Introduction

Cancer remains a significant global health challenge, consistently ranking as a leading cause of death worldwide.1 It is characterized by abnormal cell proliferation, with the ability to invade surrounding tissues and metastasize to other parts of the body, as defined by the National Cancer Institute. The increasing prevalence of cancer significantly impacts both the quality of life and average lifespan globally. By 2040, new cancer cases are projected to rise to 29.5 million annually, leading to approximately 16.4 million deaths.2,3

Phytosome technology represents an innovative drug delivery system designed to encapsulate plant extracts or phytochemicals within a phospholipid complex, thereby enhancing their absorption and effectiveness.4 Unlike traditional phytochemical formulations, which often face challenges related to poor lipid solubility and limited absorption, phytosomes significantly enhance the solubility and bioavailability of polar phytoconstituents.5 By forming a lipid-compatible complex, phytosomes improve drug absorption, distribution, and targeted delivery, maximizing therapeutic outcomes.6

While liposomes and phytosomes both utilize phospholipid-based encapsulation, their structures and applications differ significantly.7 Liposomes generally form bilayer vesicles that enclose a broad range of pharmaceutical compounds, focusing on general drug delivery. In contrast, phytosomes form a molecular complex with plant-derived secondary metabolites, specifically enhancing their solubility, stability, and targeted bioavailability.8–11 This distinction allows phytosomes to deliver polar phytoconstituents more effectively, making them more suitable for natural compound therapies.

Secondary metabolites, including flavonoids, terpenoids, alkaloids, and phenolic compounds, are recognized for their potential anticancer properties but often have low water solubility, which restricts their absorption and therapeutic efficacy.11–13 This limitation presents a challenge in drug development, as higher doses of these compounds are often needed to achieve therapeutic effects, complicating formulation and delivery processes. To overcome these limitations, the use of surfactants has been explored as a strategy to improve the solubility of certain extracts, such as rosemary.14 Surfactants reduce the surface tension between water and the solute, facilitating the dispersion of poorly soluble molecules, thereby increasing bioavailability.15,16 However, phytosome technology offers a more advanced solution by not only enhancing solubility but also improving overall pharmacokinetics, including absorption, distribution, and cellular uptake of secondary metabolites.17,18 Recent studies have demonstrated that secondary metabolites encapsulated in phytosomes, such as quercetin, curcumin, and berberine, exhibit improved solubility and enhanced anticancer efficacy compared to their non-encapsulated forms.19,20 Phytosome encapsulation enables more effective interactions with cancer pathways, such as NF-κB and PI3K/AKT,21–23 improving therapeutic outcomes in preclinical cancer models.

This review aims to investigate the transformative potential of phytosome technology in cancer treatment, particularly its ability to improve the absorption and efficacy of plant-derived secondary metabolites. The analysis will focus on key secondary metabolites, including alkaloids, flavonoids, terpenoids, and phenolic compounds, which have demonstrated anticancer properties. By examining advancements in phytosome formulations and their potential impact on cancer treatment, this review seeks to offer insights into future strategies for developing more effective oncological therapies.

Methodology

This review synthesizes studies focused on the use of phytosome for cancer treatment, emphasizing the enhancement of secondary metabolites bioavailability. The literature search targeted publications over the past decade, using databases such as PubMed, Scopus, Google Scholar, and Web of Science. Keywords used included “phytosome technology”, “cancer treatment”, “plant secondary metabolites”, and “phytochemical efficacy in cancer”. The initial search obtained 214 studies, where the inclusion and exclusion criteria were rigorously applied to the results. Inclusion criteria were studies that directly addressed the application of phytosome in cancer treatment, showed the pharmacological benefits of secondary metabolites encapsulated in phytosome, and focused on bioavailability enhancement of these compounds. The exclusion criteria removed studies focusing on non-cancer related phytosome applications, those without clear methodological details, and non-peer-reviewed literature. Additionally, studies that did not include actual biological assessments such as purely computational models without experimental validation were excluded, along with duplicates, resulting in 185 studies. A further review based on abstracts and titles led to the selection of 77 relevant studies, where full-text review identified only 20 that met all the specified inclusion criteria, as shown in Figure 1. All figures in this manuscript, including mechanisms and graphical illustrations, were created by the author using BioRender. The chemical structures shown in the figures were re-drawn utilizing ChemDraw Professional (Version 16.0.1.4, licensed to Supriatno Salam, UNPAD, License ID: 112–920,429-8380) to guarantee precision and clarity in the representation of the studied compounds, with reference to data from the PubChem database, ensuring accurate representation of the compounds.

Figure 1 Flow diagram of the method used for screening information sources in the review.

The inclusion criteria used were:

a. Literature discussing the application of phytosome in treatment of cancer.

b. Studies showing the enhanced bioavailability of secondary metabolites through phytosome.

c. Peer-reviewed studies with full experimental details.

The exclusion criteria were:

a. Literature not related to the application of phytosome in cancer treatment.

b. Non-peer-reviewed studies and those lacking empirical data.

c. Studies focusing on non-biological evaluations of phytosome.

Comprehension and Advancement of Phytosome

Phytosome was first developed in the early 1990s as an innovative advancement in the formulation and delivery of herbal remedies. These intricate formulations primarily comprised the active constituents of herbal extracts that were attached to phospholipids such as phosphatidylcholine, significantly enhancing bioavailability. Generally, complexation improves the hydrophobic properties of the phytoconstituents, facilitating their passage through lipid-rich cell membranes.24

Figure 2 shows the process of enclosing phytoconstituents within phospholipid bilayers in a graphical manner. This encapsulation modifies the hydrophobic characteristics of the phytoconstituents,25 facilitating their passage through lipid-rich cellular membranes. Phytosome significantly enhances bioavailability of bioactive compounds, leading to improved absorption by the body and increased effectiveness in treating medical conditions.

Figure 2 Structural illustration of the phytosome complex, showing phospholipid binding to plant phytoconstituents to enhance bioavailability.

Notes: Created in BioRender. Mardiana, L (2024) BioRender.com/W63W154.

Phytosome technology has shown the potential to overcome the different limitations often associated with plant extracts, including insufficient absorption, rapid metabolism, and significant systemic excretion.26Figure 3 shows the mechanism by which phytosome enhance the transportation of phytoconstituents across cellular barriers. Strategically encapsulating herbal components boosts their bioavailability and allows for regulated release, maintaining sustained therapeutic levels in the bloodstream. The use of controlled release of medication is particularly beneficial in the field of oncology, capable of reducing the need for frequent dosing and minimizing the potential adverse effects associated with high drug concentrations in the body.27 Furthermore, phytosome structure provides improved solubility and stability, enabling these compounds to effectively and consistently increase anticancer properties.

Figure 3 Mechanism of Phytosome-Encapsulated Secondary Metabolites Enhancing Cancer Treatment. The diagram illustrates improved solubility, enhanced absorption, successful cellular uptake, and targeted inhibition of cancer pathways (eg, NF-κB, PI3K/AKT), leading to apoptosis and reduced cell proliferation.

Notes: Created in BioRender. Mardiana, L (2024) BioRender.com/W63W154.

Recent Patents on Phytosomes

Recent patents on phytosomes highlight significant advancements in their development and application for improving the bioavailability of secondary metabolites in cancer treatment. These patents primarily focus on novel formulations that enhance the absorption, stability, and therapeutic efficacy of phytochemicals. For example, patents have been filed for formulations that utilize modified phospholipid structures to increase the solubility and targeted delivery of active compounds, particularly flavonoids, terpenoids, and phenolics.28,29

Patent No. WO2022135652A1 (2021) describes genistein-loaded phytosomes aimed at liver cancer treatment through oral administration, using various phospholipid types to improve solubility and bioavailability.30 Similarly, Patent No. US11207388 (2023) details a phytosomal formulation using Allium sativum and Murraya koenigii for the treatment of breast cancer, emphasizing sustained release and enhanced delivery.31 Another notable patent, Patent No. IN201841001612 (2019), focuses on a phytosomal complex combining Allium sativum and Murraya koenigii for both breast and prostate cancer treatment, aiming to prevent post-therapy recurrence.32 Additionally, Patent No. IN202341042728 (2023) introduces a phytosome loaded with biosynthesized Ag nanoparticles, designed for bone cancer treatment through second-order targeting, which improves cellular uptake and targeting efficiency.33 Some patents emphasize the development of synergistic formulations, where phytosomes are combined with other drug delivery systems to achieve enhanced anticancer activity and reduced toxicity. These innovations in phytosome technology offer promising approaches to overcoming the challenges of conventional formulations, setting new benchmarks for future cancer therapies.

Mechanism of Action: Enhancing Bioavailability Through Phytosome

Phytosome has made significant progress in the field of medication delivery by improving bioavailability of phytochemical.34 This medication delivery method uses specific phospholipid complexes that closely resemble the lipid bilayer of cell membranes. The amphiphilic properties of these complexes facilitate strong and efficient contact with cell membranes,35 enabling enhanced absorption of phytochemical through the gastrointestinal tract. Figure 3 shows the incorporation of phytosome into biological membranes. Generally, phytosome is designed to imitate the structural properties of cell membranes, protecting phytochemical from the harsh enzymatic conditions of the digestive system and improving precise transportation to specified tissues.36 It also maintains the quality and effectiveness of the bioactive substances by duplicating cellular structures.37 These structural alterations guarantee a significantly greater dispersion of active components to targeted regions, thereby boosting therapeutic capacity.38

Modified phytochemical within phytosome39,40 has shown enhanced resistance to digestive enzymes, which increases systemic availability, extending stability and lifespan. This feature is essential to guarantee that therapeutic drug retain efficacy while passing through the body and providing persistent therapeutic effects.41 Phytosome formulations are more successful than typical herbal extracts due to the ability to increase the amount of phytochemical42 absorbed by the body and enhances the effectiveness of pharmacological treatment. As a novel advancement in pharmaceutical science, phytosome improves delivery and efficacy of phytochemical treatment by making structural changes, providing protective encapsulation, and increasing availability in the body.43 This advanced delivery system represents a significant improvement in the more efficient use of natural substances, enhancing therapeutic effects in clinical trials. Phytosome technology enhances the anticancer potential of secondary metabolites through multiple mechanisms. First, the encapsulation of bioactive compounds with phospholipids increases their solubility and absorption across cell membranes, resulting in higher plasma concentrations and better therapeutic outcomes.44–46 Second, the lipid-compatible nature of phytosomes allows for more efficient penetration of cancer cell membranes,47,48 leading to increased intracellular concentrations of the active compounds. This improved cellular uptake ensures that secondary metabolites can more effectively interact with key cancer pathways, such as NF-κB and PI3K/AKT, which are critical for cancer cell survival and proliferation.49,50 By overcoming the bioavailability challenges of these compounds, phytosomes provide targeted inhibition of cancer pathways, ultimately improving their anticancer efficacy.

Comparing Phytosome and Conventional Phytochemical Delivery Methods

Comparative analyses of phytosome and conventional herbal delivery vehicles, such as capsules and tinctures, show a significant enhancement in both bioavailability and the biological efficacy of plant extracts.17 Phytosome has been shown in clinical trials to increase the absorption rate of phytochemical by approximately two times compared to non-complexed plant extracts. For example, silymarin is a well-known chemical protecting the liver and is obtained from milk thistle, which can be absorbed and used by the body when administered as phytosome,51 compared to regular milk thistle supplements. Additionally, phytosome has an extended duration of presence in the bloodstream, enabling a sustained therapeutic effect and decreased frequency of dosage. These qualities give phytosome an advantage over traditional methods, as preferred options for delivering phytochemical in clinical trials.

Secondary Metabolites in Cancer Treatment

Secondary metabolites are a wide range of chemical compounds produced by plants through metabolic pathways that are separate from their fundamental physiological functions. These chemicals, comprising more than 50,000 known varieties, provide adaptive benefits, with a substantial impact on the pharmaceutical business.52 Compounds such as terpenoids, flavonoids, alkaloids, and phenolics are well-known for their antioxidative, anti-inflammatory, antibacterial, and anticancer properties.53 The categorization and potential uses of secondary metabolites, including terpenoids, flavonoids, alkaloids, and phenolics, are illustrated in Figure 4, available at the end of the manuscript. These metabolites play a significant role in plant defense against diseases, resistance to pests, and attraction of pollinators.54 The investigation of these metabolites has shown significant progress in plants metabolomics to uncover potential in pharmaceutical study, agriculture, and diverse industrial uses.55,56 A recent investigation on particular categories of chemicals found in secondary metabolites has shown their considerable capacity as potent anti-cancer agents. Plant-derived chemicals have also been used in many therapeutic and preventive methods to hinder the progression of cancer, showing significant potential as efficacious remedies.57–60

Figure 4 Overview of secondary metabolites and their classifications, including alkaloids, flavonoids, terpenoids, and phenolics, with a focus on anticancer properties.

Notes: Created in BioRender. Mardiana, L (2024) BioRender.com/W63W154.

Secondary metabolites derived from various plant sources have demonstrated significant promise in cancer therapy due to their diverse pharmacological activities. These metabolites can be broadly categorized into flavonoids, terpenoids, alkaloids, and phenolic compounds, each exhibiting unique anticancer properties. Flavonoids, such as quercetin, kaempferol, and rutin, are known for their ability to induce apoptosis, inhibit cancer cell proliferation, and suppress metastasis.61–63 See Figure 5 at the end of the manuscript for a detailed visualization of the structures of secondary metabolites identified, including Cynaroside, Astragalin, Isorhamnetin 3-O-glukosida, Quercetin, Rutin, Flavonol, Phellopterin, Bergapten, and Isoquinoline. The encapsulation of flavonoids in phytosomes significantly enhances their solubility and stability, resulting in increased absorption and bioavailability.18,64 Similarly, terpenoids, including curcumin,65 betulinic acid,66 and ginsenoside Rg3,65 show broad-spectrum anticancer effects, such as antiproliferative and antiangiogenic activities.65 Encapsulation in phytosomes further improves the solubility and therapeutic outcomes of these terpenoids.67,68

Figure 5 Chemical structures of phytoconstituents used in phytosome-based cancer treatment.

Alkaloids, including berberine, dauricine, and vinblastine, are known for their potent anticancer effects, primarily through apoptosis induction, cell cycle arrest, and autophagy inhibition.69,70 Phytosome-based formulations of alkaloids have demonstrated enhanced pharmacokinetic properties, leading to improved bioavailability.17,71 Phenolic compounds, such as resveratrol and pterostilbene, are also effective in preventing cancer cell proliferation and inducing apoptosis.72,73 Phytosome encapsulation increases the bioavailability of these phenolic compounds, facilitating more effective targeting of cancer cells.74–76 Recent studies have supported the efficacy of phytosome-encapsulated secondary metabolites, showcasing significant improvements in therapeutic outcomes across various cancer models.

Table 1 IC50 Values of Various Phytoconstituents Against Different Cancer Cell Lines, Highlighting the Efficacy of Flavonoids and Alkaloids in Inhibiting Cancer Proliferation

The examination of secondary metabolites in several cancer cell lines shows the significance and potential of plant-derived compounds in the field of oncology. This section provides a more detailed analysis of the consequences of the results, specifically showing their substantial influence on advancement of new medication treatment and methods for cancer treatment. The IC50 values in Table 1 show that secondary metabolites, such as flavonoids and alkaloids, have strong effectiveness against a range of cancer types. For instance, efficacy of flavonoids in suppressing cell proliferation in breast, lung, and liver cancer cell lines suggests the capacity to disrupt essential pathways essential for advancement of cancer. Moreover, the impact of alkaloids on melanoma cell lines shows the ability to trigger apoptosis and interfere with cellular proliferation mechanisms.6,83

These results emphasize the adaptability of secondary metabolites as versatile agents in cancer treatment. The phytoconstituents show promise for the development of comprehensive cancer therapeutics by targeting important processes such as cell cycle progression,84,85 apoptosis induction,86,87 and metastasis inhibition.88 The variation in IC50 values among different cell lines also suggests that secondary metabolites can be customized to selectively target specific forms of cancer, thereby improving the accuracy of oncology.

Flavonoids are secondary metabolites found in plants, with significant health advantages, including strong antioxidant89 characteristics that protect cells from harm caused by free radicals. The anti-inflammatory characteristics mitigate the possibility of vascular disorders, while anticancer attributes modulate the proliferation of cancer cells. Extensive study also emphasizes the neuroprotective and cardioprotective benefits of flavonoid, which protects the heart and nerves from harm. Moreover, flavonoids possess antibacterial characteristics, underscoring their significance in medicinal contexts for combating microbial infections.17,90 The classification and specific compounds within each category are essential to identify different roles and therapeutic potentials of secondary metabolites in cancer treatment. Figure 6 presents a summary of the four primary categories of secondary metabolites, namely alkaloids, flavonoids, terpenoids, and polyphenols. It also shows essential molecules, indicating the categorization of secondary metabolites including significant anti-cancer compounds. Alkaloids, such as vinblastine,91 vincristine,92 and camptothecin,93 possess potent characteristics for inhibiting cell proliferation. These compounds interfere with cellular processes that are essential for the growth and survival of cancer cells, increasing effectiveness in chemotherapy treatment. Flavonoids, such as apigenin, genistein, and kaempferol, can serve as antioxidants, reduce inflammation, and inhibit the growth of cancer cells.94,95 The capacity to regulate signaling pathways in cell cycle and apoptosis also contributes to the high potential of inhibiting advancement and dissemination of malignancies. Terpenoids, such as lycopene and gamma-tocopherol, have important functions in preventing the growth of cancer.96 These compounds are recognized for their ability to inhibit cell division and trigger programmed cell death (apoptosis) in cancer cells, specifically in models of prostate and breast cancer. Polyphenols such as curcumin, resveratrol, and epigallocatechin gallate (EGCG) have shown significant potential in the prevention and cancer treatment.97,98 The mechanisms include the regulation of oxidative stress and inflammation, along with direct impacts on tumor cell signaling and death.99,100 The classification facilitates the identification of possible compounds that can attack cancer and emphasizes the need to improve the ability to be absorbed by the body for effective performance. This can achieved through the use of improved delivery systems such as phytosome, which enhances the solubility, absorption, and therapeutic effectiveness of powerful compounds in clinical applications by enclosing in phospholipid complexes.101

Figure 6 Overview of Secondary Metabolites and Their Classifications, Including Key Compounds with Anticancer Properties. The figure was created by the author using BioRender. Mardiana, L (2024) BioRender.com/W63W154.

Notes: The diagram categorizes secondary metabolites into four groups: Alkaloid Group: Vinblastine, vincristine, and camptothecin. Terpenoid Group: Lycopene and gamma-tocopherol. Polyphenol Group: Etoposide, resveratrol, curcumin, and epigallocatechin gallate (EGCG). Flavonoid Group: Apigenin, genistein, and kaempferol.

The existence of secondary metabolites in medicinal plants, such as alkaloids, flavonoids, and phenols, shows their significant potential in combating cancer due to strong anti-cancer characteristics. These metabolites show anti-proliferative properties against cancer cells and have the ability to control tumor growth, thereby hindering advancement of tumors. Moreover, the presence of bioactive compounds in marine algae improves the effectiveness of standard pharmaceuticals, particularly in treatment of lung cancer. This suggests a possible collaboration between natural compounds and conventional drug.102,103

Challenges in Using Phytochemical for Cancer Treatment

Although plant-derived secondary metabolites have the potential to be used in cancer treatment, there are various problems that need to be addressed. The intricate nature of their chemical structures frequently impedes the process of synthesizing and achieving large-scale manufacture. The fluctuation in the content and activity of these compounds in natural sources can impact the uniformity and treatment effectiveness. These compounds have the potential to negatively interact with standard cancer treatment, requiring serious supervision strategies.11,104

Investigation and Advancement of Anti-Cancer Compounds Derived from Secondary Metabolites

A comprehensive investigation into chemicals with anti-cancer properties has shown their function through several mechanisms. These include the inhibition of cell proliferation, induction of cancer cell apoptosis, and prevention of angiogenesis, which is essential for tumor metastasis.105 The compounds often obstruct the function of crucial enzymes that are essential for the survival and growth of cancer cells, thereby inhibiting the proliferation of cancer. This activity emphasizes the potential of plant-derived chemicals to attack cancer by selectively targeting multiple crucial pathways. The continuous advancement of novel compounds is focused on optimizing absorption, distribution, metabolism, and minimizing side effects, improving the effectiveness and safety profiles for application in cancer treatment.39

Phytosome with Secondary Metabolites in Cancer Treatment

The use of phytosome technology has significantly revolutionized the administration and efficacy of secondary metabolites in cancer treatment. This novel method includes enclosing herbal constituents in lipid molecules,106–108 leading to a significant enhancement in absorption and therapeutic efficacy. Furthermore, phytosome technology improves the capacity of hydrophobic compounds to dissolve and remain stable This technology offers innovative opportunities for advancement of therapeutic options that are more efficient and less harmful.

Phytosome technology uses lipid carriers to create compounds with active substances, facilitating precise targeting of cancer cells. The implementation of this technology focuses on enhancing treatment outcomes by enabling the use of lower drug doses and decreasing the probability of experiencing undesirable side effects often associated with greater doses of medicine. Table 2 presents a concise overview of efficacy of several phytosome formulations in treating different cancer cell types, showing their potential therapeutic outcomes.109,110

Table 2 Efficacy of Phytosome-Encapsulated Secondary Metabolites Against Various Cancer Cell Types, Showing Enhanced Therapeutic Outcomes

Efficacy of phytosome formulations, such as Sinigrin and Boswellia phytosome, includes offering strong anti-cancer properties and anti-inflammatory benefits, respectively. The synergistic application of Luteolin and Mitomycin, in combination with Luteolin phytosome, shows targeted and potent effects against certain cancer cells. Table 2 also shows the capability of phytosome technology to significantly enhance efficacy of bioactive compounds in cancer treatment. Refer to Figure 7 at the end of the manuscript for the structural visualization of Sinigrin, Luteolin, and Mitomycin, which are among the secondary metabolites discussed for their potential therapeutic effects. Furthermore, phytosome are effective in addressing deficiencies of secondary metabolites, such as flavonoids, which commonly encounter restricted bioavailability and limited interactions with target organs.83,117

Figure 7 Chemical Structures of Secondary Metabolites Used in Cancer Treatment.

Notes: The figure shows the chemical structures of: Sinigrin: A glucosinolate e known for its anticancer activity. Luteolin: A flavonoid with potential anticancer effects. Mitomycin: An alkaloid commonly used in cancer chemotherapy.

Phytochemical, such as alkaloids, phenolics, flavonoids, steroids, glycosides, and terpenoids, have shown significant anticancer effects. As shown in Figure 8 at the end of the manuscript, the structures of phytochemicals such as Fisetin, Chrysin, Curcumin, Apigenin, Withaferin, and Glycyrrhizic acid are illustrated. These compounds are utilized in both phytosome and non-phytosome formulations for cancer treatment. However, the implementation of these methods encounters obstacles such as restricted engagement with specific organs and insufficient bioavailability. As shown in Table 3, phytosome technology overcome the problems by improving the absorption into the body and the effectiveness of secondary metabolites. A comparative investigation conducted on a mouse model showed that flavonoids phytosome had enhanced bioavailability and health outcomes compared to ordinary quercetin.118

Table 3 Comparison of IC50 Values Between Phytosome and Non-Phytosome Formulations of Secondary Metabolites in Cancer Treatment

Figure 8 Structures of Phytochemical used in Phytosome and Non-Phytosome Cancer Treatment.

The incorporation of cisplatin and glycyrrhizic acid, a phenolic molecule, into nano-phytosome formulations also showed significant improvement in the effectiveness of the anticancer treatment.117 Specifically, treatment caused a decrease in the growth of DLD-1 cell line by approximately 44.3% and 95.6% in LIM-2405 cell growth when evaluated in laboratory settings at a dose of 150 μM. The significant enhancement in efficacy was measured as a 124% increase in inhibition from the lowest to highest level in DLD-1 cells. This shows the potential of PEGylated nano-phytosome created using the thin film hydration method.117 Moreover, the use of PEGylated nano-phytosome led to a substantial increase in DNA damage in DLD-1 cells compared to treatment with cisplatin alone. This emphasizes the system’s ability to improve the effectiveness and underlying mechanisms of anticancer activity by delivering phenolic compounds more efficiently. When evaluating the effects of phytosome technology on phytochemical treatment, there is an improvement in effectiveness during formulations comparison between phytosome and non-phytosome. Specifically, polyphenols targeting 4 T1 cancer cells showed the most remarkable enhancement, with a decrease in IC50 values from 39.94 µg/mL to 7.73 µg/mL, leading to an 80.67% reduction and a fivefold increase in activity. Chrysin showed a significant decrease in IC50 in HT29 cells, resulting in a nearly threefold increase in efficacy. Similarly, Terpenoids and Flavonoids showed major reductions in IC50 in Vero cell lines, leading to a threefold increase in efficacy. The Polyherbal mix showed a 35.9% reduction in IC50 and a 1.56-fold increase in activity on MCF-7 and MDA MB 231 cells. Polyphenols showed the most significant increase after being encapsulated in phytosome. This suggested the substantial influence of phytosome technology on improving the administration and efficacy of phytochemical in cancer treatment. The results also showed the role of phytosome in converting natural chemicals into powerful anticancer drug, representing an essential breakthrough in the field of oncology. Moreover, this technology improves therapeutic effectiveness of phenolics, which possess anticancer effects. Table 3 shows the ability of phytosome formulations to overcome the harmful effects on cells and restrictions in bioactive compounds processed by the body, resulting in improved effectiveness in causing programmed cell death and reducing resistance to drugs.84,122

This review uniquely contributes to the field by exploring the innovative application of phytosome technology for enhancing the anticancer efficacy of secondary metabolites. Unlike previous studies that focus primarily on general pharmacological properties, this review delves into specific mechanisms by which phytosome encapsulation optimizes solubility, absorption, and targeted delivery of natural compounds. The findings presented here provide novel insights into how such advanced delivery systems can overcome longstanding challenges in the clinical application of secondary metabolites for cancer therapy, setting a foundation for more effective, natural-based cancer treatments.

Synthesis of Phytosome Containing Secondary Metabolites

Phytosome production entails enclosing bioactive plant components in lipid matrix, mainly phospholipids, to improve bioavailability and stability. This process commonly uses various methods such as solvent evaporation, thin-layer hydration, and anti-solvent precipitation.123 The methods promote the development of a connection between the water-loving portion of phytochemical and the water-repelling section of the phospholipid, leading to a well-organized, stable compound that efficiently crosses cell membranes.124 The selection of the method depends on the physicochemical characteristics of metabolites to be enclosed, suggesting effective incorporation into the lipid framework. To optimize phytosome formulations, there is a need to alter the ratios of phospholipids to secondary metabolites, modify the synthesis parameters to improve encapsulation efficiency, and assess the bioactivity of the resulting phytosome.125 During this stage of development, it is essential to customize the properties of phytosome, such as particle size, zeta potential, and encapsulation efficiency,126 to meet therapeutic requirements of certain metabolites. Methods such as dynamic light scattering (DLS) and scanning electron microscopy (SEM) are commonly used to analyze and improve the properties of these nanoparticles, showing their effectiveness and stability in physiological environments.127

Phytosome has essential benefits in terms of enhanced bioavailability and effectiveness, although there are difficulties in stability, scalability, and manufacture. Therefore, appropriate storage conditions and suitable stabilizers are required for long-term stability.128 Scalability refers to the process of moving from small-scale production in a laboratory to large-scale manufacture in industrial settings. This process requires the development of efficient and affordable methods that can handle a high volume of output, without causing any damage to the structure of phytosome. Moreover, there is a need to overcome regulatory obstacles and ensure adherence to pharmaceutical standards on quality and safety.

Future Perspectives and Directions

Phytosome technology has made progress in developing delivery systems that can specifically transport phytochemical to cancer cells. Currently, various investigations are being carried out to investigate innovations, such as modifying the surface of phytosome with antibodies or ligands that can identify specific markers on cancer cells. These modifications are performed to enhance the selectivity of phytosome, thereby minimizing the effects on healthy cells and improving therapeutic outcomes in the field of oncology. The modular structure of phytosome technology renders it highly versatile for specific treatment to optimize effectiveness and reduce adverse effects by modifying the composition and dosage according to unique patient profiles. Phytosome being included in individualized treatment plans is a potential advancement in precision medicine, particularly in the field of cancer care, where the variability in individual response to treatment is a major obstacle.

Understanding and complying with regulations is crucial for the successful implementation of phytosome technology in clinical trials. Furthermore, there is a need to meet the rigorous demands of the regulatory body, which require thorough documentation of the synthesis process, and verification of safety, and efficacy through clinical trials. To obtain the product into clinical use, it is essential to increase manufacturing on a larger scale, while adhering to Good Manufacturing Practices (GMP). Stability tests must be conducted, along with regulatory permissions before the product can enter the market.

Conclusion

Phytosome technology demonstrates significant potential in augmenting natural chemicals for cancer treatment. Phytosomes enhance the delivery of bioactive compounds, including flavonoids, alkaloids, and terpenoids, efficiently targeting essential cancer pathways including NF-κB and PI3K/AKT, thereby establishing them as a promising asset in oncology. In addition to their anticancer properties, phytosomes mitigate the shortcomings of traditional formulations by creating molecular complexes with secondary metabolites, thereby improving their solubility and bioavailability. Comparative studies demonstrate that phytosome-based formulations attain enhanced absorption and prolonged circulation durations, resulting in increased therapeutic efficacy. This review emphasises phytosome technology as a novel delivery mechanism, facilitating future research and clinical applications in cancer therapy.

Acknowledgments

We express our gratitude to the Rector of Universitas Padjadjaran for the APC. Chemical structures were redrawn utilizing ChemDraw Professional (Version 16.0.1.4), licensed to Supriatno Salam at Universitas Padjadjaran.

Disclosure

The authors report no conflicts of interest in this work.

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