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Mol Pharm. 2017 Nov 6;14(11):3998-4007. doi: 10.1021/acs.molpharmaceut.7b00670. Epub 2017 Oct 5.

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

Author information

1
Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research , MaRS Centre, West Tower, 661 University Avenue, suite 510, Toronto, Ontario, Canada , M5G 0A3.
2
Department of Chemical and Biological Engineering, Princeton University , Princeton, New Jersey 08854, United States.
3
Faculty of Engineering and Architectural Science, Ryerson University , Toronto, Ontario, Canada , M5B 1Z2.
4
Fight Against Cancer Innovation Trust , MaRS Centre, West Tower, 661 University Avenue, suite 510, Toronto, Ontario, Canada , M5G 0A3.

Abstract

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.

KEYWORDS:

cabazitaxel; carboxymethyl cellulose; conjugated polymers; flash nanoprecipitation; nanocarrier; nanoparticle; polyethylene glycol

[Indexed for MEDLINE]

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