Globally, cancer has been referred to as one of the most debilitating diseases. The current treatment regimenfor the treatment of the same is limited to surgical, radiation, and chemotherapeutic interventions. However, these methods have a high risk of damage to healthy tissues, while not even conferring complete cancer eradication. With the advent of nanotechnology, the treatment landscape for cancer is projected to change. While these Nano particulate modalities are highly efficacious, they pose their set of caveats. Recent studies have corroborated the enormous potential of Plant-derived edible nanoparticles (PDENPs) in the treatment of a spectrum of tumors and cancers, owing to their exceptional properties such as safety profile, high stability, low immunogenicity, and rapid internalization by mammalian cells. Additionally, their anti-inflammatory, anti-proliferative, regenerative, and immunomodulatory effects upon oral administration are commendable. This article aims to explore the various facets, as well as the prospects of these PDENPs as potential vehicles for targeted and efficient drug delivery to cancerous tissues.
Plant-derived edible nanoparticles (PDENPs) are nanosizedvesicles obtained from edible plants such as grapefruit, curcumin, ginger, broccoli, and lemon. They contain miRNAs, bioactive lipids, and proteins, which play an important role in cell signaling, regulation of plant immunity, and transport of bioactive molecules into mammalian cells. As the world attempts to overcome challenges associated with drug delivery such as poor solubility, poor bioavailability, lack of specificity at the site of action, and toxic adverse effects, researchers have converged at plant derived nanoparticles (PDENP) for targeted drug delivery. They are non-toxic, have tissue-specific targeting properties, and can be mass-produced. Thus, they have great potential for clinical applications(Sarvarian et al., 2021).
Cancer is a major public health problem throughout the world. Global demographic characteristics propose a gradual increase in cancer incidence over the next decades, with more than 20 million new cancer cases expected annually by the year 2025(Zugazagoitia et al., 2016). Recently, nanotechnology has found widespread application in the field of cancer treatment. Traditional cancer treatment regimens include chemotherapy, radiation therapy, and surgical interventions. However, these therapies are associated with several dangerouscomplications that can often be fatal. Surgical interventions may be successful in removing localized tumors, but malignant tumors often require additional chemotherapeutic interventions. Currently employed chemotherapeutic drugs work by interfering with DNA synthesis and mitosis of rapidly dividing cancer cells, this stops the growth of cancer cells.However, these drugs are often non-selective, thus affecting healthy cells of the body. Chemotherapy and radiation therapy are known to cause gastrointestinal ulceration leading to loss of appetite, fatigue, malabsorption, risk of sepsis, kidney dysfunction, neurological complications, and damage to the ear. Traditional cancer treatments have several more limitations such as low penetration into cancer cells, rapid breakdownin the body, multi-drug resistance, and lack of specificity.Thus, several researchers have been turning to nanoparticle-based drug delivery systems. Nanoparticles can directly deliver drugs to cancer cells. They can do this by selectively binding to cytoplasmic or nuclear receptors, thereby reducing the toxic effects of drugs on surrounding healthy cells. As a result, we can achieve larger drug concentrations within the cancer cells, at lower doses. Although synthetic lipid-based nanoparticles such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are used most frequently as drug delivery systems, they are associated with additional challenges such as limited drug loading, drug leakage, and crystallization during storage. Synthetic nanoparticles have also been observed to form unstable compounds that cause inflammation, show limited ability to cross biological barriers, and in some cases trigger cell death(Sarvarian et al., 2021).
PDENPs show little to no cytotoxicity or immunogenicity, making them one of the safest anti-cancer therapeutic agents. Therefore, plant-derived edible nanoparticles are proving to be sustainable and non-toxic alternatives in cancer treatment to overcome the aforementioned challenges(Varghese et al., 2021).
Properties of PDENPs
The properties of PDENPs are based on their lipid, protein, and miRNA content. Lipids are among the most significant structural elements of the NP-vesicle membrane(Iravani&Varma, 2019). These lipids are responsible for the therapeutic action of many different nanoparticles. Most nanovesicle membranes contain components such as Phosphatidic Acids (PA), Phosphatidyl Ethanolamine (PE), andPhosphatidyl Choline (PC). Nanovesicles containing PC and PE, such as Grapefruit-derived nanovesicles (GDNs), show remarkable antioxidant, anti-inflammatory, and anti-colitis effects(Sarvarian et al., 2021). Further, proteins also influence the action of PDENPs. Although the protein content of PDENPs is lower than that of mammalian exosomes, they play a vital role in regulating carbohydrate and lipid metabolism within cells. Lastly, miRNAs are also important constituents of NPs. MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. They are vital components of PDENPs(Iravani&Varma, 2019). While the type and percentage of miRNA in PDENPs varies based on the plant source, miRNAs allow the nanovesicles to bind to mammalian targets. As a result, NPs can bind to specific cancer cells, and surrounding healthy cells are not affected.They are also able to suppress or activate the immune response in the body(Iravani&Varma, 2019).
Isolation and preparation of PDENPs
The standard method for the isolation of plant nanovesicles is differential ultracentrifugation, along with density gradient centrifugation(Iravani&Soufi, 2020). Here, the plants are crushed in a mixer, after which size separation is carried out using low-speed centrifugation. Medium-speed centrifugation is also employed to separate bulky particles. Furthermore, a sucrose density gradient step is also implemented to remove impurities(Iravani&Soufi, 2020).
Isolated nanovesiclescan befurther loaded with therapeutic agents such as siRNAs, miRNAs, small drug molecules, and proteins. These modified nanovesicles are alternative and efficient drug delivery systems. Targeted ligands such as antibodies, proteins, and artificial DNA/RNA segments can be loaded onto NPs, allowing them to target cancer cells specifically(Varghese et al., 2021). This specificity reduces side effects and improves recovery after cancer treatment. Electrostatic interaction and sonication techniques are frequently used to load nanoparticles with therapeutic agents(Iravani&Soufi, 2020).
PDENPs in Cancer
PDENPs have found applicability in various forms of cancer treatments. Citrus limon L. juice-derived nanoparticles have been shown to reduce the growth of cancer cells in human lung carcinoma, human colorectal adenocarcinoma, and chronic myeloid leukemia(Raimondo et al., 2015). Raimondoetal.demonstrated the high specificity of citrus NPstoward cancer cells, with no adverse effects on surrounding healthy cells(Raimondo et al., 2015).
Additionally, grapefruit-derived nanovesicles (GNVs) loaded with miR17 target brain tumor GL-26 cells(Zhuang et al., 2016). These loaded GNVs when administeredintranasally show high specificity toward cancer cells, with no observable side effects. Furthermore, folic acid (FA) loaded GNVs have also been shown to prevent brain tumor progression, reduce tumor size, and remove minimal residual chemoresistanttumor cells (Sarvarian et al., 2021).
An animal study conducted by Wang et al showed the effects of GNVs in treating colon cancer(Wang et al., 2013). It was also found that GNVs administered by intravenous route did not cross the placental barrier, making them promising carriers in pregnant patients. Curcumin conjugated plantexosomes also reduced the growth of malignant colon cancer cells when ingested(Zhang et al., 2016).
Furthermore, PDENPs have also been widely used in breast cancer treatment. Tang et al elucidated the use of aptamer-conjugated GNVs loaded with doxorubicin to treat HER2+ breast cancer(Sarvarian et al., 2021). It was found that these NPs were absorbed easily by cancer cells, showed anti-tumor activity, and also reduced damage to neighboring healthy cells.Nanosized extracellular vesicles from Dendropanaxmorbifera DM plant (DM-EV) and Tea flower-derived exosome-like nanoparticles (TFENs) can selectively target malignant breast cancer cells. In addition, corn-derived nanoparticles (cNP) also contain a lipid bilayer that is very useful in the treatment of breast cancer, without affecting healthy cells(Zhang et al., 2016).
PDENPs have applicability in various chronic diseases, including various forms of cancer, autoimmune disorders, and infectious diseases. Nanoparticulate vesicles are promising drug delivery agents. Their non-toxic, sustainable and highly specific nature makes them viable targets for further research(Varghese et al., 2021).
Future Prospects and Outlook
PDENPs display several unique traits such as the ability to cross BBB but not the placenta, lack of cytotoxicity, reduced tendency to trigger an immune response in the body, greater internalization, and high production capability. These properties make them potential candidates for commercial applications. Future applicability of PDENPs includes loading them with miRNAs, hydrophobic drugs, and chemotherapeutic agents. Utilizing them as nanosized vector molecules can vastly improve the treatment of cancers, inflammatory diseases such as Crohn's disease, ulcerative colitis, and autoimmune disorders as well.
Conclusion
Plant-derived edible nanoparticles are a group of nanosized vesicles that are obtained from dietary vegetables and fruits such as grapefruit, curcumin, ginger, broccoli, and lemon. They show high drug delivery efficiency, desirable therapeutic effects, and low toxicity. Additionally, since these drugs are sourced from edible plants, they are safe, sustainable, and easy to mass produce. They display marked anti-inflammatory, anti-tumor, anti-oxidant, and anti-colitis activity. PDENPs can be loaded with proteins, plant secondary metabolites, chemotherapy drugs, siRNAs, miRNAs, and DNA expression vectors to display the desired therapeutic effects. Thus, further exploration and research in the field of plant-basednanomedicine can vastly improve their commercialization and also discover newer applications of the same.
References
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Student and Researcher, Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University.
Abha Deshpande is affiliated with Poona College of Pharmacy, Bharati Vidyapeeth Deemed University. Her work thus far has explored AI in healthcare sciences, drug delivery systems in cancer, and drug targets in Alzheimer's. Her research interests include metabolomics, nanomedicine, neuroscience, and genomics. With a keen interest in academia, she aspires to pursue a career in pharmaceutical sciences.
Clinical Pharmacist and Medical Affairs Executive,River Route Creative Group LLP
Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University; Department of Entomology, University of California; UC Davis Comprehensive Cancer Center, University of California.
