Paclitaxel-loaded polymer

Lee, Y, Graeser, R., Kratz, F., Geckeler, K. E. (2011). Paclitaxel-loaded polymer nanoparticles for the reversal of multidrug resistance in breast Cancer cells. Advanced Functional Materials, 21, 4211 218. 

Liggins RT, Burt HM (2001) Paclitaxel loaded poly(L-lactic acid) microspheres properties of microspheres made with low molecular weight polymers. Int J Pharm 222 19-33... 

In vitro kinetics studies with 20-40% (w/w) paclitaxel-loaded pCPPrSA (20 80) pol3maers demonstrated sustained drug release approaching 1000 h. Biodistribution studies concordantly revealed tiunorcidal pachtaxel concentrations in the rat brain for > 30 days post-implantation. Median survival in the established rat 9L gliosarcoma model improved from 19.5 days in rats treated with blank polymers to 61.5 days with 20% paclitaxel-loaded pol3rmers (p < 0.001) (105). 

Pending completion of the canine toxicity studies and demonstration of safety, phase I-II clinical trials for pachtaxel-loaded polymer treatment of intracranial tumors are plamned. Paclitaxel in loaded polymer has already been utilized clinically for recurrent ovarian cancer. 

Li, F., Wu, H., Zhang, H., Li, F., Gu, C. h. Yang, Q. (2009). Antitumor drug Paclitaxel-loaded pH-sensitive nanoparticles targeting tumor extracellular pH. Carbohydrate Polymers, Article in Press. 

The Taxus stent by Boston Scientific uses a tri-block copolymer [poly(styrene-b-isobutylene-b-styrene)] for sustained delivery of paclitaxel. This new polymer is specifically designed for this use and has a trade name of Translute , Paclitaxel can be released at a fast or a slow rate by varying the drug loading in the polymer matrix as shown in Figure 4. 

The polymer formulations containing anticancer agents (paclitaxel and cis-platin) were evaluated in vivo in heterotrophic (mouse bladder tumor) and orphotrophic (rat prostate cancer) models. Single administration of polymer-pactlitaxel formulation intratumorally in a mouse bladder tumor model increased the survival rate of the animals compared to untreated animals and to animals treated with paclitaxel dispersion (conventional administration method) (27). The optimal load of paclitaxel in the polymer was established as 10% w/w. Mice treated with this formulation showed median survival rate (MSR) of... 

The polymer-paclitaxel formulation was also evaluated for treatment of orthotopic prostate cancer (28). Treatment with the polymer formulation of paclitaxel (single injection of 200 pi polymer formulation with 10% w/w load) increased the survival rate of the rats. Rats treated with parental formulation of paclitaxel died 25 days post tumor cells inoculation. Only one rat in the polymer-paclitaxel group died three weeks post tumor cell inoculation, while all the remaining rats survived until the end point of the experiment (35 days). The control animals also developed lymph node metastases. No metastases were found in polymer-paclitaxel treated rats. The treatment with polymer-paclitaxel formulation reduced the prostate volume of the rats from 14.8 cm (untreated animals) to 0.862 cm while the volume of healthy prostate gland injected with 200 pi of polymer is about 0.4 cm The polymeric formulation released paclitaxel into local tumor tissues and induced necrosis and reduction of the tumor mass, while prolonging lifespan in an orthotopic prostate cancer rat model. 

The solid dispersion method (Fig. 2B) was used for solubilization of paclitaxel into PEG-poly(D,L-lactide) diblock copolymer micelles. Paclitaxel and the polymer were dissolved in acetonitrile followed by evaporation of the solvent under a stream of nitrogen at 60°C to obtain a gel-like polymer-drug matrix. Dissolution of the solid matrix in water at about 60° C with stirring led to formation of drug-loaded micelles. Because a heating is needed to completely dissolve the polymer-drug matrix, this method may not be not desirable for thermally unstable drugs. 

Hydrophobically modified glycol chitosan (HGC) with 5p cholanic acid has been extensively studied both in vitro and in vivo. This polymer was developed as a new Cremophor EL-free alternative carrier systems for docetaxel [74] and paclitaxel. Physical characteristics of the nanoparticules such as size, hydrophobic core, and stability depend on the degree of 5-p cholanic acid substitution. The maximum loading content of paclitaxel into HGC nanoparticles was 10 wt% and the loading efficiency was above 90% [120]. Cytotoxicity studies on MCF7 breast cancer cells showed that HGC nanoparticles were less toxic than Cremophor EL, and allowed a higher dose of paclitaxel administration. The survival rate of mice that received 50 mg/kg paclitaxel in HGC nanoparticles increased substantially compared to 20 mg/kg PTX in Cremophor EL-ethanol solutions [120]. 

The initial burst effect followed by the sustained release of paclitaxel from these polymers does not appear to be associated with the polyacrylate or the hard block polymers at a 25% loading, but there may be some effect at lower percentage loadings. 

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