{"id":194,"date":"2019-03-28T19:24:32","date_gmt":"2019-03-28T19:24:32","guid":{"rendered":"https:\/\/wwwtest.pharmacy.wisc.edu\/faculty\/kwon-research-group\/?p=194"},"modified":"2025-05-27T19:47:31","modified_gmt":"2025-05-27T19:47:31","slug":"polyethylene-glycol-block-polydl-lactic-acid-micelles-containing-oligolactic-acid-8-paclitaxel-prodrug-in-vivo-conversion-and-antitumor-efficacy","status":"publish","type":"post","link":"https:\/\/wwwtest.pharmacy.wisc.edu\/faculty\/kwon-research-group\/2019\/03\/28\/polyethylene-glycol-block-polydl-lactic-acid-micelles-containing-oligolactic-acid-8-paclitaxel-prodrug-in-vivo-conversion-and-antitumor-efficacy\/","title":{"rendered":"Poly(ethylene glycol)-block-poly(d,l-lactic acid) Micelles Containing Oligo(lactic acid) 8-paclitaxel Prodrug: In Vivo Conversion and Antitumor Efficacy"},"content":{"rendered":"
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March 28, 2019<\/div>\r\nCite this<\/a>\r\n\r\n<\/div>\r\n
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Abstract<\/h2>\r\nPoly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles affect drug solubilization, and a paclitaxel (PTX) loaded-PEG-b-PLA micelle (PTX-PM) is approved for cancer treatment due to injection safety and dose escalation (Genexol-PM\u00ae) compared to Taxol\u00ae. However, PTX-PM is unstable in blood, has rapid clearance, and causes dose-limiting toxicity. We have synthesized a prodrug for PTX (7-OH), using oligo(lactic acid) as a novel pro-moiety (o(LA)8-PTX) specifically for PEG-b-PLA micelles, gaining higher loading and slower release of o(LA)8-PTX over PTX. Notably, o(LA)8-PTX prodrug converts into PTX by a backbiting reaction in vitro, without requiring esterases. We hypothesize that o(LA)8-PTX-loaded PEG-b-PLA micelles (o(LA)8-PTX-PM) has a lower Cmax\u00a0and higher plasma AUC than PTX-PM for improved therapeutic effectiveness. In Sprague-Dawley rats at 10 mg\/kg, compared to o(LA)8-PTX-PM (10% w\/w loading) and PTX-PM (10%), o(LA)8-PTX-PM (50% w\/w loading) produces a 2- and 3-fold higher plasma AUC0-24\u00a0of PTX, lactic acid-PTX, and o(LA)2-PTX (o(LA)0-2-PTX), respectively. For o(LA)8-PTX-PM at 10 and 50% w\/w loading, PTX and lactic acid-PTX are major bioactive metabolites, respectively. Fast prodrug conversion of o(LA)8-PTX in vivo versus in vitro (by backbiting) suggests that o(LA)8\u00a0is a good substrate for esterases. At 60 mg\/kg (qwx3), o(LA)8-PTX-PM (50%) has higher antitumor activity than o(LA)8-PTX-PM (10%) and PTX-PM (10%) in a syngeneic 4T1-luc breast tumor model based on measurements of tumor volume, 4T1-luc breast tumor bioluminescence, and survival. Importantly, intravenous administration of o(LA)8-PTX-PM is well tolerated by BALB\/c mice. In summary, oligo(lactic acid)8-PTX is more compatible than PTX with PEG-b-PLA micelles, more stable, and may expand the role of PEG-b-PLA micelles from \u201csolubilizer\u201d into \u201cnanocarrier\u201d for PTX as a next-generation taxane for cancer.\r\n\r\n\"image\r\n\r\n<\/div>\r\n

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