Nanoparticle Formulation Derived from Carboxymethyl Cellulose, Polyethylene Glycol, and Cabazitaxel for Chemotherapy Delivery to the Brain.

Nanoparticles provide a unique opportunity to explore the benefits of selective distribution and release of cancer therapeutics at sites of disease through varying particle sizes and compositions that exploit the enhanced permeability of tumor-associated blood vessels. Though delivery of larger as opposed to smaller and/or actively transported molecules to the brain is prima facie a challenging endeavor, we wondered whether nanoparticles could improve the therapeutic index of existing drugs for use in treating brain tumors via these vascular effects. We therefore selected a family of nanoparticles composed of cabazitaxel-carboxymethyl cellulose amphiphilic polymers to investigate the potential for delivering a brain-penetrant taxane to intracranial brain tumors in mice. Among a small set of nanoparticle formulations, we found evidence for nanoparticle accumulation in the brain, and one such formulation demonstrated activity in an orthotopic model of glioma, suggesting that such nanoparticles could be useful for the treatment of glioma and brain metastases of other tumor types.

Using Flash Nanoprecipitation To Produce Highly Potent and Stable Cellax Nanoparticles from Amphiphilic Polymers Derived from Carboxymethyl Cellulose, Polyethylene Glycol, and Cabazitaxel.

We report the use of flash nanoprecipitation (FNP) as an efficient and scalable means of producing Cellax nanoparticles. Cellax polymeric conjugates consisting of carboxymethyl cellulose functionalized with PEG and hydrophobic anticancer drugs, such as cabazitaxel (coined Cellax-CBZ), have been shown to have high potency against several oncology targets, including prostate cancer. FNP, a robust method used to create nanoparticles through rapid mixing, has been used to encapsulate several hydrophobic drugs with block copolymer stabilizers, but has never been used to form nanoparticles from random copolymers, such as Cellax-CBZ. To assess the potential of using FNP to produce Cellax nanoparticles, parameters such as concentration, mixing rate, solvent ratios, and subsequent dilution were tested with a target nanoparticle size range of 60 nm. Under optimized solvent conditions, particles were formed that underwent a subsequent rearrangement to form nanoparticles of 60 nm diameter, independent of Cellax-CBZ polymer concentration. This intraparticle relaxation, without interparticle association, points to a delicate balance of hydrophobic/hydrophilic domains on the polymer backbone. These particles were stable over time, and the random amphiphilicity did not lead to interparticle attractions, which would compromise the stability and corresponding narrow size distribution required for parenteral injection. The amphiphilic nature of these conjugates allows them to be processed into nanoparticles for sustained drug release and improved tumor selectivity. Preferred candidates were evaluated for plasma stability and cytotoxicity against the PC3 prostate cancer cell line in vitro. These parameters are important when assessing nanoparticle safety and for estimating potential efficacy, respectively. The optimal formulations showed plasma stability profiles consistent with long circulating nanoparticles, and cytotoxicity comparable to that of free CBZ. This study demonstrates that FNP is a promising technology for development of Cellax nanoparticles.

Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer's disease.

The UBITh AD immunotherapeutic vaccine for Alzheimer's disease uses an amyloid-beta (Abeta) immunogen having two designer peptides that have been engineered to elicit anti-N terminal Abeta(1-14) antibodies while minimizing potential for the generation of adverse anti-Abeta immune responses. The vaccine has been further designed for minimization of inflammatory reactivities through the use of a proprietary vaccine delivery system that biases Th2 type regulatory T cell responses in preference to Th1 pro-inflammatory T cell responses. In vitro studies and in vivo studies in small animals, baboons and macaques show that anti-Abeta antibodies are generated with the expected N-terminus site-specificity, and that these antibodies have functional immunogenicities to neutralize the toxic activity of Abeta and promote clearance of plaque deposition. The antibodies appear to draw Abeta from the CNS into peripheral circulation. Results indicate that the UBITh AD vaccine did not evoke anti-Abeta cellular responses in a transgenic mouse model for AD. The vaccine was safe and well tolerated in adult Cynomolgus macaques during a repeat dose acute and chronic toxicity study.