-products and the use of green extraction processes offer opportunities to obtain bioactive
compounds in an efficient, economical, and environmentally responsible manner. The
integration of omics technologies and artificial intelligence will facilitate progress toward
personalized formulations, the identification of response profiles, and the enhancement of
synergies between natural compounds and conventional therapies.
It is also essential to emphasize that bioactive compounds should not be considered
substitutes for established oncological treatments. Instead, they hold greater potential as
complementary or adjuvant agents that can enhance therapeutic responses, reduce adverse
effects, or improve patient-specific outcomes when integrated with conventional therapies.
Clarifying this distinction is critical to ensure their appropriate clinical positioning and to
guide future research toward realistic, evidence-based applications.
Overall, technological advances, the development of specific regulatory frameworks,
and the integration of sustainability, innovation, and personalized medicine outline a
favorable scenario for bioactive compounds to evolve from potential complementary
therapies into more effective and standardized clinical interventions. The current challenge
is not only to optimize their delivery but also to translate their biological complexity into
safe, reproducible, and clinically meaningful applications within contemporary oncology.
Author Contributions: Conceptualization, C.A.L.-S. and M.L.H.-C.; methodology, C.A.L.-S. and
M.L.H.-C.; investigation, J.M.R.P., D.F.C.H., J.A.M.-H., B.V.G., M.M.B.G., J.C.M.-S. and W.C.C.-P.;
data curation, J.M.R.P. and D.F.C.H.; writing—original draft preparation, C.A.L.-S., M.L.H.-C.;
writing—review and editing, J.A.M.-H. and B.V.G.; visualization, M.M.B.G. and J.C.M.-S.; supervision,
W.C.C.-P.; project administration, J.M.R.P. and D.F.C.H.; funding acquisition, J.A.M.-H. and B.V.G.;
validation, M.M.B.G. and J.C.M.-S.; resources, W.C.C.-P. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Acknowledgments: The authors acknowledge the Food Nanotechnology Research Laboratory and
the Research Group on Nutraceuticals and Biomaterials of the UNAJMA. Grammarly was used solely
for language support, and the authors take full responsibility for the final content.
Conflicts of Interest: The authors declare no conflicts of interest.
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Abbreviations
The following abbreviations are used in this manuscript:
ATG5 Autophagy-related gene 5; key regulator of autophagosome formation.
AuNPs Gold nanoparticles.
Bad Bcl-2 antagonist of cell death; proapoptotic protein that antagonizes Bcl-2 function.
Bad/Bax Proapoptotic proteins of the Bcl-2 family that promote mitochondrial permeabilization.
Bax Bcl-2 associated X protein; proapoptotic mediator of mitochondrial permeabilization.
BACH1
BTB and CNC homology 1; transcription factor involved in oxidative stress response
and ferroptosis regulation.
Bcl-2 B-cell lymphoma 2; antiapoptotic protein that inhibits cell death.
BRAF/ERK
BRAF serine/threonine kinase and extracellular signal-regulated kinase; components
of the MAPK pathway involved in tumor growth.
CB2 Cannabinoid receptor type 2; receptor involved in immune regulation and inflammation.
Caspase-3 Key protease in the execution phase of apoptosis.
DNA Deoxyribonucleic acid.
Doxil® Liposomal doxorubicin.
DoE Design of Experiments; statistical method for experimental optimization.
EGCG Epigallocatechin-3-gallate; major bioactive catechin from green tea.
EMT Epithelial–Mesenchymal Transition; process associated with invasion and metastasis.
ERK1/2
Extracellular signal-regulated kinases 1 and 2; regulators of proliferation, differentia-
tion, and survival.
FDA U.S. Food and Drug Administration.
FGFR3 Fibroblast growth factor receptor 3.
GMP Good Manufacturing Practice.
GPX4
Glutathione peroxidase 4; enzyme that protects cells from lipid peroxidation and
ferroptosis.
GSH Reduced glutathione; major intracellular antioxidant.
HO-1 Heme oxygenase 1; antioxidant and cytoprotective enzyme.
HSP90 Heat shock protein 90; molecular chaperone involved in cancer cell survival.
IAP Inhibitor of Apoptosis Proteins; family of apoptosis-suppressing proteins.
IC50 Half-maximal inhibitory concentration.
IKK IκB kinase; complex that activates NF-κB by phosphorylating IκB.
JAK/STAT Janus kinase/Signal transducer and activator of transcription pathway.
JNK c-Jun N-terminal kinase; kinase involved in stress response, apoptosis, and proliferation.
Keap1 Kelch-like ECH-associated protein 1; negative regulator of Nrf2 signaling.
LC3 Microtubule-associated protein 1A/1B-light chain 3; marker of autophagy.
MAPK
Mitogen-activated protein kinase; pathway regulating proliferation, differentiation,
and stress responses.
MDR Multidrug Resistance; resistance to multiple chemotherapeutic agents.
MOF Metal–organic framework; porous coordination material used in drug delivery.
mTOR Mammalian target of rapamycin; key regulator of cell growth, metabolism, and survival.
NF-κB Nuclear factor kappa B; regulator of inflammation and cell survival.
NLC Nanostructured lipid carriers.
NP Nanoparticles; nanometer-scale carriers used for drug delivery.
NQO1 NAD(P)H quinone dehydrogenase 1; enzyme involved in cellular redox balance.
Nrf2
Nuclear factor erythroid 2–related factor 2; regulator of antioxidant and cytoprotective
responses.
O/W Oil-in-water emulsion.
Onivyde® Liposomal irinotecan.
p-Bad Phosphorylated Bad; proapoptotic protein inactivated by phosphorylation.
p-ERK1/2 Phosphorylated ERK1/2; regulators of proliferation and differentiation.
pH Potential of hydrogen; measure of acidity or basicity.
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p-JNK
Phosphorylated c-Jun N-terminal kinase; component of the MAPK pathway involved
in apoptosis and stress response.
p-p38 Phosphorylated p38 kinase; MAPK member associated with stress and apoptosis.
p38 MAPK p38 mitogen-activated protein kinase; regulator of inflammation and stress signaling.
PARP Poly(ADP-ribose) polymerase; enzyme involved in DNA repair and cell death signaling.
PDI Polydispersity index; measure of particle size distribution.
PI3K/Akt Phosphatidylinositol 3-kinase/Akt signaling pathway.
PLGA Poly(lactic-co-glycolic acid); biodegradable copolymer.
PLA Polylactic acid; biodegradable polymer.
PLK1 Polo-like kinase 1; regulator of mitosis and cell cycle progression.
PDOs Patient-derived organoids.
REDOX Reduction–oxidation reactions; key cellular metabolic processes.
ROS Reactive oxygen species; chemically reactive molecules involved in oxidative stress.
SLN Solid lipid nanoparticles.
SOD1 Superoxide dismutase 1; enzyme responsible for reactive oxygen species detoxification.
STAT1/3
Signal transducer and activator of transcription 1 and 3; transcription factors involved
in inflammation and apoptosis.
Survivin Inhibitor of apoptosis protein (IAP family) and mitosis regulator.
TNBC Triple-negative breast cancer.
Tyk2 Tyrosine kinase 2; JAK family member involved inimmune and inflammatory signaling.
ZIF Zeolitic imidazolate framework; subclass of metal–organic frameworks.
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Co-Crystals Induces Apoptosis via Dual Covalent/Noncovalent Inhibition of Caspases in Endometrialdesign of innovative systems and their eventual clinical and
regulatory translation [18,19]. Moreover, the persistent disconnect between promising
preclinical results and modest or inconsistent clinical outcomes highlights the need for
stronger translational approaches. Incorporating standardized methodologies, predictive
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biomarkers, clinically relevant dosing strategies, and regulatory considerations is essential
to bridge laboratory innovation with real therapeutic impact.
Within this framework, this review article aims to offer a critical and forward-looking
summary of innovations in the delivery of bioactive compounds applied to cancer preven-
tion and therapy. To this end, the following objectives are set out:
• Integrate mechanistic evidence of bioactive compounds relevant to oncology.
• Analyze recent advances in delivery systems, including nano- and microstructures,
liposomes, hydrogels, and stimulus-responsive platforms.
• Coordinate the transition from laboratory to clinical practice under quality and
safety standards.
• Incorporate the dimension of sustainability, considering alternative sources, green
extraction processes, and the valorization of by-products.
This approach seeks to link prevention, treatment, technological innovation, and sus-
tainability, and to outline the main challenges and prospects in a field of growing scientific
and social relevance. Figure 1 presents an integrative conceptual map summarizing the
relationships among sources of bioactive compounds, the main chemical groups identified,
emerging delivery technologies to overcome their limitations, the molecular mechanisms
involved, and, finally, their impact on cancer prevention and therapy. To systematically
address these challenges, this review synthesizes the current evidence on the molecular
mechanisms, physicochemical limitations, innovative delivery platforms, and translational
advances of key bioactive compounds, providing an integrated framework that guides
their potential application in cancer prevention and therapy. This conceptual figure was
constructed by synthesizing recurring themes identified across the analyzed literature,
allowing for a visual representation of the integrated framework proposed in this review.
 
Figure 1. Integrative concept map illustrating the relationships among sources of bioactive com-
pounds, major chemical groups, emerging delivery technologies, molecular mechanisms involved,
and their applications in cancer prevention and therapy.
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2. Review Methodology
This narrative review follows a structured approach and uses a structured biblio-
graphic search methodology [20,21] to provide a clear, up-to-date, and critical overview
of recent advances in the delivery of bioactive compounds for cancer prevention and
treatment. The review was not designed as a systematic or scoping review, but rather as
a critical narrative synthesis of the current state of the art. Searches were conducted in
the PubMed, Scopus, Web of Science, and ClinicalTrials.gov databases, supplemented by
queries across MDPI, Elsevier, SpringerLink, Taylor & Francis, and Wiley, and limited to
articles published preferably between 2020 and 2025.
The search strategy included keywords such as bioactive compounds, cancer pre-
vention, cancer therapy, phytochemicals, drug delivery, nanoparticles, encapsulation, and
clinical trials. No formal reporting guidelines such as PRISMA or PRISMA-ScR were
applied, given the narrative nature of the review; however, general principles of clarity,
transparency, and critical appraisal commonly recommended for narrative reviews were
considered. After removing duplicate records and reviewing titles and abstracts, inclusion
criteria were applied, prioritizing thematic relevance, methodological rigor, and relevance
to oncology and pharmaceutical nanotechnology.
Studies that were not directly related to cancer or delivery systems, those with method-
ological deficiencies or without verifiable data, and those focused exclusively on general
antioxidant activity were excluded. A total of 260 articles were selected for detailed anal-
ysis and critical synthesis, covering in vitro and in vivo studies, clinical trials, and recent
reviews. This selection allowed for a basic stratification of evidence levels, facilitating a
comparative assessment of the translational maturity of the included studies. The infor-
mation obtained was organized and analyzed comparatively, with a critical approach, to
identify advances, limitations, and knowledge gaps relevant to future research.
3. Bioactive Compounds with Potential in Cancer Prevention
and Therapy
The bioactive compounds present in plants, fruits, vegetables, and other natural
organisms have attracted considerable interest due to their ability to prevent or slow the
development of cancer. These compounds belong to different chemical groups, including
polyphenols, carotenoids, terpenes, alkaloids, and other emerging compounds, which can
act on various processes involved in tumor onset and progression, helping to block or
reverse these mechanisms.
Among the most important actions are the activation of cancer cell death (apoptosis),
the reduction in the formation of new blood vessels that feed the tumor (angiogenesis), the
arrest of uncontrolled cell growth, and the regulation of genes and signals that influence
the tumor environment and the body’s response [22–24]. However, despite encouraging
results from preclinical in vitro and in vivo studies, the therapeutic application of these
compounds remains limited by issues of bioavailability, physicochemical stability, and
poor clinical translation into human trials [25,26]. Despite the wide range of biological
actions attributed to these compounds, the therapeutic effects observed in clinical studies
remain limited. Although polyphenols, terpenes, alkaloids, and carotenoids influence
apoptosis, angiogenesis, inflammation, and other central processes in tumor development,
these mechanisms rarely lead to meaningful clinical improvements. Most early-phase trials
report modest or inconsistent changes in surrogate biomarkers, and the impact on tumor
progression, recurrence, or patient survival is usually minimal. This persistent gap be-
tween mechanistic promise and clinical performance highlights the difficulty of translating
preclinical efficacy into real therapeutic benefit. It emphasizes the need for research ap-
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proaches that connect biological mechanisms with pharmacokinetics, pharmacodynamics,
and clinically relevant outcomes.
In addition, the biological activity of these compounds is strongly influenced by in-
terindividual variability related to metabolism, gut microbiota composition, and genetic
polymorphisms involved in absorption and detoxification pathways. These factors can alter
circulating concentrations and therapeutic responses, partly explaining the heterogeneous
outcomes of clinical trials. Establishing standardized analytical methods, dose–response
relationships, and clinically relevant biomarkers is therefore essential to improve compara-
bility among studies and strengthen the clinical translation of bioactive compounds. Table 1
below summarizes the main bioactive compounds included in this review, their natural
sources, mechanisms of action, available evidence, and known limitations.
Table 1. Molecular mechanisms of action of the main bioactive compounds in cancer prevention
and therapy.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Polyphenols
Ellagic acid
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	Introduction 
	Review Methodology 
	Bioactive Compounds with Potential in Cancer Prevention and Therapy 
	Innovative Platforms for the Delivery of Bioactive Compounds 
	Clinical and Translational Evidence 
	Challenges and Opportunities 
	Future Perspectives 
	Conclusions 
	ReferencesFragaria vesca L.,
pomegranate,
walnuts, almonds,
hazelnuts, flaxseed,
chia, loquat, Quercus
spp., Eucalyptus spp.,
Castanea spp.
Inhibition of cell
proliferation and
angiogenesis through the
PI3K/Akt pathway;
induction of apoptosis;
modulation of gene
expression and cell
signaling.
Colon, breast,
liver, prostate,
pancreas,
stomach, lung,
endometrial,
ovarian, and skin
cancers.
Low bioavailability,
which may limit efficacy;
no established optimal
dose or treatment
duration in humans.
[27–29]
Catechins
Green tea, cocoa,
dark chocolate,
apples, blueberries,
blackberries,
raspberries,
strawberries, pecans,
and hazelnuts.
Inhibition of cell
proliferation through the
PI3K/Akt pathway.
Induction of apoptosis.
Modulation of signal
transduction pathways,
including NF-κB
inhibition and reduction
in inflammation.
Inhibition of
angiogenesis.
Modulation of oxidative
stress.
Breast, prostate,
colorectal, lung,
esophageal,
gastric, and liver
cancers.
Low bioavailability due
to rapid metabolism and
elimination.
Effective dose is not
established in humans.
Possible interaction with
anticoagulants.
[30–33]
Curcumin Curcuma longa
Inhibition of
angiogenesis.
Inhibition of cancer cell
proliferation.
Induction of apoptosis.
Antioxidant activity.
Modulation of NF-κB
and other pathways
associated with
inflammation and cell
survival.
Breast, colorectal,
gastric,
pancreatic,
ovarian, lung,
prostate,
esophageal, and
endometrial
cancers.
Prolonged consumption
may cause hepatic
alterations.
May exert anticoagulant
effects.
May cause
gastrointestinal
discomfort.
Low bioavailability,
which limits its clinical
efficacy.
[34–37]
Quercetin
Onion, dark cocoa,
elderberries,
cranberries, capers,
apples, asparagus,
cabbage, broccoli,
oregano, fennel,
watercress,
Fagopyrum
esculentum, Opuntia
stricta, pear, grape,
and cherry.
Antioxidant activity.
Anti-inflammatory
effects.
Induction of apoptosis.
Breast, prostate,
colon, lung, liver,
nasopharyngeal,
kidney,
pancreatic,
ovarian, brain,
and oral cavity
cancers.
Variable bioavailability,
influenced by the food
matrix and metabolism.
No consensus on the
optimal dose required to
achieve clinical effects in
humans.
[38–43]
https://doi.org/10.3390/ph19010060
https://doi.org/10.3390/ph19010060
Pharmaceuticals 2026, 19, 60 6 of 39
Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Polyphenols
Resveratrol
Grape skin, red wine,
strawberries,
blueberries,
blackberries,
walnuts, almonds,
peanuts, pistachios,
and chocolate.
Inhibition of cancer cell
proliferation.
Antioxidant activity.
Modulation of gene
expression.
Induction of apoptosis.
Regulation of
inflammation.
Breast, prostate,
lung, colorectal,
pancreatic, liver,
ovarian, and
endometrial
cancers.
Low bioavailability due
to rapid metabolism and
elimination.
Limited
pharmacokinetics, with
low effective plasma
concentrations.
Possible nephrotoxicity
at high doses.
Drug interactions,
especially with
anticoagulants, which
may increase the risk of
bleeding.
[44–47]
Hesperidin
Citrus sinensis, Citrus
limon, lime,
grapefruit, mint.
Inhibition of cell
proliferation.
Induction of apoptosis.
Early cell cycle arrest.
Antioxidant activity.
Modulation of signaling
pathways.
Breast cancer.
Low water solubility.
Limited bioavailability.
Rapid systemic excretion.
High affinity for plasma
proteins.
Susceptibility to
degradation caused by
light, oxygen, and
temperature fluctuations.
A mandatory
requirement for its
clinical viability is the
development of complex
formulations that
enhance its stability and
bioavailability.
[48]
Naringenin Grapefruit, orange.
Inhibition of cell
proliferation.
Induction of apoptosis.
Modulation of
autophagy.
Autophagy modulation
through gene regulation
of ATG5 and LC3.
Disruption of
DNA–protein
interactions.
Inhibition of polyamine
synthesis.
Liver, breast,
gastric, cervical,
pancreatic, colon,
and
hematological
cancers.
Low systemic
bioavailability.
Suboptimal
pharmacokinetics at
tumor sites.
Low water solubility.
Insufficient hepatic
retention.
A mandatory
requirement for clinical
viability is the
development of complex
formulations.
[49]
Eriodictyol
Eriodictyon
californicum, lemon,
lime.
Induction of ferroptosis.
BACH1 stabilization.
GPX4 repression.
GSH (reduced
glutathione) depletion.
Bone cancer.
Low bioavailability and
rapid metabolism.
Hydrophobic nature and
limited systemic
distribution.
Short biological half-life.
Requirement for
nanocarriers to enable
tumor-targeted delivery.
Risk of non-specific
distribution.
Limited clinical data on
toxicity and therapeutic
window.
[50]
https://doi.org/10.3390/ph19010060
https://doi.org/10.3390/ph19010060
Pharmaceuticals 2026, 19, 60 7 of 39
Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Polyphenols
Didymin Orange and lemon.
Modulation of the
PI3K/Akt pathway.
Induction of apoptosis.
Inhibition of cell
migration and invasion.
Inhibition of cell
proliferation.
Gastric cancer
and
neuroblastoma.
Low bioavailability and
rapid metabolism.
Hydrophobic nature and
limited systemic
distribution.
Short biological half-life.
Risk of non-specific
distribution.
Limited clinical evidence.
Requirement for
advanced delivery
systems.
[51]
Poncirin Poncirus trifoliata.
Induction of apoptosis.
Inhibition of cancer cell
viability.
Inhibition of cell
proliferation.
Cervical and
breast cancers.
Low bioavailability.
Limited clinical evidence,
as current findings are
largely restricted to
in vitro models.
Short biological half-life,
requiring sustained
delivery systems or high
doses to maintain
therapeutic effects.
A mandatory
requirement for clinical
viability is the
development of complex
formulations.
[52]
α-mangostin Garcinia mangostana
L.
Induction of apoptosis.
Modulation of
autophagy.
Inhibition of cell
proliferation via the
PI3K/Akt pathway.
Breast cancer.
Low bioavailability due
to rapid metabolism and
elimination.
Limited
pharmacokinetics, with
low effective plasma
concentrations.
Possible nephrotoxicity
at high doses.
Drug interactions,
especially with
anticoagulants.
A mandatory
requirement for clinical
viability is the
development of complex
formulations.
[53]
γ-mangostin Garcinia mangostana
L.
Induction of apoptosis.
Inhibition of cell
proliferation.
Modulation of the
PI3K/Akt/mTOR
pathway.
Inhibition of cell
migration and invasion.
Breast, colorectal,
lung, liver,
glioma, and
hematological
cancers.
Low bioavailability due
to rapid metabolism and
elimination.
Limited
pharmacokinetics.
A mandatory
requirement for clinical
viability is the
development of complex
formulations.
[54]
https://doi.org/10.3390/ph19010060
https://doi.org/10.3390/ph19010060
Pharmaceuticals 2026, 19, 60 8 of 39
Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Polyphenols
Gambogic acid Garcinia hanburyi
Hook f.
Stimuli-responsive
release.
Induction of apoptosis
and oxidative stress.
Inhibition of HSP90.
Breast cancer.
Low bioavailability due
to rapid metabolism and
elimination.
Limited
pharmacokinetics, with
low effective plasma
concentrations.
Systemic toxicity and
adverse effects.
Possible nephrotoxicity
at high doses.
A mandatory
requirement for clinical
viability is the
development of complex
formulations.
[55]
Garcinone E Garcinia
mangostana L.
Inhibition of autophagic
flux.
Inhibition of cancer cell
proliferation.
Nasopharyngeal
cancer.
Low bioavailability due
to rapid metabolism and
elimination.
Limited
pharmacokinetics and
low plasma
concentrations.
Possible systemic toxicity
and adverse effects.
The development of
advanced delivery
systems is essential to
improveits stability.
[56]
Carotenoids
Lycopene
Tomato, watermelon,
papaya, pink guava,
plum, red bell
pepper, carrot, pink
grapefruit,
asparagus, and red
cabbage.
Antioxidant activity.
Antiproliferative effect.
Modulation of gene
expression.
Induction of apoptosis.
Prostate, breast,
colon, esophageal,
liver, ovarian,
oral cavity, and
lung cancers.
Low bioavailability,
influenced by its
lipophilic nature and the
food matrix.
Dose and treatment
duration have not been
established in humans.
[57–59]
β-Carotene
Carrot, papaya,
mango, Cucurbita
pepo, spinach,
broccoli, and lettuce.
Antioxidant activity.
Inhibition of cancer cell
proliferation.
Modulation of gene
expression.
Lung, breast,
colon, stomach,
prostate, bladder,
head and neck,
ovarian, skin, and
hematologic
cancers.
Low bioavailability,
influenced by the dietary
matrix and variability in
absorption.
Dose and treatment
duration have not been
established in humans.
Intake above 20 mg/day
in smokers may increase
the risk of adverse effects,
particularly lung cancer.
[60–63]
Lutein
Spinach, carrot,
yellow corn, peppers,
Xenostegia tridentata,
eggs.
Antioxidant activity.
Inhibition of cancer cell
proliferation and
migration.
Promotion of apoptosis
through inhibition of the
PI3K/Akt pathway.
Modulation of gene
expression.
Breast, prostate,
liver, stomach,
lung, cervical,
bladder, ovarian,
testicular, head
and neck, and
esophageal
cancers.
Low bioavailability,
influenced by its
lipophilic nature.
Optimal treatment dose
and duration are not
established in humans.
[64–68]
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Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Carotenoids
Zeaxanthin
Spinach, carrots,
yellow corn, peppers,
egg yolk, microalgae,
saffron, and
seaweeds.
Antioxidant activity.
Inhibition of cancer cell
proliferation.
Modulation of gene
expression.
Ocular, prostate,
colon, breast, and
skin cancers.
Low bioavailability,
influenced by its
lipophilic nature.
[69,70]
Astaxanthin
Haematococcus
pluvialis, shrimp,
euphausiids, crabs,
salmon, and trout.
Antioxidant activity.
Inhibition of cancer cell
proliferation at
concentrations between
150 and 200 µM (in vitro).
Modulation of gene
expression (caspase-3,
PARP, p-p38, p-JNK, and
p-ERK1/2).
Induction of apoptosis
through the
downregulation of
anti-apoptotic proteins
(Bcl-2, p-Bad, survivin)
and the upregulation of
proapoptotic proteins
(Bax/Bad and PARP).
Colorectal,
prostate, breast,
gastric, skin, and
lung cancers.
Low bioavailability,
conditioned by its
lipophilic nature.
Optimal human dose
and treatment duration
are not established.
More comprehensive
in vivo studies are
required to validate
efficacy and safety in
human populations.
[71–75]
Terpenes
Limonene
Lime, lemon,
grapefruit, orange,
tangerine, mint,
cannabis, pine
needles, and
turpentine.
Inhibition of cell
proliferation through the
PI3K/Akt pathway.
Induction of apoptosis
through Bcl-2
modulation.
Modulation of multiple
signaling pathways.
Antioxidant activity.
Antitumor activity.
Colon, lung,
breast, skin,
stomach, liver,
lymphatic system,
and bladder
cancers.
Low bioavailability due
to rapid metabolism.
Possible adverse effects
associated with high
doses.
Toxicity observed at
doses above 1200–1600
mg/m2 per
administration.
[76–80]
Betulin
Betula pendula, Betula
pubescens, Ziziphus
spp., Syzygium spp.
Induction of apoptosis.
Inhibition of
angiogenesis.
Inhibition of cell
proliferation.
Modulation of multiple
signaling pathways.
Antioxidant activity.
Inhibition of
carcinogenesis and
metastasis.
Liver, colorectal,
lung, prostate,
skin, breast, head
and neck,
pediatric, brain,
soft-tissue, bone,
hematologic,
lymphatic, and
cervical cancers.
Low water solubility.
Optimal dose has not
been established for
humans.
May exhibit cytotoxic
effects in healthy cells at
high concentrations.
[81–85]
Ursolic Acid
Ocimum sanctum L.,
apple, Eriobotrya
japonica, Sambucus
chinensis, pear,
Lavandula angustifolia,
olive, rosemary,
Punica granatum,
Lychnis floscuculi,
Calluna vulgaris.
Induction of apoptosis.
Inhibition of cell
proliferation.
Antioxidant activity.
Reduction in
inflammation and
downregulation of
pro-inflammatory gene
expression.
Inhibition of
angiogenesis.
Inhibition of metastasis
through modulation of
epithelial–mesenchymal
transition (EMT).
Modulation of NF-κB,
JAK/STAT,
PI3K/Akt/mTOR,
MAPK, PLK1,
IKK/NF-κB, and
BRAF/ERK signaling
pathways.
Hematologic and
bone marrow
cancers, hepatic,
colorectal, breast,
ovarian, lung,
prostate,
gastrointestinal,
and skin cancers.
Low water solubility,
which limits absorption.
Optimal human dose has
not been established.
May exhibit cytotoxicity
in healthy cells at high
concentrations.
[86–90]
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Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Terpenes
β-
Caryophyllene
Syzygium aromaticum
(clove), hops, rosemary,
Piper nigrum,
Cannabis sativa,
Commiphora
gileadensis, copaiba,
Spondias pinnata,
Pimpinella kotschyana,
and Cananga odorata.
Inhibition of cell growth
and proliferation.
Anti-inflammatory
activity.
Induction of apoptosis.
Inhibition of
angiogenesis.
Activation of the CB2
cannabinoid receptor.
Hematologic and
bone marrow
cancers, prostate,
breast, colorectal,
skin, lymphatic
system, ovarian,
oral cavity, liver,
pancreatic, bone,
head and neck,
and bladder
cancers.
Low bioavailability due
to rapid metabolism.
Optimal human dose has
not been established.
[91–93]
Geraniol
Palmarosa
(Cymbopogon
martinii), Pelargonium
graveolens, Zingiber
officinale, turmeric,
lemongrass, citronella,
Rosaceae species,
lavender, citronella.
Induction of apoptosis.
Inhibition of cell
proliferation.
Antioxidant activity.
Modulation of the
Tyk2–STAT1/3 pathway.
Inhibition of cancer cell
proliferation.
Hematologic and
bone marrow
cancers, lung,
colon, breast,
central nervous
system, prostate,
skin, liver, kidney,
pancreatic,
endometrial,
ovarian, and
gastric cancers.
Low bioavailability due
to rapid metabolism.
Optimal human dose has
not been established.
[94–97]
Alkaloids
Vinblastine Catharanthus roseus
Induction of apoptosis.
Inhibition of cell
proliferation.
Antioxidant activity.
Testicular, breast,
lung, uterine,
soft-tissue,
bladder, central
nervous system,
gastric, and
kidney cancers.
Grade III toxicity.
Neurotoxicity.
Multidrug resistance
(MDR).
May cause leukopenia,
mucositis (oral ulcers),
nausea, and pain as
frequent adverse effects.
[98–101]
Vincristine Catharanthus roseus
Induction of apoptosis.
Inhibition of cell
proliferation.
Antioxidant activity.
Hematologic and
bone marrow
cancers,
soft-tissue
cancers, bone
cancer, testicular,
uterine, breast,
and lung cancers.
Neurotoxicity, including
peripheral neuropathy.
Multidrug resistance
(MDR).
[98,99,
101,102]
Taxol
(paclitaxel)
Taxus brevifolia, Taxus
wallichiana, Taxus
baccata, Taxus
cuspidata, Taxus ×
media (incl. cv.
Hicksii), species of
Cephalotaxus and
Corylus avellana.
Induction of apoptosis.
Inhibition of
angiogenesis.
Mitotic arrest through
microtubule stabilization.
Antioxidant activity.
Breast, ovarian,
lung, prostate,
uterine,
esophageal, and
head and neck
cancers.
Hematological toxicity
(neutropenia, anemia,
thrombocytopenia).
Neurotoxicity
(peripheral neuropathy).
Low solubility, which
limits its formulation.
Multidrug resistance
(MDR).
Common side effects:
hair loss, muscle pain,
and allergic reactions.
[103–106]
Colchicine Colchicum autumnale,
Gloriosa superba L.
Inhibition of
inflammation.
Inhibition of
angiogenesis.
Induction of apoptosis.
Inhibition of cancer cell
migration, invasion,and
adhesion.
Antioxidant activity.
Breast, prostate,
colorectal, head
and neck,
esophageal,
gastric, liver,
pancreatic, lung,
skin, cervical,
endometrial,
ovarian, bladder,
kidney, brain, and
hypopharyngeal
cancers.
Low bioavailability.
Multiorgan toxicity.
Very narrow therapeutic
window, complicating
clinical use.
Potential for significant
cytotoxicity, even in
healthy cells.
[107–112]
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Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Alkaloids
Camptothecin Camptotheca
acuminata Decne.
Inhibition of DNA
topoisomerase I.
Induction of DNA strand
breaks during replication.
Cell cycle arrest at the S
phase.
Genomic
damage–dependent
induction of apoptosis.
Colorectal, lung,
ovarian, cervical,
breast, liver,
gastric, pancreatic
cancers, and
advanced solid
tumors.
Low aqueous solubility.
Instability of the lactone
form at physiological pH.
Rapid conversion to the
inactive carboxylate
form.
High systemic toxicity
and a narrow therapeutic
window limit its direct
clinical use.
Semisynthetic
derivatives (irinotecan
and topotecan) have
been approved for
clinical use to overcome
these limitations. At the
same time,
nanoformulation-based
delivery systems (e.g.,
polymeric nanoparticles,
liposomes, and
biomimetic carriers) are
actively investigated to
improve stability,
bioavailability, and
therapeutic index.
[113–115]
Berberine
Mahonia chinensis,
Mahonia bealei (Fort.)
Carr.,
Phellodendron
chinense Schneid.,
Coptidis chinensis
Franch.
Inhibition of cell
proliferation.
Inhibition of
angiogenesis.
Modulation of multiple
signaling pathways.
Inhibition of cancer cell
invasion and metastasis.
Antioxidant activity.
Blood and bone
marrow cancers,
breast, lung,
gastric, liver,
colorectal,
prostate, cervical,
and ovarian
cancers.
Low bioavailability due
to rapid metabolism.
Optimal human dosage
not yet established.
Poor absorption because
of its hydrophilic nature.
[116–120]
Emerging
com-
pounds
(other
phytocon-
stituents
with
growing
oncological
relevance)
Apigenin
Oranges, onion,
quinoa, basil,
Anethum graveolens,
Petroselinum crispum,
Coriandrum sativum,
Apium graveolens,
Mentha spp., Salvia
plebeia R.Br.,
Matricaria chamomilla,
Thymus vulgaris,
Origanum vulgare,
Chrysanthemum
morifolium, tea, beer,
and wine.
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
angiogenesis.
Inhibition of cell growth
and survival.
Antioxidant activity.
Breast, prostate,
ovarian, colon,
lung, oral cavity,
liver, gastric,
brain, skin, and
bladder cancers.
Low bioavailability due
to limited metabolism
and absorption.
Potential interactions
with other drugs,
particularly
anticoagulants.
Hydrophobic nature,
reducing systemic
availability.
[121–124]
Fisetin
Strawberries,
kiwifruit, grapes,
onion, garlic,
peppers, Hedyotis
diffusa Willd.,
Nelumbo nucifera,
Diospyros kaki, apple,
peach, cucumber,
and nuts.
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
inflammation.
Antioxidant activity.
Inhibition of
angiogenesis.
Breast, prostate,
lung, colon, brain,
head and neck,
bladder,
laryngeal,
pancreatic,
kidney, liver,
biliary tract,
gastric, skin, oral
cavity, bone
marrow, ovarian,
cervical,
endometrial,
bone, lymphatic
system, and
thyroid cancers.
Low bioavailability due
to rapid metabolism.
Potential interactions
with other medications,
particularly
anticoagulants.
[125–129]
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Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Emerging
com-
pounds
(other
phytocon-
stituents
with
growing
oncological
relevance)
Ginsenoside
Rg3
Panax bipinnotifidus,
Panax elegantior,
Panax ginseng, Panax
japonicus, Panax
major, Panax
notoginseng, Panax
omeiensis, Panax
pseudoginseng, Panax
quinquefolius, Panax
sikkimensis, Panax
sinensis, Panax
stipuleanatus, Panax
trifolius, Panax
vietnamensis, Panax
wangianus, Panax
zingiberenensis
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
angiogenesis.
Antioxidant activity.
Lung, gastric,
skin, liver, breast,
colon, and
cervical cancers.
Low bioavailability due
to limited absorption and
metabolism.
Hydrophobic compound,
reducing systemic
availability.
Possible interactions
with other medications,
especially anticoagulants.
May cause mild to
moderate
gastrointestinal effects.
[56,130–
134]
Luteolin
Chocolate, broccoli,
Brussels sprouts,
onion,
chrysanthemum,
celery, carrot, pepper,
rosemary, parsley,
chicory, spinach,
lemon, mint,
oregano, artichoke,
green tea, and
rooibos tea.
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
inflammation.
Antioxidant activity.
Breast, prostate,
lung, colorectal,
ovarian, skin, oral
cavity, pancreatic,
liver, kidney,
cervical,
esophageal,
bladder, gastric,
bone, brain,
thyroid, and
lymphatic system
cancers.
Low bioavailability
affecting absorption.
Potential interactions
with other medications,
especially anticoagulants.
Toxicity at high doses.
Hydrophobic compound
with limited absorption.
Rapid metabolism
reduces biological
efficacy.
[135–139]
Epigallocatechin-
3-gallate
(EGCG)
Camellia sinensis
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
inflammation.
Antioxidant activity.
Inhibition of
angiogenesis.
Colorectal, breast,
lung, ovarian,
endometrial,
gastric, glial, and
liver cancers.
Low bioavailability,
limiting absorption and
systemic efficacy.
Possible interactions
with other medications,
especially anticoagulants.
Preclinical toxicity
reported in animal
models and in vitro
studies at high
concentrations.
[140–144]
Honokiol Magnolia officinalis,
Magnolia obovate
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
inflammation.
Inhibition of
angiogenesis.
Antioxidant activity.
Colon, skin, bone,
nasopharyngeal,
tongue, liver,
breast, prostate,
ovarian, lung,
gastrointestinal,
and brain cancers.
Limited studies on
drug–drug interactions.
May cause
gastrointestinal effects.
Hydrophobic compound
with limited absorption.
Optimal human dosage
not yet established.
[145–149]
Sulforaphane Broccoli, kale, and
cauliflower.
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
inflammation.
Antioxidant activity.
Breast, prostate,
bladder,
gastrointestinal,
brain,
gynecological,
skin, lung, kidney,
and pancreatic
cancers.
Low bioavailability,
affecting systemic
absorption.
Possible interactions
with other medications.
May cause
gastrointestinal effects in
some individuals.
[150–154]
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Table 1. Cont.
Group of
Com-
pounds
Representative
Examples
Common Natural
Sources
Molecular Mechanisms
of Action
Scientific
Evidence and
Oncological
Applications
Criticisms and
Limitations Reference
Emerging
com-
pounds
(other
phytocon-
stituents
with
growing
oncological
relevance)
PEITC
(Phenethyl
isothio-
cyanate)
Watercress, broccoli,
Brussels sprouts.
Inhibition of cell
proliferation.
Induction of apoptosis.
Inhibition of
inflammation.
Antioxidant activity.
Gastric and colon
cancers.
Low bioavailability.
Hormetic effect.
Low water solubility.
Rapid metabolism.
[155]
BITC (Benzyl
isothio-
cyanate)
Broccoli and
mustard.
Induction of apoptosis.
Inhibition of
angiogenesis.
Inhibition of metastasis.
Enzymatic modulation.
Breast,
hematological,
lung, oral, and
head and neck
cancers.
Uncertain
pharmacokinetics in
humans.
Low stability and
bioavailability.
Rapid elimination.
A mandatory
requirement for clinical
viability is the
development of complex
formulations.[156]
Taken together, the bioactive compounds described exhibit a wide range of molecular
mechanisms that can intervene at key stages of tumor development. Their antioxidant,
anti-inflammatory, proapoptotic, and antiangiogenic activities, combined with modulation
of signaling pathways involved in cell cycle regulation and metastasis, support the grow-
ing interest in their study as preventive agents or adjuvants in cancer therapy. However,
the evidence also highlights important limitations, particularly regarding bioavailability,
metabolic variability, potential drug interactions, and the limited standardization of effec-
tive doses in humans. Therefore, although preclinical results are promising, there is a need
to advance to better-designed clinical studies to determine their true efficacy, safety, and
potential integration into complementary therapeutic strategies. This synthesis reinforces
the need to continue investigating both their biological activities and the technological
approaches that may optimize their stability, absorption, and clinical use.
4. Innovative Platforms for the Delivery of Bioactive Compounds
The design of nanostructured delivery systems has become a key tool for improving
the therapeutic performance of bioactive compounds used in cancer prevention and treat-
ment [11–14]. Most of these molecules have intrinsic limitations such as low solubility,
instability to oxidation or pH changes, accelerated metabolism, and limited accumulation
in the tumor microenvironment, which restrict their clinical efficacy [10–14]. In response,
platforms have been developed that can protect compounds during their biological tran-
sit, modulate their release, and direct them to specific tissues, thereby optimizing their
absorption, bioavailability, and antitumor activity [11–14].
These technologies include lipid and polymeric nanoparticles, liposomes, micelles,
nanoemulsions, hydrogels, stimulus-responsive systems, as well as hybrid platforms and
emerging approaches based on self-assembly or self-emulsification. Although they all share
the purpose of improving the transport and stability of bioactives, they differ in key aspects
such as composition, internal architecture, encapsulation mechanism, loading capacity,
release kinetics, and the degree of experimental or clinical advancement [11–14].
Each platform offers particular advantages. Lipid and polymeric nanoparticles stand
out for their versatility in encapsulating polyphenols, terpenes, and alkaloids; liposomes are
considered mature, biocompatible technologies; micelles and nanoemulsions facilitate the
solubilization of highly hydrophobic compounds; and hydrogels or stimulus-responsive
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systems allow for localized release under specific tumor conditions. Hybrid systems and
emerging platforms seek to integrate complementary properties to maximize stability and
selectivity [11–14]. A key mechanistic rationale for these delivery systems is their ability to
overcome the intrinsic physicochemical limitations of bioactive compounds, such as low
solubility, chemical instability, poor membrane permeability, and rapid metabolism, thereby
restricting systemic exposure. These constraints justify the use of platforms that enhance
dissolution (nanoemulsions and micelles), protect labile compounds during circulation (li-
posomes or coacervates), improve cellular uptake (surface-engineered nanoparticles), or
regulate release kinetics (polymeric matrices). Each platform targets a specific mechanistic
barrier, aligning molecular stability, bioavailability, and pharmacokinetics with oncology
therapeutic goals. Given this technological heterogeneity, it is necessary to compare their fun-
damental characteristics and levels of validation critically. Table 2 summarizes these aspects,
contrasting the types of platforms, the compounds evaluated, the delivery mechanisms, their
advantages, technical limitations, and the current state of preclinical and clinical evidence.
Table 2. Critical comparison of innovative delivery platforms for bioactive compounds.
Type of
Platform
Bioactive
Compounds
Evaluated
Delivery
Mechanism or
Principle
Main Advantages
Technical
Limitations and
Challenges
Validation
Phase/Scientific
Evidence
Reference
Lipid
nanoparticles
Ellagic acid,
curcumin,
quercetin,
resveratrol,
lutein,
zeaxanthin,
astaxanthin,
limonene,
apigenin,
berberine, and
vincristine.
Composed of solid
or partially liquid
lipids that are
biocompatible and
biodegradable.
They can exist as
solid lipid
nanoparticles (SLN)
or nanostructured
lipid carriers (NLC),
which provide high
affinity for lipophilic
compounds.
Drug release occurs
mainly through
diffusion and, in
some systems,
through erosion of
the lipid matrix.
Biocompatibility
and
biodegradability.
High capacity to
encapsulate
lipophilic
compounds.
Improved oral
bioavailability and
protection against
chemical/photo-
oxidative
degradation.
Limited physical
and chemical
stability
(recrystallization,
drug expulsion).
Challenges in
scaling up
production.
Dependence on
surfactants and
excipients that may
cause irritation or
cumulative toxicity.
Extensive preclinical
evidence in in vitro
and in vivo models.
Phase I and II clinical
trials available for
several lipid
nanoparticle-based
formulations.
Some lipid-based
formulations (not
necessarily pure
SLN/NLC) have
been approved for
clinical application,
supporting the safety
of this approach.
[121,157–
166]
Polymeric
nanoparticles
Curcumin,
quercetin,
resveratrol,
ellagic acid,
berberine,
ginsenoside Rg3,
and
epigallocatechin-
3-gallate.
Synthesized from
biodegradable
polymers such as
polylactic acid (PLA)
or polylactic-co-
glycolic acid (PLGA).
They can be
engineered to
provide controlled
drug release in
response to specific
stimuli.
Flexibility in
synthesis and
surface
modification.
Ability to
encapsulate a wide
variety of
compounds.
Controlled drug
release.
Difficulty in
precisely
controlling drug
release.
Potential issues
related to
biodegradability
and
biocompatibility.
Higher production
costs compared
with conventional
formulations.
Preclinical studies
have evaluated their
potential for drug
delivery.
Some formulations
are currently in
clinical development
phases.
[167–173]
Liposomes
Ellagic acid,
curcumin,
quercetin,
resveratrol, and
berberine.
Spherical vesicles
composed of lipid
bilayers that
encapsulate
hydrophilic or
lipophilic drugs.
Drug release occurs
through diffusion
across the lipid
bilayer or via
endocytosis.
Biocompatibility
and
biodegradability.
Ability to
encapsulate both
hydrophilic and
lipophilic drugs.
Improved
bioavailability and
reduced toxicity.
Limited physical
and chemical
stability.
Challenges in
scaling up
production.
Potential long-term
toxicity issues.
Several liposomal
products have been
approved for clinical
use, such as Doxil®
(liposomal
doxorubicin) and
Onivyde®
(liposomal
irinotecan).
Other formulations
are currently under
in vitro and in vivo
investigation.
[174–178]
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Table 2. Cont.
Type of
Platform
Bioactive
Compounds
Evaluated
Delivery
Mechanism or
Principle
Main Advantages
Technical
Limitations and
Challenges
Validation
Phase/Scientific
Evidence
Reference
Micelles
Curcumin,
quercetin,
resveratrol,
ellagic acid,
berberine, and
ginsenoside Rg3.
Spherical structures
composed of
amphiphilic
molecules that
self-assemble in
aqueous media.
Lipophilic drugs are
encapsulated within
the hydrophobic core
of the micelle.
High loading
capacity for
lipophilic drugs.
Stability in aqueous
environments.
Easy surface
modification for
targeted delivery.
Limited stability in
biological
environments.
Difficulty in
controlling drug
release.
Potential toxicity
issues due to the
presence of
surfactants.
In vitro and in vivo
studies have
demonstrated
inhibition of cancer
cell growth.
Ongoingpreclinical
and clinical studies
are evaluating the
efficacy and safety of
micelles as drug
delivery platforms.
[172,179–
182]
Nanoemulsions
Curcumin,
quercetin,
resveratrol,
ellagic acid,
lutein,
zeaxanthin,
astaxanthin, and
limonene.
Oil-in-water
dispersions
stabilized by
surfactants.
Lipophilic drugs are
dissolved in the oil
droplets.
High loading
capacity for
lipophilic drugs.
Good physical and
chemical stability.
Easy scaling-up and
production.
Limited physical
stability.
Difficulty in
controlling droplet
size.
Potential toxicity
issues due to the
presence of
surfactants.
In vitro and in vivo
studies show that
they can prevent the
migration of cancer
cells.
Ongoing preclinical
and clinical studies
are evaluating the
efficacy and safety of
nanoemulsions as
drug delivery
platforms,
particularly for
dermatological and
nutritional
applications.
[183–190]
Hydrogels
Ellagic acid,
curcumin,
quercetin,
resveratrol,
berberine, and
ginsenoside Rg3.
Three-dimensional
networks of
hydrophilic
polymers capable of
absorbing and
retaining large
amounts of water.
Drug release occurs
through diffusion
across the hydrogel
matrix.
Biocompatibility
and
biodegradability.
Ability to
incorporate a wide
variety of bioactive
compounds.
Controlled drug
release.
Limited physical
and chemical
stability.
Difficulty in
achieving precise
drug release control.
Potential issues
related to
biocompatibility
and
biodegradability.
Preclinical and
clinical studies have
demonstrated their
efficacy and safety in
drug delivery.
Some formulations
have been approved
for clinical use.
[191–196]
Stimuli-
responsive
smart systems
Ellagic acid,
curcumin,
quercetin,
resveratrol, and
berberine.
Hydrogels that
respond to
environmental
changes such as pH,
temperature, light,
redox conditions,
and more.
Drug release occurs
in response to these
stimuli, which alter
the structure and
permeability of the
hydrogel.
Targeted and
controlled drug
release in response
to specific stimuli.
Improved drug
bioavailability and
efficacy.
Reduction in side
effects.
Complexity in
synthesis and
design.
Difficulty in
achieving precise
and controlled
responsiveness to
stimuli.
Potential issues
related to stability
and scalability.
Preclinical studies
have evaluated their
potential in drug
delivery.
Some formulations
are currently in
clinical development
phases.
[197–201]
Hybrid
systems
Ellagic acid,
curcumin,
quercetin,
resveratrol,
berberine, and
ginsenoside Rg3.
These systems
combine different
technologies—such
as liposomes,
micelles, and
nanoemulsions—to
create customized
delivery platforms.
They may
incorporate external
stimuli such as pH,
temperature, or light
to control the release
of the bioactive
compound.
Greater flexibility
and customization
in the delivery of
bioactive
compounds.
Improved
bioavailability and
stability of the
compounds.
Ability to
incorporate
multiple bioactive
compounds into a
single system.
Complexity in
formulation and
scale-up.
Potential issues
related to stability
and
biodegradability.
Regulatory
challenges and
approval
requirements from
health authorities.
Preclinical and
clinical studies are
underway to
evaluate the efficacy
and safety of these
systems.
[178,202–
206]
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Table 2. Cont.
Type of
Platform
Bioactive
Compounds
Evaluated
Delivery
Mechanism or
Principle
Main Advantages
Technical
Limitations and
Challenges
Validation
Phase/Scientific
Evidence
Reference
Emerging
platforms
Curcumin,
quercetin,
resveratrol,
ellagic acid,
lutein,
zeaxanthin,
astaxanthin, and
limonene.
Isotropic mixtures of
lipids, surfactants,
and cosolvents that
generate fine
oil-in-water (O/W)
emulsions upon
exposure to
gastrointestinal
fluids, thereby
improving the
solubility and
bioavailability of
lipophilic drugs.
Significant
improvement in the
oral bioavailability
of poorly
water-soluble drugs.
Enhanced stability
of drug molecules.
Possibility of
delivering the final
product in various
pharmaceutical
dosage forms.
Difficulty in
predicting drug
precipitation within
the gastrointestinal
tract.
Require careful
formulation
optimization.
Potential long-term
physical and
chemical stability
issues.
Preclinical and some
clinical studies have
demonstrated their
potential to enhance
the bioavailability of
poorly soluble drugs.
Several formulations
are currently in
clinical development
phases.
[207–214]
In the relationship between the bioactive compound and the delivery platform, the se-
lection of the most appropriate system should primarily consider the bioactive compound’s
physicochemical properties, such as solubility and lipophilicity profiles and stability, as
well as the intended therapeutic objective. In the case of markedly hydrophobic molecules,
often characterized by high lipophilicity and low aqueous solubility, polymeric micelles and
nanoemulsions are advantageous alternatives because they can incorporate the bioactive
compound into hydrophobic lipid domains, thereby facilitating solubilization and transport
in aqueous systems [179–184]. By contrast, when greater encapsulation versatility and
flexibility in system design are required, for example, to tailor release profiles, functionalize
surfaces, or adapt to different classes of compounds, polymeric nanoparticles based on
biodegradable polymers stand out as robust and highly modulable platforms [167–173].
Likewise, in clinical scenarios where localized administration, retention at the site of action,
and sustained release are prioritized, as is often the case for sensitive compounds or local
therapeutic strategies, hydrogels and, at a more advanced stage of development, stimuli-
responsive systems sensitive to pH, temperature, redox state, or external stimuli provide
more precise spatial and temporal control, albeit at the cost of increased design complexity
and scalability challenges [193–200].
Overall, the comparison shows that no single platform can overcome all the limitations
associated with bioactive compounds. Each technology offers specific advantages, but
also has restrictions that must be considered depending on the chemical structure of the
bioactive compound, its solubility profile, the route of administration, and the therapeutic
purpose. Lipid and polymeric nanoparticles remain the most versatile; liposomes maintain
a strong position due to their safety record; micelles and nanoemulsions are particularly
suitable for highly hydrophobic molecules; and hydrogels and stimulus-responsive systems
represent promising alternatives for localized delivery. Hybrid systems and emerging
platforms, while attractive, require further standardization, reproducibility, and clinical
validation before widespread implementation. These contrasts reinforce the need for
formulation approaches tailored to each compound and each oncology indication, as
well as the development of multimodal strategies that integrate multiple technologies to
maximize efficacy and safety.
Beyond predominantly passive nanocarriers, an emerging and genuinely innovative
direction in the field of drug delivery involves active micro- and nanomotors and micro-
robots capable of self-propulsion or external actuation. These systems may operate through
chemical or biochemical reactions or be controlled by external physical fields, such as
magnetic fields or acoustic stimuli, enabling active navigation, enhanced tissue penetration,
and more localized delivery of therapeutic agents compared with passive platforms, which
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are limited by diffusion and systemic circulation [215–218]. In oncology-oriented applica-
tions, micro- and nanomotor-based concepts have been proposed as strategies to overcome
some of the limitations of conventional nanomedicine, including insufficient intratumoral
penetration and heterogeneous drug distribution, by introducing controlled motion and
spatiotemporalguidance [218]. Nevertheless, despite their high innovative potential, these
active systems remain primarily at the proof-of-concept and preclinical evaluation stages,
and their clinical translation will require substantial advances in areas such as biosafety
and biodegradability, in vivo control and tracking, scalability of manufacturing processes,
and regulatory standardization [215–218].
5. Clinical and Translational Evidence
The clinical and translational evidence on bioactive compounds in oncology presents
a heterogeneous landscape, encompassing diverse chemical groups, including polyphenols,
carotenoids, terpenes, alkaloids, and emerging compounds, and evaluated across a wide
range of cancer types and at various stages of drug development. According to the recent
literature, most of these compounds remain in preclinical phases, involving cell-based and
animal model studies, while only a limited number have advanced to early clinical stages,
mainly Phase I and Phase II, with variable results in tumors such as breast, prostate, colon,
lung, and skin cancers [10,12,25]. This uneven distribution reflects both the therapeutic
potential demonstrated in experimental models and the barriers that have hindered their
progression toward more robust clinical trials.
Within the field of cancer prevention, some bioactive compounds show more consis-
tent evidence when evaluated in prevalent tumors such as colorectal, prostate, esophageal,
and breast cancers. Curcumin, for example, has demonstrated beneficial effects in col-
orectal cancer prevention through epigenetic modulation and inflammation reduction in
early clinical studies, although results vary depending on formulation and administered
dose [34,36]. Lycopene has also been widely studied in prostate and gastrointestinal can-
cers, with meta-analyses supporting its protective association when consumed consistently
either through diet or improved formulations [57–60]. Another notable compound is EGCG,
which has been explored in preventive settings for prostate and esophageal cancer, showing
reductions in tumor progression markers in controlled trials. However, limitations persist
due to low bioavailability and interindividual metabolic variability [13,140–142]. Together,
these studies reveal significant preventive potential, although the evidence remains insuffi-
cient to support broad clinical recommendations because of the lack of standardization in
concentrations, duration, and administration methods.
In the therapeutic setting, several bioactive compounds have been evaluated as ad-
juvants in breast, prostate, lung, colon, and bladder cancers. Resveratrol stands out for
its anti-inflammatory, proapoptotic, and mitochondrial signaling-modulating effects, with
early clinical studies reporting modest reductions in tumor markers in breast and prostate
cancer. However, its overall therapeutic impact remains limited due to rapid metabolism
and low stability in vivo [160,165]. Quercetin has also shown promising results as a coad-
juvant, particularly in bladder cancer and hormone-dependent tumors, where advanced
formulations, including lipid nanoparticles and intravesical gels, have improved local
delivery and cytotoxicity [159,168]. Despite these advances, most clinical trials continue
to yield mixed results, with variability attributed to interindividual metabolic differences,
inconsistent standardization of evaluated formulations, and heterogeneous dosing. These
limitations highlight the need for pharmacokinetic optimization strategies and more rig-
orous clinical trial designs to translate the therapeutic potential observed in preclinical
models effectively.
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Despite growing interest in the use of bioactive compounds for cancer prevention
and treatment, their progression into advanced clinical stages remains limited, with a
predominance of preclinical studies and minimal transition into Phase III or Phase IV trials.
Among the main challenges is the lack of standardization in evaluated formulations, which
complicates comparison across studies and prevents the establishment of reproducible ther-
apeutic doses [25,159]. Pronounced interindividual metabolic variability, driven by factors
such as genetic differences, gut microbiota composition, and dietary habits, also affects
the bioavailability and clinical consistency of molecules such as polyphenols, carotenoids,
and terpenes, thereby limiting their therapeutic impact in real-world settings [140,160]. In
addition, the absence of predictive biomarkers of response restricts the identification of
patient subgroups most likely to benefit from these interventions, slowing their integration
into larger clinical trials. These factors explain the gap between the strong performance
observed in experimental models and the modest effects recorded in clinical studies, under-
scoring the need for more standardized strategies, personalized medicine approaches, and
biomolecular validation before these compounds can be consolidated as therapeutic tools.
It is essential to clearly distinguish the different types of clinical studies conducted to
date, as their conclusions vary considerably depending on methodological rigor. Observa-
tional studies frequently report associations between higher dietary intake of polyphenols,
carotenoids, or terpenes and a lower risk of several cancers. However, these findings cannot
be interpreted as causal because they are strongly influenced by diet, metabolic differences,
and lifestyle factors that are difficult to control. More solid information comes from in-
terventional studies, mainly Phase I and Phase II clinical trials, yet their results remain
inconsistent. Some studies report modest improvements in inflammatory or oxidative
stress markers or in indicators such as prostate-specific antigen.
In contrast, others show no meaningful effects on tumor progression, recurrence,
or survival. In many cases involving compounds such as curcumin, EGCG, or resvera-
trol, the absence of significant clinical benefits has been attributed to insufficient dosing,
rapid metabolism, or low systemic availability. Understanding these differences in study
design helps clarify the current clinical landscape. It underscores the need for larger, well-
standardized, and mechanistically informed trials better to assess the true therapeutic
potential of these bioactive molecules.
A further barrier limiting clinical translation is the insufficient characterization of toxi-
city, safety, and regulatory readiness for most bioactive compounds and their formulations.
Although many phytochemicals are generally regarded as safe in dietary contexts, their
behavior changes substantially when administered at pharmacological doses or encap-
sulated in nanostructured systems. Issues such as nanoparticle-induced oxidative stress,
off-target accumulation, immunogenicity, and long-term biopersistence remain poorly
defined in current studies. Moreover, the absence of standardized safety assays, GMP-
compliant manufacturing protocols, and well-established regulatory pathways for complex
delivery systems poses additional obstacles to advancing these compounds into late-stage
clinical trials. These gaps highlight the need for rigorous toxicological profiling and early
engagement with regulatory frameworks to ensure that promising experimental results
can be translated into safe and clinically viable oncology interventions. Table 3 shows how
these bioactive compounds are associated with different types of cancer and the available
preclinical and early clinical evidence.
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Table 3. Preclinical, early clinical, and translational evidence of bioactive compounds formulated for
oncological applications.
Bioactive
Compounds
Drug Delivery Technological
Platform Study Phase/Target Cancer Biomedical RelevanceReference
Quercetin
Plasma-derived exosomes
(biomimetic).
Derived exosomes
(biomimetic)
In vitro and in vivo (murine
glioma model).
The Que/mAb GAP43-Exo system
significantly reduced ROS production and
upregulated the expression of four key
antioxidant enzymes (NQO1, HO-1, SOD1,
and GPx1) through activation of the Nrf2
signaling pathway.
[219]
Gold nanoparticles (AuNPs). In vitro (A549 and HeLa
cancer cell lines).
The formulation exhibited a half-maximal
inhibitory concentration (IC50) of
45.23 µg/mL in A549 cells and 38.42 µg/mL
in HeLa cells.
[220]
Fisetin
Senolytic
nanomicelles/polymeric
nanomicelles.
In vivo (MCF-7 breast
cancer model).
The formulation achieved a drug loading
efficiency of 82.50 ± 1.78%, with an average
nanoparticle diameter of 103.2 ± 6.1 nm,
resulting in a six-fold increase in
bioavailability compared with free fisetin.
[221]
Kaempferol
Niosomal nanoparticles. In vitro (MCF-7 breast
cancer cells).
The formulation achieved an IC50 value of
0.0873 µM in MCF-7 cells, inducing 64%
apoptosis, with no significant toxicity
observed in healthy cells.
[222]
Metal–organic frameworks
(Kae–Fe photothermal
nanoparticle platform).
In vitro and in vivo (4T1
TNBC model).
The photothermal Kae–Fe nanoparticle
platform achieved 87% cell death in 4T1 cells,
with a photothermal conversion efficiency of
91.0%.
[223]
Apigenin Bio-responsive Metal–Organic
Framework Nanoplatform.
In vitro and in vivo (4T1
TNBC model).
The ZDAP system (ZIF-90/AP/DOX)
enabled an effective triple therapy combining
chemotherapy, photothermal therapy, and
metabolic lactate/ATP depletion.
[224]
Luteolin Self-assembling
supramolecular hydrogel.
In vivo (pre-colorectal
cancer model).
The hydrogel protected luteolin from gastric
degradation, enabling the delivery of an
effective therapeutic dose to the site of
inflammation in the colon.
[225]
Epigallocatechin
gallate (EGCG)
NanoCubeSpray delivery
system.
Ex vivo and in vivo (oral
submucous fibrosis model).
The formulation reduced type I collagen
deposition and TGF-β1 expression, thereby
preventing fibrosis and restoring antioxidant
levels.
[226]
Catechin Gold–catechin nanohybrids. In vitro (breast cancer
model).
The nanohybrid system enabled a combined
therapeutic strategy involving photothermal
therapy (laser-induced heating) and natural
chemotherapy.
[227]
Hesperidin Mucoadhesive biopolymeric
nanoparticles.
In vitro (MDA-MB-231
breast cancer cells).
The formulation exhibited superior
qualitative efficacy in terms of antioxidant
activity, apoptosis induction, and cell cycle
arrest compared with the free compound.
[48]
Naringenin
Biomimetic red blood cell
membrane–coated
nanoparticles.
In vitro (HepG2
hepatocellular carcinoma
cells).
The NARNPs reduced the IC50 to 1.6 µg/mL
compared with 22.32 µg/mL for free
naringenin and induced late apoptosis in
56.1% of cancer cells.
[49]
Eriodictyol Mesoporous nanocubes. In vitro and in vivo
(osteosarcoma model).
The nanocube formulation markedly
enhanced ferroptosis and cisplatin sensitivity
without evident systemic toxicity.
[50]
Didymin Direct administration of the
compound.
In vitro and in vivo (AGS
and HGC-27 gastric cancer
models).
Didymin significantly reduced cell viability
and tumor volume in vivo (p 25 µM).
[232]
Viscumin Surface-imprinted
polymer-based nanobiosensor. In silico.
A 9-mer epitope (QQTTGEEYF) was
identified, with a molecular weight of
1102.1 Da, an isoelectric point of 3.79, and a
prediction accuracy greater than 50%.
[233]
Lectin Glycan-targeted
biotherapeutic agent.
In vitro (A549, H460, and
H1299 lung cancer cell lines);
clinically used formulation:
Iscador
(Swissmedic-approved) for
breast, colorectal, lung,
gastric, and melanoma
cancers.
The combined treatment reduced cell
viability to 40% (compared with 70–90% for
monotherapies) and inhibited invasion and
migration to levels below 20%.
[234]
Ellagic acid Metal–organic framework
nanoplatform (CS/NP).
In vitro and in vivo
(MCF-7/Adr, MCF-7, and
4T1 breast cancer models).
The nanoplatform significantly reversed
chemoresistance by inducing cuproptosis
and effectively eliminating tumors of
approximately 250 mm3.
[235]
Camptothecin
Nanoliposomal formulation of
irinotecan.
Phase III (lung cancer);
FDA-approved derivatives:
irinotecan (colorectal cancer)
and topotecan (ovarian and
lung cancer).
The liposomal formulation doubled the
objective response rate (44.1% vs. 21.6%) and
significantly reduced grade ≥3
treatment-related adverse events (42.0% vs.
83.4%) compared with topotecan.
[236–238]
pH-responsive polymeric
nanoparticles with sustained
release.
In vitro and in vivo (A431
epidermoid carcinoma
model).
The nanoformulation achieved a five-fold
increase in bioavailability, an IC50 value of
3 µg/mL, and an 80% survival rate in animal
models.
[239]
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Table 3. Cont.
Bioactive
Compounds
Drug Delivery Technological
Platform Study Phase/Target Cancer Biomedical Relevance Reference
Vinblastine
Panel of isogenic