Monday, June 22, 2015

Increased efficacy of PEG-P(DL)La over PEG-PLLA for nanoparticle paclitaxel delivery to tumors

PolySciTech ( division of Akina, Inc. provides a wide array of biodegradable block copolymers including mPEG-P(DL)La and mPEG-P(L)La. Recently a report from the University of Utah compared these two related polymers in terms of their efficacy for use as nanoparticle carriers of paclitaxel (PTX, a chemotherapeutic agent) to pancreatic tumors. For this they used PolyVivo AK09 from Polyscitech for the mPEG-P(DL)La test polymer. Poly(lactide) is commonly available in two forms. The ‘L’ and the ‘D’ are references to the chirality, or molecular arrangement, of the side methyl units of the poly-lactide chain relative to the main branch. For the enantiomerically pure poly-L-lactide, all the methyl units are aligned on the same side so the polymer chains tend to stack into crystalline forms. For the racemic poly-DL-lactide, the methyl units are randomly aligned and as such the polymer chains tend to be amorphously aggregated rather than crystalized to each other. This is a relatively minor difference in chemistry, but an interesting result from the recent research paper is that it does matter quite a bit in terms of drug delivery and, for this application, the amorphous P(DL)La form has advantages over the crystalline PLLA form. Read more: Gupta, Roohi, Jill Shea, Courtney Scafe, Anna Shurlygina, and Natalya Rapoport. "Polymeric Micelles and nanoemulsions as drug carriers: Therapeutic efficacy, toxicity, and drug resistance." Journal of Controlled Release (2015).

“Abstract: The manuscript reports the side-by-side comparison of therapeutic properties of polymeric micelles and nanoemulsions generated from micelles. The effect of the structure of a hydrophobic block of block copolymer on the therapeutic efficacy, tumor recurrence, and development of drug resistance was studied in pancreatic tumor bearing mice. Mice were treated with paclitaxel (PTX) loaded poly(ethylene oxide)-co-polylactide micelles or corresponding perfluorocarbon nanoemulsions. Two structures of the polylactide block differing in a physical state of micelle cores or corresponding nanodroplet shells were compared. Poly(ethylene oxide)-co-poly(D,L-lactide) (PEG-PDLA) formed micelles with elastic amorphous cores while poly(ethylene oxide)-co-poly(L-lactide) (PEG-PLLA) formed micelles with solid crystalline cores. Micelles and nanoemulsions stabilized with PEG-PDLA copolymer manifested higher therapeutic efficacy than those formed with PEG-PLLA copolymer studied earlier. Better performance of PEG-PDLA micelles and nanodroplets was attributed to the elastic physical state of micelle cores (or droplet shells) allowing adequate rate of drug release via drug diffusion and/or copolymer biodegradation. The biodegradation of PEG-PDLA stabilized nanoemulsions was monitored by the ultrasonography of nanodroplets injected directly into the tumor; the PEG-PDLA stabilized nanodroplets disappeared from the injection site within 48 hours. In contrast, nanodroplets stabilized with PEG-PLLA copolymer were preserved at the injection site for weeks and months indicating extremely slow biodegradation of solid PLLA blocks. Multiple injections of PTX-loaded PEG-PDLA micelles or nanoemulsions to pancreatic tumor bearing mice resulted in complete tumor resolution. Two of ten tumors treated with either PEG-PDLA micellar or nanoemulsion formulation recurred after the completion of treatment but proved sensitive to the second treatment cycle indicating that drug resistance has not been developed. This is in contrast to the treatment with PEG-PLLA micelles or nanoemulsions where all resolved tumors quickly recurred after the completion of treatment and proved resistant to the repeated treatment. The prevention of drug resistance in tumors treated with PEG-PDLA stabilized formulations was attributed to the presence and preventive effect of copolymer unimers that were in equilibrium with PEG-PDLA micelles. PEG-PDLA stabilized nanoemulsions manifested lower hematological toxicity than corresponding micelles suggesting higher drug retention in circulation. Summarizing, micelles with elastic cores appear preferable to those with solid cores as drug carriers. Micelles with elastic cores and corresponding nanoemulsions both manifest high therapeutic efficacy, with nanoemulsions exerting lower systemic toxicity than micelles. The presence of a small fraction of micelles with elastic cores in nanoemulsion formulations is desirable for prevention of the development of drug resistance. Keywords: Polymeric micelles; nanoemulsions; paclitaxel; tumor recurrence; drug resistance; hematological toxicity; poly(ethylene oxide)-co-poly(L-lactide); poly(ethylene oxide)-co-poly(D,L-lactide)”

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