Liposome as nanocarriers for the delivery of phytomedicines: implication in the treatment of cancer

Abstract

The researchers have been facing several challenges in the designing of the treatment strategies to fight against the cancer. Since ancient times, the addition of natural foods in the diet has been reported for the prevention of several diseases including cancer.[1] The recent advancements have shown immense attention in the discovery of drug utilizing the herbal products with minimal toxicity.[2] Several studies support the claim that more than 30% cancer related death could be avoided by including high amount of natural foods in the diet.[3] Noticeably, almost half of the drugs that have been made available in the market in the last three decades are either directly from the plants or altered chemically.[4] Numerous studies demonstrated the use of plant materials in different ways as the crude extracts, bioactive secondary metabolites etc. as phytomedicine.[5] The phytomedicines also known as nutraceuticals, are exploited individually or in  combination with chemotherapeutic agents in the chemoprevention as well treatment of different types of cancers.[6,7]. However, the major downsides of most of the phytomedicines are the variability in the acidic pH, insolubility, low bioavailability, that can lead to minimal therapeutic index.[8] Keeping these challenges into considerations, the researchers have made immense attention to design the effective strategies to utilize their maximum potential without any adverse effects. In the last two decades, the researchers have proposed different types of delivery systems as niosomes, phytosomes, nanoparticles, microspheres, emulsions, liposomes etc. These carriers have opened the new vistas for the delivery of phytomedicines to augment their therapeutic potential. Among them, the liposomal formulations have several advantages in the efficacy of phytoconstituents due to enhanced stability of the carriers and bioavailability of the payloads with  minimal toxicity as reviewed by Cheng et al. 2022.[9] The liposomes  are the colloidal vesicles with varying range from 15 nm to 5 mm in diameter that are formed spontaneously following the hydration of various lipids in the aqueous solution. The liposomes can encapsulate the hydrophobic payloads in the phospholipid bilayer, hydrophilic in the aqueous core and amphiphilic in the bilayer surface according to the lipophilicity of the drugs. They can have single or multiple concentric membranes represented as unilamellar (ULV) or multilamellar vesicles (MLV) respectively. However, the ULVs can also be categorized into two sub classes as larger unilamellar (LUV) and small unilamellar vesicles (SUV).

So far, the herbal extracts or phytoconstituents encapsulated many liposomal formulations have been characterized and evaluated against different types of cancer models in vitro as well as in vivo. Among them, several liposomal formulations of phytomedicine have been exhibited to augment the solubility, bioavailability, prolonged release and site-specific delivery of payloads as well. Therefore, these carriers of herbal drugs are categorized into four generations according to their characteristics and functions, as conventional, stimuli responsive, sterically stabilized, actively targeted and theranostic liposomes.[10–12]

Currently, the use of conventional liposomes has been limited in the preparation of herbal drug formulations due to their rapid clearance from the bloodstream, degradation, aggregation, and coalescence. However, the selection of lipids, their molar concentration with phase-transition temperature (Tc), surface charge, size and the methods of preparation define the characteristics of liposomes. Several studies suggested the inclusion of cholesterol in the suitable amount enhance the stability of conventional liposomes.[13–15] The stealth or sterically stabilized liposomes are commonly used in the clinical trials, increase the stability in circulation and reduce their uptake by reticuloendithelial system (RES). These liposomes are also called PEGylated liposomes as the polyethylene glycol (PEG), a hydrophilic polymer is coated on the surface of conventional liposomes.[16] Recently, my research group prepared and characterized the PEGylated liposomal formulations of diallyl disulfide (DADS) and demonstrated the use of DADS to enhance the activity of oxaliplatin in colorectal cancer (CRC) model in vitro.[17] Subsequently, we also exhibited the chemopreventive effect of diallyl trisulfide (DATS) encapsulated PEGylated liposomes in azoxymethane induced CRC model in vivo.[18] Besides, we have developed the stealth liposomes of thymoquinone and reported the stability, increased sensitivity to lung cancer cells in vitro and safety level of doses in vivo.[19]

The stimulus responsive liposomes are prepared by modifying the conventional liposomes with the addition of different phospholipids and other chemical constituents to trigger the structure that are capable of releasing the high concentration of herbal drugs at tumor sites. Several strategies have been proposed by the researchers in the activation of this class of liposomes using internal as well as external stimuli. According to the form of triggering approaches, they denoted as thermosensitive, ultrasound responsive, enzyme responsive and pH-sensitive liposomes to name a few.[20] Recently, we developed the novel PEGylated pH-responsive liposomal formulation of thymoquinone considering low solubility of the compound and pulmonary delivery challenges. We reported the inhibition of cancer promotion and progression in the lungs and protection of liver metastasis as well  in chemically induced small cell lung carcinoma model in vivo.[21] The engraftment of targeted ligand or antibody on the surface of liposomes, to specific receptors specifically expressed on the cancer cells is the third-generation strategy of the liposomal formulation for site specific delivery of herbal drugs.[22] The fourth generation theranostic liposomes have the competence of site-directed delivery of phytomedicine with controlled release responsive to the triggering mechanism and imaging efficiency with diagnostic agents.[23] Certainly, the various classes of liposomes as carriers of herbal drugs have shown great potential and will significantly promote the drug designing approaches. Therefore, it is concluded that different strategies should be applied according to the characteristics of the molecule/s for the development of novel delivery system of phytomedicines.