Thursday, July 14, 2016

PEG-PLA and oligomeric PLA used for paclitaxel delivery

PolySciTech division of Akina, Inc. (www.polyscitech.com) provides a wide array of biodegradable research products including short-chain PLA and PEG-PLA copolymers. Recently, researchers at the University of Wisconsin-Madison conjugated short-chain PLA to paclitaxel in order to form a prodrug (e.g. a molecule which degrades in the human body to generate a medicinal molecule). Subsequently, they loaded this prodrug into PEG-PLA nanocarriers. This system was tested in mice and it was found that the tumors (A549 human lung cancer) actually shrunk and regressed wheras loose PTX only served to only delay tumor growth. This research holds promise for improved chemotherapeutic outcomes. Read more: Tam, Yu Tong, Jieming Gao, and Glen S. Kwon. "Oligo (lactic acid) n-paclitaxel prodrugs for poly (ethylene glycol)-block-poly (lactic acid) micelles: Loading, release and backbiting conversion for anticancer activity." Journal of the American Chemical Society (2016). http://pubs.acs.org/doi/abs/10.1021/jacs.6b03995

“Poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles are nanocarriers for poorly water-soluble anticancer agents and have advanced paclitaxel (PTX) to humans due to drug solubilization, biocompatibility, and dose escalation. However, PEG-b-PLA micelles rapidly release PTX, resulting in widespread biodistribution and low tumor exposure. To improve delivery of PTX by PEG-b-PLA micelles, monodisperse oligo(l-lactic acid), o(LA)8 or o(LA)16, has been coupled onto PTX at the 7-OH position, forming ester prodrugs: o(LA)8-PTX and o(LA)16-PTX, respectively. As expected, o(LA)n-PTX was more compatible with PEG-b-PLA micelles than PTX, increasing drug loading from 11 to 54%. While in vitro release of PTX was rapid, resulting in precipitation, o(LA)n-PTX release was more gradual: t1/2 = 14 and 26 h for o(LA)8-PTX and o(LA)16-PTX, respectively. Notably, o(LA)8-PTX and o(LA)16-PTX in PEG-b-PLA micelles resisted backbiting chain end scission, based on reverse-phase HPLC analysis. By contrast, o(LA)8-PTX and o(LA)16-PTX degraded substantially in 1:1 acetonitrile:10 mM PBS, pH 7.4, at 37 °C, generating primarily o(LA)2-PTX. The IC50 value of o(LA)2-PTX was 2.3 nM for A549 human lung cancer cells, equipotent with PTX in vitro. After weekly IV injections at 20 mg/kg as PEG-b-PLA micelles, o(LA)8-PTX induced tumor regression in A549 tumor-bearing mice, whereas PTX delayed tumor growth. Surprisingly, o(LA)8-PTX caused less toxicity than PTX in terms of change in body weight. In conclusion, o(LA)n acts as a novel promoiety, undergoing backbiting conversion without a reliance on metabolizing enzymes, and o(LA)n-PTX improves PTX delivery by PEG-b-PLA micelles, providing a strong justification for clinical evaluation.”


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