There are many challenges with RSV delivery using various routes. RSV possesses low solubility in an aqueous medium and almost zero bioavailability profile which is not fit for oral and topical applications alone. That is where novel drug delivery systems play an essential role. Although it is a perfect anti-oxidant, chemoprotective and anti-inflammatory agent [27], problems arise due to insolubility, less skin penetration, poor photostability, and bioavailability.

Oral route—RSV contributes various effects, as discussed above, but comes with challenging problems like low solubility (in water—0.05 mg/mL) and metabolism [17]. RSV quickly absorbs into the portal veins nearly 75% due to its lipophilic nature having Log P/Ko/w is 3.10. On the other hand, it is aggressively metabolized by the liver through phase 2 metabolism and the formation of sulfated, methylated, and glucuronidated complexes. Sulfate complexes with phenolic groups play a rate-limiting step in the bioavailability of RSV. Some of these complexes come back to the gastrointestinal tract (GIT) to induce metabolism [6]. It is fascinating to know that RSV itself increases the metabolism of its own. A significantly less amount of drug passes to the systemic circulation in unchanged form, but most drugs make complexes with albumin and lipoprotein. It also enabled passive diffusion and temperature-mediated diffusion. However, most drugs combined with albumin complexes are responsible for the drug’s transportation and distribution to the various compartment for cellular uptake [28]. The active metabolite of RSV also has the activity of anti-cancer and others (Figure 3). The study indicates that after 25 mg, oral administration of doses shows somewhere 70% absorption and peak plasma level of 491 ± 90 ng/mL, and a half-life of 9.2 ± 0.6 h. Most of the doses are found in the urine, which liquid chromatography-mass spectrometry (LC-MS) detects. RSV is easily uptaken by epithelial cells. Hence the concentration of drugs in these cells is high [29].

Topical route—A marked topical therapy requires excellent apparent permeability across the skin while showing less skin irritation. The topical application of RSV is limited because of its low permeability and poor skin retention [30]. This causes a decrease in the concentration of API required for efficacy, and less amount of drug reaches the target site. With molecular weight > 500 Da and a high partition coefficient, RSV fails to penetrate the stratum corneum. Furthermore, RSV is also associated with mild allergic reactions and erythema, which causes poor patient compliance. Hence, the lacks of effective delivery of RSV and undesirable skin interactions are the main reasons for its poor therapeutic efficacy.

Parenteral route—Transition points, where pharmaceutical errors are more likely to occur, require specific attention for safe medication delivery. Compared to other drug delivery methods, parenteral administration is favored, such as in cases of cardiac arrest and anaphylactic shock [31]. This method of administration has many benefits, including avoiding first-pass metabolism, improved bioavailability, and consistent dose. Parenteral delivery, which is more controlled than oral administration in terms of dose and pace, results in more predictable pharmacodynamic and pharmacokinetic characteristics. As a result of the serious danger that could result from improper usage, several parenteral pharmaceuticals are categorized as high-alert drugs [32]. However, the parenteral administration of RSV causes severe adverse reactions like anaphylactic shock, muscle spasms, mild inflammation, etc. During multiple dosing, steady-state concentrations are unable to maintain leading to repetitive dosing leads to poor patient compliance.

To show its effect, RSV exerts an effect on the various pathways, receptors, and other modulators. However, the causes of cancer are still unclear, but some hypothesis includes cytoplasmic cell division, abnormal cell, and gene hypothesis. RSV activates the SIRT1 [31], an enzyme located in the cell nucleus responsible for the deacetylation of histone and non-histone proteins, including transcription factors [32]. It is also required to regulate the various pathways that affect circadian rhythms, endothelial function, inflammation, immune function, metabolism, cell survival, and stress resistance. In cancer, SIRT1 regulates abnormal metabolic control, defects in the cell cycle, and inflammation [33]. It also regulates other conditions like cardiovascular diseases, obesity, and neurodegenerative diseases. RSV modulates the nuclear factor-κB (NF-κB) pathway by inhibiting the proteasome in human articular chondrocytes [34], which regulates the protein responsible for apoptosis and cell cycle progression. NF-κB regulates the antiapoptotic gene [35]. The active form of NF-κB results in the expression of a gene responsible for cell proliferating and protecting cells from apoptosis [programmed cell death (PCD)]. Whereas defects in the NF-κB result in increased apoptosis. NF-κB alters the activity of the caspase family enzyme, which is responsible for most apoptotic processes. RSV inhibits interleukin 1 (IL-1)-induced apoptosis simulation of caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage in human articular chondrocytes [36]. RSV suppressed the NF-κB regulated gene products such as matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-9, vascular endothelial growth factor (VEGF), COX-2 and also inhibited apoptosis [B-cell lymphoma-extra large (Bcl-xL), B cell lymphoma protein-2 (Bcl-2), tumor necrosis factor-α (TNF-α) factor 1] [37].

Suppression of MMP-2 lead to the inactivation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein kinases (MAPK) signaling pathway, which causes inhibition of A549 cell invasion beneficial for epithelial carcinoma. RSV inhibits the COX enzyme, which stops prostaglandin formation from arachidonic acid. Prostaglandin is responsible for synthesizing an inflammatory compound that promotes tumor cell proliferation or tumorigenesis. RSV inhibits the insulin-like growth factor-1 receptor (IGF-1R)/Akt/Wingless and int-1 (Wnt) signaling pathways that activate tumor protein (p53), leads to the suppression of colon cancer cell proliferation and induces apoptosis [38]. PI3K/Akt/mTOR pathway regulates various cellular activities such as cell proliferation and differentiation, cellular growth, survival, and mobility [39]. Components of these pathways show several abnormalities during various tumor growth, making it an exciting target for anti-cancer therapy. RSV inhibits PI3K/Akt/mTOR pathways, which are combined with other therapy [40]. RSV also downgraded cell cycle-regulated proteins such as retinoblastoma (Rb), cyclin-dependent kinase 2 (CDK2), CDK4, cyclin E, cyclin D1, and proliferating cell nuclear antigen (PCNA) [41], which inhibits the Akt pathways, causing the death of bladder cancer cell, liver cancer cell, and rats aortic vascular smooth muscle cell. RSV induces cell death, inhibits cell proliferation, and affects cell progression in the ovarian cancer cell line (A2780 cell) [42]. RSV induces the release of cytochrome c from the mitochondria to cytosol, which bind to apoptotic protease activating factor 1 (Apaf-1) to cause caspase activation and cause apoptosis or PCD. RSV also induces auto-phagocytosis, and the Bcl-2 and Bcl-xL do not inhibit the action of RSV in ovarian cancer cell A2780 [43].

A nanomaterial employed as a transport component for another chemical, such as a drug, is called a nanocarrier [44]. Micelles, polymers, carbon-based materials, liposomes, and other substances are frequently utilized as nanocarriers. Nanocarriers’ distinctive properties suggest a potential utility in chemotherapy, and they are now being investigated for their use in medication delivery [45]. Since micro-capillaries have a diameter of 200 nm and a diameter range of 1–1,000 nm for nanocarriers [46], nanomedicine frequently refers to objects with a diameter of less than 200 nm. Nanocarriers can deliver medications to parts of the body that would not typically be accessible due to their small size [47]. Because nanocarriers are so tiny, it is frequently challenging to administer substantial pharmacological doses using them. The low drug loading and drug encapsulation that frequently results from the emulsion procedures used to create nanocarriers presents a challenge for therapeutic application. Polymer conjugates, polymeric nanoparticles, lipid-based carriers, dendrimers, carbon nanotubes, and gold nanoparticles are a few of the newly identified nanocarriers [48]. Liposomes and micelles are two types of lipid-based carriers. Gold nanoshells and nanocages are two types of gold nanoparticles. Hydrophobic and hydrophilic medications can be distributed throughout the body thanks to the employment of several types of nanomaterial in nanocarriers. Since the human body is mainly made up of water, one important therapeutic advantage of nanocarriers is their capacity to transport hydrophobic medications to people successfully. Depending on the orientation of the phospholipid molecules, micelles can contain either hydrophilic or hydrophobic medicines [49]. Some nanocarriers have nanotube arrays that enable them to hold medications that are both hydrophilic and hydrophobic. Unwanted toxicity from the sort of nanomaterial being employed is one potential issue with nanocarriers. If inorganic nanomaterial builds up in specific cell organelles, it can also be hazardous to humans. To create safer, more efficient nanocarriers, new research is being done. Since protein-based nanocarriers are found in nature and often exhibit lower cytotoxicity than synthetic compounds, they hold promise for use as therapeutic agents [50, 51].

Because they can deliver pharmaceuticals to site-specific targets, nanocarriers are helpful in the drug delivery process because they allow drugs to be administered in some organs or cells but not in others [52]. Site-specificity is a significant therapeutic advantage since it stops medications from being administered to the incorrect locations. Nanocarriers have promise for application in chemotherapy because they can lessen the chemotherapy’s harmful, widespread toxicity on the body’s healthy, rapidly dividing cells. Chemotherapy medications must be given to the tumor without spilling over into healthy tissue because they can be highly damaging to human cells.

However, many patents have been filled in the last two decades, which shows a significant interest in this area. Many challenges have been addressed, and various methods have continuously improved product quality by innovation in formulating RSV. Some of them are nanoformulation which improves severe problem that occurs during the drug delivery of RSV. A list of such patented formulations and methods is given in Table 2.

There is a number of RSV studies that are listed on ClinicalTrials.gov, the database of publicly and privately financed human clinical research. Numerous of these trials have been conducted to assess RSV’s pharmacokinetics, bioavailability, safety, and tolerability. Only a few of the studies mentioned are concerned with determining whether RSV is effective in treating particular malignancies [104]. Trans-RSV, Polygonum cuspidatum (Japanese knotweed) extract, SRT501 (micronized RSV), RSV-rich seedless red grapes/grape juices (muscadine grapes), and micro-encapsulated RSV are some of the types of RSV used in these studies. Numerous cancer types, including multiple myeloma, breast cancer, follicular lymphoma, and neuroendo-crine tumors are the subject of these trials, although the majority of them examine how RSV affects the growth of colon malignancies. In reality, RSV has shown to be slightly effective in colon cancer clinical trials, which may be related to RSV’s potential direct contact and extended exposure to colonic tissues [105]. The gut epithelium also appears to be well-suited for absorbing nutrients and active chemicals from food and food components [106].

According to ClinicalTrials.gov, it is exciting to note that while planning the new clinical trials, researchers used what they had learned from earlier trials, which should provide improved outcomes. Two of the four ongoing trials are aimed at gastrointestinal malignancies. The goal of one of these trials (NCT00433576) is to determine the ideal RSV dosage that will produce bioactive levels in the colon mucosa. This is significant because an ideal dose has not yet been identified despite extensive RSV studies on colon cancer [106]. Additionally, the researchers will determine whether there are correlated levels of COX-2 and pyrimido[1,2-α]purin-10(3H)-one (M1G) adduct in cancer tissues to examine the mechanistic consequences of RSV treatment of colorectal adenocarcinoma. Given that both of these molecules have been proven to be regulated in colon cancer, this might offer some relevant information. The goal of the other ongoing colon cancer experiment (NCT00578396), which uses seedless red grapes, is to ascertain the highest dietary RSV levels possible. This may be crucial for colon cancer prevention because it would be simple to develop new dietary guidelines for the general public. These trials ought to yield some information that will be beneficial in more in-depth human research that aims to make RSV available in clinics for the treatment of diseases. Diets high in RSV may also be encouraged for improved health and illness prevention [107, 108].