A Novel Micellar PEGylated Hyperbranched Polyester as a Prospective Drug Delivery System for Paclitaxel (original) (raw)

2008, Macromolecular Bioscience

A hyperbranched aliphatic polyester has been functionalized with PEG chains to afford a novel water-soluble BH40-PEG polymer which exhibits unimolecular micellar properties, and is therefore appropriate for application as a drug-delivery system. The solubility of the anticancer drug paclitaxel was enhanced by a factor of 35, 110, 230, and 355 in aqueous solutions of BH40-PEG of 10, 30, 60, and 90 mg Á mL À1 , respectively. More than 50% of the drug is released at a steady rate and release is almost complete within 10 h. The toxicity of BH40-PEG was assessed in vitro with A549 human lung carcinoma cells and found to be nontoxic for 3 h incubation up to a 1.75 mg Á mL À1 concentration while LD 50 was 3.5 mg Á mL À1. Finally, it was efficiently internalized in cells, primarily in the absence of foetal bovine serum, while confocal microscopy revealed the preferential localization of the compound in cell nuclei. Paclitaxel is a microtubule stabilizing agent and a chemotherapeutic agent that has shown substantial clinical efficacy for ovarian, breast, colon, head and neck, and non-small cell lung cancers. [50,51] In its commercial form, paclitaxel is formulated as a 1:1 mixture of Cremophor EL, a polyethoxylated castor oil, and ethanol, which is diluted in normal saline or dextrose solution to a final paclitaxel concentration of 5% for administration. [52] This formulation can even cause hypersensitivity reactions mainly because of the cytotoxicity of the amphiphilic compounds and the organic solvent. [53] Therefore, several attempts have been made to increase the poor paclitaxel solubility (0.3 mg Á mL À1) using various formulations [54-60] or prodrug conjugates. [61,62] It is our intention to develop alternative paclitaxel delivery vehicles by the use of biodegradable unimolecular micelles and extend this investigation (work in progress) by preparing hyperbranched polymers of varying degrees of PEGylation in an attempt to find the optimum loading. This PEGylation process coupled with the introduction of targeting ligands [63,64] and molecular transporting moieties, [65,66] will render the systems more effective drug-delivery systems compared with the one described, for the first time, in this manuscript. The work involved is extremely broad to be covered in one publication. The scope of the present manuscript is to present our initial albeit quite promising results.