Paclitaxel is a chemotherapeutic agent that is approved for treating various types of cancers, including breast cancer, lung cancer, AIDs or acquired immunodeficiency syndromes, and ovarian cancers, to name a few (Zhu and Chen 2019). Paclitaxel is essentially a hydrophobic drug having inferior properties in water solubility, consequently affecting its clinical administration. Various drug delivery systems have been developed to enhance Paclitaxel’s pharmacological properties and solubility like nanoparticles, liposomes, micelles, cosolvent mechanisms, microparticles, cyclodextrins, and so on. Current clinical application procedures utilize adjuvants having severe side effects that have undesirable biodistribution and pharmacokinetics. The development of alternative drug delivery systems would also increase the drug’s stability and permeability for promoting a controlled sustained and targeted delivery, aiding the plausible therapeutic effects. Pharmaceutical nanotechnology can provide solutions for solving issues concerning drug formulation and delivery to change how drugs are actually made. Drug delivery systems involve formulations, manufacturing techniques, approaches, storage systems, and technologies to transport a pharmaceutical compound to meet desired therapeutic effects. Various nanocarriers have higher efficiency in the encapsulation of drugs and cellular uptake. They need to escape from being eliminated by macrophages for their surface modification, appropriate size and inducing ligand-conjugated targeted delivery.
Improvement of chemotherapeutic substances depends on explaining mechanisms related to cancer and various molecular targets, like inhibitors of signal transduction that govern various processes in cells like growth, differentiation, and survival (Feitelson et al. 2015). The substances possess capabilities to prevent injuries occurring from cancer cells, involving their proliferation and invasion of tissues. Consideration of inducing enhancement of cytotoxic drugs acting on targets like DNA or tubulin is also significant (Zhou et al.2021). An emerging need for developing newer delivery approaches or therapeutic agents has been predominant for reducing extreme side effects and increasing anticancer agents’ efficacy.
Paclitaxel has been isolated from the bark of the plant Pacific Yew or Taxus brevifolia and is a white crystalline powder with a melting point of 210 °C (El-Sayed et al. 2020). The drug’s action mechanism promotes and stabilizes microtubules and inhibits M or late G2 phases in the cell cycle, thereby inducing cell death. Paclitaxel’s antitumor activity is caused by its high binding affinity with microtubules and improved tubulin polymerization. It leads to inhibition of cell mitosis, intracellular motility and transport and consequently apoptosis. Paclitaxel is a reputed antineoplastic drug obtained from natural sources throughout the last decade. It is a pseudoalkaloid containing a taxane ring. It was recognized after having screened over 35000 plant species for conducting assessments on its antitumour activities by the “National Cancer Institute (NCI) in the year 1958. In addition to this, modifiable moieties in the structure make it difficult to chemically alter it. The poor solubility of the drug arises from multiple factors. It has a molecular weight of more than 500, hydrogen bond acceptors greater than 10, and a more than 140 A2 polar surface area. It leads to a “permeability coefficient value” ranging nearly 10−6 cm/s. Consequently, Paclitaxel is administered intravenously (IV route) along with suitable cosolvents, namely Cremophor EL and ethanol, resulting in various directly adverse effects like neurovirulence and acro-anaesthesia, causing tremendous pain and inducing high costs.
Fig: Chemical Structure of Paclitaxel
Source: (Zhu and Chen 2019)
Paclitaxel is found in 30 mg (5 ml), 100 mg (16.7 ml) and 300 mg (50 ml) multidose vials. Every ml of nonpyrogenic sterile solutions have 6 mg paclitaxel, 527 mg polyoxyl castor oil, 2 mg anhydrous citric acid and 49.7% (v/v) dehydrated alcohol (Haddad et al. 2022).
Commercial formulations of the drug widely utilized in clinical settings contain Cremophor EL or “polyethoxylated castor oil” and dehydrated ethanol in a 1:1 v/v mixture (Mao et al. 2018). It can remain stable in vials that are not opened for nearly 5 years at 4°C. Constituents of Cremophor can induce the release of histamine and elucidate hypersensitivity and hypotension reactions after administration of the infusions directly or administration of IV bolus. This formulation should also be infused over several hours to reduce the frequency or intensity of side effects. Taxol is therefore administered slowly in 135-175 mg/m2 doses by infusion over 4-24 hour every 3 weeks.
Abraxane, another marketed drug name of Paclitaxel, had been FDA approved in 2005 and performed using “human serum albumin (HSA)” (AlQahtani et al. 2019). It is an abundantly found plasma protein in the blood, with a large half-life reaching up to 19h, being able to bind hydrophobic substances irreversibly, effectively transporting them in the body and delivering them to the surface of the cells. HSA, being bound to gp60, also plays a role in transcytosis and cellular uptake, highly expressed in malignant cells like SPARC (“Secreted proteins acidic rich in cysteine).
Due to the complicated physicochemical properties of Paclitaxel, several delivery systems have been developed to improve the solubility and pharmacological characteristics of the drug.
Fig 2: Common developed strategies and biomolecules to improve paclitaxel drug delivery.
Source: (Kianfar 2021)
Solid lipid nanoparticles (SLNs) are derived from solid lipids like complex glycerides, waxes and “highly purified triglycerides. Several surfactants and lipids can be utilized for SLN engineering and production (Duan et al. 2020). The simple production method, scaling-up rates, stability, low cost, low toxicity, controlled release of the drug, and versatility make it a desirable option for IV injection. Cellular uptake of SLNs is dependent on time and concentration, along with the melting points of lipid materials, hydrocarbon chain lengths, and particle size. Paclitaxel-loaded PEGylated steric acid SLNs have higher cellular uptake and 10-fold greater cytotoxicity than plain Paclitaxel.
Polymers used in developing paclitaxel nanoparticles are“lactic-co-glycolic acid or PLGA” and chitosan. PLGA is a biodegradable, biocompatible, synthetic non–toxic polymer approved by the FDA for its superior traits of delivering therapeutic agents. PLGA with more glycolic acid is largely hydrophilic and can absorb more water to degrade faster. Loading Paclitaxel to PLGA nanoparticles can be obtained through “emulsion solvent evaporation”, methods of interfacial deposition, and nanoprecipitation. The improved delivery of Paclitaxel can be caused by improved surface modifications of PLGA particles and albumin as the time of circulation for nanoparticles in the blood increases. Chitosan is introduced to Paclitaxel delivery systems for reducing toxicity and efficiency enhancement (Cheng et al. 2017). Paclitaxel loaded with micelle based “N-Octyl-O-sulphate chitosan” or OSC is derived from water-soluble chitosan in paclitaxel delivery but with superior toxic properties. Chitosan nanoparticles are often formulated with polymers like “PE-gylated chitosan nanoparticle with Arg-Gly-Asp’, transferrin, poly NIPAAm, and n-Palmitoyl chitosan.
Preparing Paclitaxel nanoparticles using the procedure of interfacial deposition can be noted (Madani et al. 2018). Organic PLGA solutions with Paclitaxel in acetone can be added to the aqueous poloxamer 188 solutions. It can be conducted at room temperature with constant stirring utilizing magnetic fields, accompanied by ultracentrifugation harvesting and washing of these nanoparticles. In vitro studies find the conduction of measuring residual Paclitaxel amounts at specific time points on having PLGA-nanoparticles containing Paclitaxel, which is diluted in PBS and incubated in viable horizontal shakers at 37°C. These particles project biphasic patterns of releasing Paclitaxel, along with the faster release on the first day and comparatively constant slower release later.
Nanocrystal formulations have also gained recognition for delivering chemotherapy as they eliminate the requirement of chemical carriers, eradicating toxic side effects induced by excipients. They also provide 100% loading of the drug, ensuring suitable concentrations for the drug even at low doses. Top-down techniques involve mechanical energy for producing nanocrystals from larger crystals through high-pressure homogenization and media milling. In the bottom-up approach involving antisolvent perception methods, nanocrystals are formulated directly from drug solutions (Haddad et al. 2022).
These are molecular drug derivatives that can be transformed enzymatically or chemically in the body for releasing pharmacologically active ingredients. Chemical linkages commonly form prodrugs with reduced variation across batches and efficient quality control. Prodrugs are usually created for overcoming issues related to parent drugs. The Paclitaxel prodrug is fabricated at 7-OH group or Carbon number 123 usually (Haddad et al. 2022). They are formulated using polymers like PLA, PEG, Polyamidoamine, HPMA or methacrylamide, and PGA (Poly-m glutamic acid). Protein-based prodrugs can be made utilizing various proteins like the market product of Abraxane, which is created using LyP-1 and CREKA. Prodrugs can be also obtained using“Fmoc-L-glutamic acid 5 tert-butyl ester” and transferrin for particularly targeting tumor cells and tissues. The 2’place in Paclitaxels molecular structure is ideal for inserting functional groups to create Paclitaxel loaded prodrugs, as different derivatives of 2-acyl Paclitaxel can quickly hydrolyze in the blood (Raza et al. 2022). C-7 Paclitaxel prodrug esters can be made as the hydroxyl group in the C-7 place does not impact cytotoxicity. Strong electron releasing substituents like the alkoxy group of the alpha position in the ester helps in faster hydrolytic cleavages. Prodrugs induce quicker cytotoxic reactions as opposed to Paclitaxel against cancer. The pursuit of designing prodrugs use PEG imparting proper aqueous solubility focus on designing water-soluble Paclitaxel derivatives and structural analogues.
Liposomes are spherical structures with a membrane composed of phospholipid bilayers. Its aqueous core helps encapsulate hydrophilic drugs while being loaded in this bilayer membrane. LipusuTM is the first Paclitaxel liposome injected and used for treating cancers. LEP-ETU is the name of another liposome loaded with Paclitaxel. It has shown little difference between pharmacokinetic properties and Taxol while being safe at high doses. Despite the ability of liposomes to deliver compounds inducing cytotoxicity to particular tissues, they can be eliminated by the phagocytic mononuclear system in the body. Liposomal circulation time also increases by PEGylation, where it can be altered using active targeting measures to improve efficacy. It occurs by covalently binding peptides or proteins to liposomal surfaces. PEGylated Paclitaxel liposomes have provided appropriate mitochondrial targeting in cancer cells (Steffes et al. 2019). The sterile preparation and stabilization of Paclitaxel liposomes are often differentiated from conventional liposomes for its ability to circulate in the blood for longer. PEGylated liposomes are formed by mixing Paclitaxel with phospholipids and cholesterol, with their molar ratio deemed to be 1:30 (mol drug: mol lipid). Incorporation of over 20% cholesterol can decrease the physical stability of the formulation and tamper with its incorporation efficiency. The liver and spleen distribution of PEGylated liposomes containing Paclitaxel has been evaluated after extracting Paclitaxel from tissues utilizing “t-butyl methyl ether”. The formulations are found to be properly tolerated by mice while they are administered via intravenous and intraperitoneal bolus doses. Maximum doses recorded to be tolerated have been assessed to be within 200 mg/kg for “liposomal Paclitaxel”, 30 mg/kg for intravenous administration, and nearly 50 mg/kg for loading free Paclitaxel along intraperitoneal routes (Huang et al. 2018).
Emulsions are heterogeneous systems consisting of an oil phase dispersed in an aqueous phase or vice versa, and remains stabilized by emulsifiers. O/W emulsion formulations for delivering anticancer drugs tend to produce haemolytic reactions (Singh et al. 2017). The particular drug must be completely incorporated in the dispersed phase to form stable emulsions. Thus, formulating the drug as oil-water emulsions can only be possible when it can be adequately soluble in the oil phase. Paclitaxel’s O/W emulsion was possible using “triacetin” as an internal phase. Paclitaxel is greatly soluble (75 mg/ml) in triacetin. The drug precipitates when this emulsion is properly diluted, up to 9 times in 5% dextrose. Paclitaxel was first prepared containing 10-15 mg/ml Paclitaxel, in 50% triacetin, 1.5% pluronic F68, 1.5% soy-lecithin, and 2% ethyl oleate. 10% glycerol is essentially added to curb “creaming”. The system is stable for 6 months when it is stored at 4°C. However, this dose would induce antitumour activity on intravenous administration to mice. Later, O/W emulsions for Paclitaxel utilize triacylglycerols for solubilizing Paclitaxel. Mineral oils should not be used for emulsion preparation for poor solubility due to hydrocarbon structures. It is poorly soluble in Tricaprylin (C8:0), with eight carbons in the hydrocarbon chain instead of short-chain triacylglycerols like tricaproin and tributyrin. Paclitaxel concentration in an emulsion for 50% inhibition of “HeLa cells” is around 30 nM, almost similar to Paclitaxel in Diluent 12 (6 mg Paclitaxel in 1 ml of 50:50 ethanol: Cremophor EL)
The development of injectable emulsion containing Paclitaxel formulation utilizing Vitamin E as the oil phase was observed. Pre-emulsion could be prepared through the addition of α-tocopherol in PEG 400 consisting of surfactants Pluronic F-127 and TGPS, with Paclitaxel, for injection to degassed water (Kumbhar et al. 2022). It is vigorously mixed at 45°C followed by proper homogenization and sterile based filtrations through 0.2 μm posidyne filters. Tocopherol emulsions are better tolerated and is more productive than Taxol in melanoma tumour models.
Preparation of Paclitaxel consisting of biodegradable polymeric micelles utilizing low molecular weight, biodegradable, non-toxic, amphiphilic deblock polymer known as “monomethoxy poly (ethylene glycol)-block poly.” (Yadav et al. 2022). The technique of solid dispersion could prepare polymeric micelles.
Other micellar formulations could be prepared using “N-lauryl carboxymethyl-chitosan” for preparing paclitaxel micelles with particle sizes lesser than 100 nm. Paclitaxel concentration could be maintained at 2.37 mg/ml in micellar solution, recorded as cytotoxic in vitro than free Paclitaxel at lower concentrations. Paclitaxel solubilization was increased by increasing the molar ratio of “bile salt/phospholipid” and the total concentration of the lipid. When mixed micelles are not extremely stable on being hydrated, they are freeze-dried for prolonging storage stability.
Conclusion
Biomaterials have been deemed to be effective substances that could be engineered for interaction with the chosen drug Paclitaxel for inducing positive medical effects. The study has examined the therapeutic augmentation of Paclitaxel by necessitating a significant combination of the drug with various biomaterials. Nanoparticles, micelles, liposomes, prodrugs and various emulsion systems have been studied for aiding the antitumor activity of Paclitaxel. Nanoparticles are effective for inducing therapeutic effects through the mediation of drug delivery. One would be able to suffice with a lesser dosage and few side effects.
References
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