Nanoparticles of Biodegradable Polymers for Clinical Administration of Paclitaxel

Abstract

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 Kaposi's 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.

Drug transport to brain with targeted nanoparticles

“…Various kinds of conventional drugs were formulated as PLA, PLGA, or mPEG-PLA nanoparticles. Examples are savoxepine, 84 doxorubicin, 85 irinotecan, 86 paclitaxel, 87,88 antiestrogen RU58668, 89 tyrphostin AG-1295, 90 lidocaine, 91 propranolol hydrochloride, 92 heparin, 93 and enalaprilat. 94 Basically, drug entrapment efficiency depends on the solid-state drug solubility in PLA/PLGA polymer (solid dissolution or dispersion), which is related to the polymer composition (lactic/glycolic ratio), the molecular weight, the drugpolymer interaction and the presence of end-functional groups (ester or carboxyl).…”

“…Drug entrapment efficiency can reach more than 80% 84,92,91 and drug content up to 50%. 91 In most cases, however, drug contents are 5-10% (wt/wt) of nanoparticle weights 86,88,94,96,97,102 or even less. 87 Therefore, when formulating drug nanoparticles, it should always be kept in mind that generally as high as 90% of the material to be administered will likely be nanoparticle excipients with their potential toxicity.…”

“…103 Depending on formulations in vitro, drug releases last from a few hours 84,91,92 or a few days 87 to several weeks. 61,84,88,90 Administered locally, betamethasone sodium phosphateloaded PLGA nanoparticles were efficient at controlling inflammation over at least 3 weeks in a rabbit model of arthritis, compared with one day for the solution. 61 Peptides, polypeptides, and protein drugs.…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Another example of a nanomaterial-based drugs now available for disease treatment is albumin-bound paclitaxel [114]. In addition, nanoparticles made of poly(D,L,lactide-co-glycolide) (PLGA) and other biodegradables have the potential to enhance delivery of drugs, genes, and vaccines to combat disease [115].…”

Identification of differential gene expression between intestinal and diffuse gastric cancer using cDNA microarray

“…The down-regulation in expression of the cytoskeleton-related genes, tubulin ·6 and tubulin ß5, was unexpected because tubulin was a chemotherapeutic target. The taxanes, paclitaxel and docetaxel, which act on microtubules to arrest mitosis, were the best antineoplastic drugs 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 Kaposi's sarcoma (44). The identification of down-regulated expression in MMP-2 and MMP-10 was unexpected because one would expect the MMP genes to be overexpressed in tumor cells, especially in metastastic tumor cells (45).…”