Tapping the potential of nanophytomedicine

Almost 50 per cent of the drugs in current usage are derived either directly from natural sources or are chemical analogues of natural origin molecules. The primary handicap in harnessing the hitherto unrealized potential of phytomedicines has often been the poor in vivo response of actives that have otherwise demonstrated excellent in vitro pharmacological activity. The reasons have been manifold; ranging from poor solubility profiles and impaired membrane permeability to inadequate deposition of drug at the site of action.

Novel drug delivery systems are increasingly being applied as effective tools in overcoming these issues and helping design physiologically effective phytoformulations. The ideal drug delivery system should be able to target the drug release at the site of action in a controlled manner so as to obtain optimum therapeutic effect with minimal side effects. Various nano-particulate and vesicular platforms, including polymeric, lipoidal and macromolecular types, have been deployed for achieving these end-points. Here we discuss few of the systems that are in use in phytoformulation design.

Polymeric nanoparticles (PNPs) are colloidal systems made up of biodegradable and biocompatible polymers of natural or synthetic origin, ranging in size from 10 nm to 1000 nm. The drug is either encapsulated within the polymeric shell (Nanocapsules), or entrapped within the matrix (Nanospheres) or adsorbed or conjugated on the surface (Figure 1).

Dextran, gelatin and chitosan are naturally derived polymers and poly(esters), poly(anhydrides), poly(amides), methacrylic acid copolymers, acrylic and methacrylic acid esters poly-L-lactic acid (PLA) and copolymers with glycolic acid are some of the synthetic polymers that have been studied for developing PNPs. PNPs have been applied for improving bioavailability and therefore pharmacological activity and manipulating release profiles of a host of phytomolecules including curcuminoids, artemisinin, berberine, camptothecin and breviscapin. Abraxane®, an albumin nanoparticulate product of paclitaxel has been developed by Abraxis Biosciences and has been approved by FDA in 2005 for use in cancer. Genexol-PM® (PEG-PLA nanoparticles of Paclitaxel by Samyang, approved in Korea) is another example of the marketed nanoparticulate formulations available currently. BIND-014 is a peptide conjugated PEGylated PLGA nanoparticulate formulation of Docetaxel that has been developed by BIND Biosciences and is currently in Phase 1 study.

Solid lipid nanoparticles (SLNs) are colloidal carrier systems made up of biodegradable physiological lipids stabilized using biocompatible surfactants (Figure 2). The lipids used in formulating SLNs include mono-, di-, or triglycerides, lipid acids, and glyceride mixtures or waxes that are solid at room and body temperature and hold the drug within the solid matrix.

Due to their small size and biocompatibility of lipids, SLNs can be used for administering drugs via various routes, ranging from oral, parenteral, to percutaneous. SLNs containing quercetin, curcuminoids, podophyllotoxin and host of other phytomolecules have been reported, with consequent increment in bioavailability and diminution in side effects and toxicity.    

Lipoidal vesicular systems are spherical, highly ordered assemblies of one or several concentric lipid bilayers that entrap an aqueous solvent core and separate the core from the surrounding solvent. Of the numerous lipoidal vesicular systems, liposomes are considered as first generation vesicles. Liposomes are unilamellar or multilamellar, spherical vesicles ranging in diameter less than 100 nm to over 400 nm and are primarily composed of neutral glycerophospholipids and cholesterol, along with suitable additives including charged species, natural acidic glycerophospholipids and cardiolipin  and antioxidants that help in manipulating stability and structural and permeability attributes of these vesicles. Incorporation of saturated fatty acid lipids, PEGylated lipids, cationic lipids and targeting moieties are some of the strategies deployed for improving the drug delivery profile of these systems (Figure 3).

Liposome technology has been applied to phytomolecules for a diverse group of therapeutic segments; chemotherapeutic agents, antibacterials, pain killers, antioxidants and immune modulators.

Extensive work has been reported on development of liposomes of paclitaxel. Multicentre, open – label Phase 2 study of LEP-ETU for efficacy and safety evaluation in patients with metastatic breast cancer has been completed and results are awaited. A Phase 2 IIT (investigator initiated trial) showed promising preliminary activity of EndoTAG®-1, a liposomal paclitaxel preparation, as preoperative treatment, especially in patients with triple-negative breast cancer (TNBC). The product is scheduled to enter into Phase 3 studies for use in TNBC, in the second half of 2014.

PEGylated liposomes of vincristine and vinorelbine have been developed and investigated. Use of triethylammonium salt of sucrose octasulfate (TEA8SOS) and sulfosalicylate mediates for optimizing drug loading of these extremely lipophilic molecules, has been explored. NanoXTM is a PEGylated liposome technology platform developed by Taiwan Liposome Company. NanoVNB®, developed by encapsulating vinorelbine into NanoXTM, is currently under Phase 2 study for head and neck cancer.

DepoDur®, a single dose extended release liposomal injectable formulation of morphine sulphate, has been developed using SkyePharma PLC's DepoFoam® technology. DepoDur® was approved by the US FDA in 2004 and is administered as single epidural injection, with general systemic and intrathecal drug distribution.                        

Sphingosomes have been positioned as improvized liposomes, with use of sphingolipids instead of glycerophospholipids as the major lipid component and have demonstrated better drug retention characteristics.

OptisomeTM is a sphingosomal drug delivery platform developed by Talon Therapeutics, Inc., San Fransisco, and applied in development of a couple of products under various phases of clinical study. Marqibo® is vincristine sulphate injection based on OptisomeTM that was approved by US FDA in 2012 for acute lymphoblastic leukemia. The product is currently being developed for non-Hodgkin's lymphoma (NHL) and is presently under Phase 3 study. Talon Therapeutics are also developing AlocrestTM, vinorelbine injection, again based on OptisomeTM technology. A Phase 1 dose-escalation trial of AlocrestTM has demonstrated promising anti-cancer activity, with acceptable toxicity in heavily pre-treated patients with advanced solid tumors refractory to standard therapy or for which no standard therapy was known to exist, including non-small cell lung cancer (NSCLC) and advanced stage breast cancer. AlocrestTM is scheduled for Phase 2 trials for NSCLC.       

Ethosomes and transfersomes are derivatives of liposomes designed for improved transdermal drug delivery. Relatively higher concentrations of alcohol are incorporated in ethosomes to make them malleable whereas transfersomes are made elastic by inclusion of edge activators or non – ionic surfactants. Transdermal preparations based on ethosomes and transfersomes entrapping glycyrrhizinates, black tea extract, curcuminoids and various phytoalkaloids have been formulated, with ultimately improved topical and systemic drug activity.  

Pharmacosomes are colloidal, lipoidal vesicular dispersions of drug - lipid complexes, wherein the drug molecules are covalently bound to lipids. Pharmacosomes leverage some distinctly unique advantages over other vesicular types particularly with respect to drug leakage that is so common with the other vesicles. Phytosome® is a patented technology developed by Indena®, Italy, which incorporates standardized plant extracts or water soluble phytoconstituents like flavanoids, terpenoids and tannins, into phospholipids to produce lipid compatible molecular complexes with vastly improved absorption and bioavailability.     

Archaeosomes are modified liposomes made with one or more of the ether lipids found in Archaea (a large and widely distributed group of organisms), with higher stabilities as compared to conventional liposomes, to low or high temperatures, acidic or alkaline pH, oxidative stress, extreme pressure conditions, lipolytic action of phospholipases and serum proteins. Archaeosomes can be used as vehicles for cytosolic delivery of hydrophilic macromolecules, proteins and peptides, antigens and an entire plethora of therapeutic agents that are otherwise unable to gain entry into the host cell.

Light-sensitive liposomes are formulated by incorporating light- sensitive molecules like retinoyl lipids and molecular dyes, which get converted into modified forms on irradiation with light of suitable wavelength and destabilize the vesicle membrane, thus releasing the encapsulated contents. These are being widely used for delivering antioxidant compounds, DNA repair enzymes, sunscreen compounds and the like, in skincare and anti – ageing products. The applicability of light – sensitive liposomes in delivering phytochemicals, chemicals and biochemicals as photosensitizers in photodynamic therapy for treating superficial tumors is colossal and yet to be exploited fully.

Layersomes are conventional liposomes coated with one or multiple layers of biocompatible polyelectrolytes in order to stabilize their structure; basically designed as liposomes with improved physical stability and less predisposition towards content leakage due to aggregation and fusion. Layersomes present a breakthrough as far as oral administration of liposomes is concerned, with the promise of presenting viable oral chemotherapeutic regimens. Paclitaxel and insulin – loaded layersomes have been recently developed and have been found to be stable in simulated gastrointestinal fluids and at accelerated stability conditions.

Almost all the modifications of liposomes have attempted to manipulate the chemical and physical attributes of the lipid bilayer, but with limited success. Vesosomes and capsosomes have been developed as novel systems that alter the structure of unilamellar liposomes, while retaining the lipid bilayer as the fundamental structural unit.

Vesosomes are nested lipid bilayer compartments or vesicles enclosed within a single large bilayer vesicle. Vesosomes thus, have distinct inner compartments separated from the outer limiting membrane that have same or different bilayer compositions and can encapsulate different materials (Figure 4).

The nested compartment structure addresses one of the major problems with conventional liposomes, the overly fast release rates of most drugs in serum, possibly by shielding the internal compartments from the serum components responsible for degrading the bilayer and increasing permeability. Vesosomes therefore, have the most promising application in delivering drugs that have shown improved efficacy when administered as liposomes, but handicapped by uncontrolled, fast drug release. Vincristine is one such example, where, increased duration of therapeutic alkaloid concentrations at the tumor site has shown to have a positive correlation with drug efficacy.

Capsosomes are cell mimics with a large, defined number of lipid compartments encapsulated within a structurally stable polymer scaffold. Capsosomes are formed by sequentially layering liposomes and charged polymers onto particle substrates, followed by removal of the substrate cores (Figure 5).

In this context, degradable polymer capsules are employed as carriers, while the liposomes serve as entrapped drug deposits, with an increased cargo retention time of at least 2 weeks, and can be positioned as drug depot – type delivery systems. While the core strength of casposomes is expected to be in cell mimicry by using enzyme – loaded liposomes and thus presenting greater opportunities in development of functional artificial cells, their potential for intracellular delivery of chemotherapeutic agents is something that ought to be worked on.

As reported in scientific and patent literature, and the few products that have been developed and approved for clinical use, the synergy of a versatile delivery system with the chemically diverse assemblage of phytotherapeutic molecules can be the panacea for most modern day diseases and disorders and the many resurgent infections that remain a challenge today. The need of the hour is to overcome the inherent challenges associated with phytoformulation development such as scale-up feasibility, meeting prescribed standards of toxicity and the in-depth understanding of interaction of nanomaterials with biological systems.