A majority of anti-tumor drugs are hydrophobic and require a dispersing agent or other solubilization process to facilitate their delivery. For this reason, nanotechnology can have a profound effect on the delivery of pharmaceuticals with poor bioavailability by improving their stability, circulation times in the body and permeability through cell membranes.
The principal aim of this research is to parenterally deliver therapeutic agents at high local concentrations and with physiologically appropriate timing directly to cancer cells, thereby interrupting the growth and metastasis of the tumor. We have recently developed a unique nanosphere system based on a biodegradable, non-cytotoxic polymeric architecture that provides a high degree of structural versatility for complexing and delivering a wide array of hydrophobic drugs. Our symmetrical ABA-type block copolymers consist of hydrophilic poly(ethylene glycol) A-blocks and hydrophobic polyarylate oligomers of desaminotryosyl-tyrosine esters (DTR) and diacid as the B-blocks (Figure 1). These triblock copolymers self-assemble into spherical structures with hydrodynamic diameters between 50 nm and 100 nm, thus providing particle size and surface chemical properties superior to conventional drug delivery designs. Particularly relevant to this and all nanosphere-based projects is that tyrosine-derived polyarylate technology has received FDA clearance for use in a hernia repair medical device (PIVIT™ - 2006) and a cardiac rhythm medical device anti-bacterial envelope (AIGISRX™ - 2008). Similar biocompatible properties are expected for the polyarylate-derived nanospheres.
Figure 1. A general structure of the tyrosine-derived triblock copolymers. These polymers consist of polyarylate oligomers (tyrosine dipeptide derivative and a non-toxic diacid) and PEG end blocks. By varying either the length of the diacid (XA) or the pendent chain (R) of the dipeptide (DTR), or molecular weight of PEG (n) /molecular weight of hydrophobic core (m), a large number of interrelated polymers can be obtained.
Our recent results demonstrated that paclitaxel-loaded nanosphere formulation retains high anti-tumor activity. In vitro, nanospheres significantly enhanced (6 and 13 fold) delivery of paclitaxel (PTX) to KB human uterine carcinoma cells and Sum159 breast cancer stem cell line, respectively. Further, nanospheres toxicity and anti-tumor efficacy was evaluated in in vivo preclinical studies. No significant weight loss (< 15%) and no change in vital behavior were detected when mice were inoculated with the empty nanospheres. Maximum tolerated dose (MTD) of paclitaxel administered to mice via nanospheres is significantly higher (Figure 2) compared to the MTD of clinically used paclitaxel formulation (paclitaxel-Cremaphor, TaxolTM ). Further, using an equal dose and the same schedule of administration, nanospheres-paclitaxel exhibited anti-tumor activity similar to TaxolTM in a breast cancer xenograft model.
Figure 2. Determination of MTD for PTX delivered via nanospheres and CrEL. PTX doses from 5 to 25 mg/kg are well tolerated when administered as PTX-nanospheres: mice gained weight in a linear fashion as expected during their natural growth and no change in their vital behavior was observed. PTX-CrEL doses from 15 to 25 mg/kg PTX caused a notable weight loss, visible signs of appetite loss, and stress and pain were also noted.
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Project Leader: Larisa Sheihet, PhD
Funding Source: US Army Medical Research and Materiel Command, Breast Cancer Research Program (W81XWH-06-10623) and the New Jersey Center for Biomaterials, US Department of Defense
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