Si-Shen Feng

A novel controlled release formulation for the anticancer drug paclitaxel (Taxol®): PLGA nanoparticles containing vitamin E TPGS

Paclitaxel (Taxol) is one of the best antineoplastic drugs found from nature in the past decades. Like many other anticancer drugs, there are difficulties in its clinical administration due to its poor solubility. Therefore an adjuvant called Cremophor EL has to be employed, but this has been found to cause serious side-effects. However, nanoparticles of biodegradable polymers can provide an ideal solution to the adjuvant problem and realise a controlled and targeted delivery of the drug with better efficacy and fewer side-effects. The present research proposes a novel formulation for fabrication of nanoparticles of biodegradable polymers containing d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) to replace the current method of clinical administration and, with further modification, to provide an innovative solution for oral chemotherapy. In the modified solvent extraction/evaporation technique employed in this research, the emulsifier/stabiliser/additive and the matrix material can play a key role in determining the morphological, physicochemical and pharmaceutical properties of the produced nanoparticles. We found that vitamin E TPGS could be a novel surfactant as well as a matrix material when blended with other biodegradable polymers. The nanoparticles composed of various formulations and manufactured under various conditions were characterised by laser light scattering (LLS) for size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray photoelectron spectroscopy (XPS) for surface chemistry and differential scanning calorimetry (DSC) for thermogram properties. The drug encapsulation efficiency (EE) and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC). It was concluded that vitamin E TPGS has great advantages for the manufacture of polymeric nanoparticles for controlled release of paclitaxel and other anti-cancer drugs. Nanoparticles of nanometer size with narrow distribution can be obtained. A drug encapsulation efficiency as high as 100% can be achieved and the release kinetics can be controlled.

Effects of emulsifiers on the controlled release of paclitaxel (Taxol®) from nanospheres of biodegradable polymers

Paclitaxel (Taxol) is an antineoplastic drug effective for various cancers especially ovarian and breast cancer. Due to its high hydrophobicity, however, an adjuvant such as Cremophor EL has to be used in its clinical administration, which causes serious side-effects. Nanospheres of biodegradable polymers could be an ideal solution. This study investigates the effects of various emulsifiers on the physical/chemical properties and release kinetics of paclitaxel loaded nanospheres fabricated by the solvent extraction/evaporation technique. It is shown that phospholipids could be a novel type of emulsifiers. The nanospheres manufactured with various emulsifiers were characterized by laser light scattering for their size and size distribution; scanning electron microscopy (SEM) and atomic force microscopy (AFM) for their surface morphology; zeta potential analyser for their surface charge; and, most importantly, X-ray photoelectron spectroscopy (XPS) for their surface chemistry. The encapsulation efficiency and in vitro release profile were measured by high performance liquid chromatography (HPLC). It is found that dipalmitoyl-phosphatidylcholine (DPPC) can provide more complete coating on the surface of the products which thus results in a higher emulsifying efficiency compared with polyvinyl alcohol (PVA). Our result shows that the chain length and unsaturation of the lipids have a significant influence on the emulsifying efficiency. Phospholipids with short and saturated chains have excellent emulsifying effects.

Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol®)

The D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was applied in the present investigation as surfactant stabiliser to fabricate paclitaxel-loaded PLGA nanospheres in the solvent evaporation/extraction technique with successful achievement. Laser light scattering system (LLS), scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) were employed to characterise the nanopsheres fabricated in various recipes under various preparation conditions for size and size distribution, surface morphology, thermogram property and surface chemistry. Encapsulation efficiency and in vitro release was measured by the high-performance liquid chromatography (HPLC). The outcomes were discussed with respect to the development of polymeric nanospheres delivery system of the anticancer drug, paclitaxel (Taxol((R))). The produced nanospheres were found in fine spherical shape with smooth surfaces and without aggregation or adhesion. There was no significant difference in morphology between the vitamin E TPGS emulsified and PVA emulsified PLGA nanospheres. However, it was found that, in comparison with the traditional chemical emulsifier PVA, the TPGS could significantly improve the encapsulation efficiency of the drug in the PLGA nanospheres, which could be as high as 100%. The size of the vitamin E TPGS emulsified nanospheres ranged from 300 to 800 nm and the size distribution was narrow with polydispersity of 0.005-0.045. XPS investigation demonstrated that there were residual surfactant molecules remained on the surface although the TPGS could be washed out relatively thoroughly in the process of nanospheres formation. This finding was also confirmed by FTIR-PAS investigation of the nanospheres. The in vitro release indicated that the release property of paclitaxel from the nanospheres strongly depends on the emulsifier type employed in the fabrication. Our research shows that vitamin E TPGS could be an ideal and effective emulsifier.

Nanoparticles of biodegradable polymers for clinical administration of paclitaxel.

Paclitaxel is one of the best antineoplastic drugs found from nature in the past decades, which has been found effective against a wide spectrum of cancers including ovarian cancer, breast cancer, small and non small cell lung cancer, colon cancer, head and neck cancer, multiple myeloma, melanoma, and Kaposis sarcoma. Like many other anticancer drugs, it has difficulties in clinical administration due to its poor solubility in water and most pharmaceutical reagents. In its current clinical application, an adjuvant called Cremophor EL has to be employed, which has been found to be responsible for many serious side effects. Nanoparticles of biodegradable polymers can provide an ideal solution to such an adjuvant problem and realize a controlled and targeted delivery of the drug with better efficacy and less side effects. With further development, such as particle size optimization and surface coating, nanoparticle formulation of paclitaxel can promote a new concept of chemotherapy to realize its full efficacy and to improve quality of life of the patients, which includes personalized chemotherapy, local chemotherapy, sustained chemotherapy, oral chemotherapy, chemotherapy across the blood-brain barrier, chemotherapy across the microcirculation barrier, etc. The present research proposes a novel formulation for fabrication of nanoparticles of poly(lactic-co-glycolic acid) (PLGA) by a modified solvent extraction/evaporation technique, in which natural emulsifiers, such as phospholipids, cholesterol and vitamin E TPGS are creatively applied to achieve high drug encapsulation efficiency, desired drug released kinetics, high cell uptake and high cytotoxicity. The nanoparticles composed of various recipes and manufactured under various conditions were characterized by laser light scattering (LLS) for size and size distribution, scanning electron microscopy (SEM) and atomic force microscopy (AFM) for morphological properties, X-ray photoelectron spectroscopy (XPS) and Fourier Transformation Infrared Spectroscopy (FTIR) for surface chemistry, zeta-potential for surface charge, and differential scanning calorimetry (DSC) for the thermogram properties. The drug encapsulation efficiency and the drug release kinetics under in vitro conditions were measured by high performance liquid chromatography (HPLC). It was found that these natural emulsifiers have great advantages for nanoparticle formulation of paclitaxel over the traditional macromolecular emulsifiers, such as polyvinyl alcohol (PVA). Nanoparticles of desired small size and narrow size distribution can be obtained. The drug encapsulation efficiency can be achieved as high as 100 %. The released kinetics can be made under control. The HT-29 cancer cell line experiment showed that after 24 hours of incubation, the cell mortality caused by the drug administered by such nanoparticle formulation could be more than 13 times higher than that caused by the free drug under similar conditions.

Vitamin E TPGS as a molecular biomaterial for drug delivery.

D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers for drug delivery, including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration (CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drug delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance (MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we briefly discuss its physicochemical and pharmaceutical properties and its wide applications in composition of the various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.

Preparation and characterization of poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel

Microspheres of a new kind of copolymer, poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA), are proposed in the present work for clinical administration of an antineoplastic drug paclitaxel with hypothesis that incorporation of a hydrophilic PEG segment within the hydrophobic PLA might facilitate the paclitaxel release. Paclitaxel-loaded PLA-PEG-PLA microspheres of various compositions were prepared by the solvent extraction/evaporation method. Characterization of the microspheres was then followed to examine the particle size and size distribution, the drug encapsulation efficiency, the colloidal stability, the surface chemistry, the surface and internal morphology, the drug physical state and its in vitro release behavior. The effects of polymer types, solvents and drug loading were investigated. It was found that in the microspheres the PEG segment was homogeneously distributed and caused porosity. Significantly faster release from PLA-PEG-PLA microspheres resulted in comparison with the PLGA counterpart. Incorporation of water-soluble solvent acetone in the organic solvent phase further increased the porosity of the PLA-PEG-PLA microspheres and facilitated the drug release. A total of 49.6% sustained release of paclitaxel within 1 month was achieved. Potentially, the presence of PEG on the surface of PLA-PEG-PLA microspheres could improve their biocompatibility. PLA-PEG-PLA microspheres could thus be promising for the clinical administration of highly hydrophobic antineoplastic drugs such as paclitaxel.

Fabrication, characterization and in vitro release of paclitaxel (Taxol®) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers

Spray dry technique was applied to produce paclitaxel loaded microspheres of biodegradable poly (lactic-co-glycolic acid) (PLGA) as an alternative delivery system. Various emulsifiers such as L-alpha-dipalmitoyl-phosphatidylcholine (DPPC), cholesterol, polyvinyl alcohol (PVA), gelatin were incorporated in order to achieve high encapsulating efficiency of paclitaxel in the microspheres and desired properties for a sustained release. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) showed that the surface of the microspheres with high ratio of lipid was spherical and smooth. Those made with other emulsifiers had rougher surface with pores. Incorporation of lipid, cholesterol or gelatin can significantly increase the drug content in the microspheres. The differential scanning calorimetry (DSC) result indicated that the paclitaxel trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. The zeta potential of the microspheres was negative in general and was strongly influenced by the type of the emulsifiers used in fabrication. The system formulated with cholesterol was most stable. The release profiles of various formulations with PVA, gelatin as well as low ratio of DPPC showed almost zero-order release kinetics in the first 3 weeks after an initial burst less than 5% in the first day. The release rate then gradually decreased. The microspheres fabricated with high ratio of DPPC exhibited large initial burst. When cholesterol was combined together with DPPC as an emulsifier, the release became faster.

Nanotheranostics ˗ Application and Further Development of Nanomedicine Strategies for Advanced Theranostics

Nanotheranostics is to apply and further develop nanomedicine strategies for advanced theranostics. This review summarizes the various nanocarriers developed so far in the literature for nanotheranostics, which include polymer conjugations, dendrimers, micelles, liposomes, metal and inorganic nanoparticles, carbon nanotubes, and nanoparticles of biodegradable polymers for sustained, controlled and targeted co-delivery of diagnostic and therapeutic agents for better theranostic effects with fewer side effects. The theranostic nanomedicine can achieve systemic circulation, evade host defenses and deliver the drug and diagnostic agents at the targeted site to diagnose and treat the disease at cellular and molecular level. The therapeutic and diagnostic agents are formulated in nanomedicine as a single theranostic platform, which can then be further conjugated to biological ligand for targeting. Nanotheranostics can also promote stimuli-responsive release, synergetic and combinatory therapy, siRNA co-delivery, multimodality therapies, oral delivery, delivery across the blood-brain barrier as well as escape from intracellular autophagy. The fruition of nanotheranostics will be able to provide personalized therapy with bright prognosis, which makes even the fatal diseases curable or at least treatable at the earliest stage.

Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel.

Four systems of nanoparticles of biodegradable polymers were developed in this research for oral delivery of anticancer drugs with Docetaxel used as a model drug, which include the poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), the poly(lactide)-vitamin E TPGS nanoparticles (PLA-TPGS NPs), the poly(lactic-co-glycolic acid)-montmorillonite nanoparticles (PLGA/MMT NPs) and the poly(lactide)-vitamin E TPGS/montmorillonite nanoparticles (PLA-TPGS/MMT NPs). Vitamin E TPGS stands for d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), which is a water-soluble derivative of natural vitamin E formed by esterification of vitamin E succinate with polyethylene glycol (PEG) 1000. The design was made to take advantages of TPGS in nanoparticle technology such as high emulsification effects and high drug encapsulation efficiency, and those in drug formulation such as high cellular adhesion and adsorption. MMT of similar effects is also a detoxifier, which may cure some side effects caused by the formulated drug. The drug-loaded NPs were prepared by a modified solvent extraction/evaporation method and then characterized for their MMT content, size and size distribution, surface charge and morphology, physical status and encapsulation efficiency of the drug in the NPs, and in vitro drug release profile. Cellular uptake of the coumarin 6-loaded NPs was investigated. In vitro cancer cell viability experiment showed that judged by IC(50), the PLA-TPGS/MMT NP formulation was found 2.89, 3.98, 2.12-fold more effective and the PLA-TPGS NP formulation could be 1.774, 2.58, 1.58-fold more effective than the Taxotere((R)) after 24, 48, 72h treatment, respectively. In vivo PK experiment with SD rats showed that oral administration of the PLA-TPGS/MMT NP formulation and the PLA-TPGS NP formulation could achieve 26.4 and 20.6 times longer half-life respectively than i.v. administration of Taxotere((R)) at the same 10mg/kg dose. One dose oral administration of the NP formulations could realize almost 3 week sustained chemotherapy in comparison of 22h of i.v. administration of Taxotere((R)). The oral bioavailability can be enhanced from 3.59% for Taxotere((R)) to 78% for the PLA-TPGS/MMT NP formulation and 91% for the PLA-TPGS NP formulation respectively. Oral chemotherapy by nanoparticles of biodegradable polymers is feasible.

Folic acid conjugated nanoparticles of mixed lipid monolayer shell and biodegradable polymer core for targeted delivery of Docetaxel.

A system of nanoparticles of mixed lipid monolayer shell and biodegradable polymer core was developed for targeted delivery of anticancer drugs with Docetaxel as a model drug, which provide targeting versatility with a quantitative control of the targeting effect by adjusting the lipid component ratio of the mixed lipid monolayer, and combine the advantages and avoid disadvantages of polymeric nanoparticles and liposomes in drug delivery. X-ray photoelectron spectroscopy (XPS) confirmed the coating of the mixed lipid monolayer on the polymeric core. Fluorescent microscopy proved the targeting efficacy of the folic acid conjugated on the mixed lipid monolayer for the cancer cells of over expression of folate receptors. The folic acid conjugated nanoparticles of mixed lipid monolayer shell and biodegradable polymer core were proved to possess sustainable, controlled and targeted delivery of anticancer drugs with Docetaxel as a model drug, which may provide a drug delivery system of precise control of the targeting effect.