Dataset Information

Plasma Stability and Plasma Metabolite Concentration-Time Profiles of Oligo(Lactic Acid)₈-Paclitaxel Prodrug Loaded Polymeric Micelles.

ABSTRACT: Paclitaxel (PTX) is a frequently prescribed chemotherapy drug used to treat a wide variety of solid tumors. Oligo(lactic acid)₈-PTX prodrug (o(LA)₈-PTX) loaded poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles have higher loading, slower release and higher antitumor efficacy in murine tumor models over PTX-loaded PEG-b-PLA micelles. The goal of this work is to study plasma stability of o(LA)₈-PTX-loaded PEG-b-PLA micelles and its pharmacokinetics after IV injection in rats. In rat plasma, o(LA)₈-PTX prodrug is metabolized into o(LA)₁-PTX and PTX. In human plasma, o(LA)₈-PTX is metabolized more slowly into o(LA)₂-PTX, o(LA)₁-PTX, and PTX. After IV injection of 10 mg/kg PTX-equiv of o(LA)₈-PTX prodrug loaded PEG-b-PLA micelles in Sprague-Dawley rats, metabolite abundance in plasma follows the order: o(LA)₁-PTX > o(LA)₂-PTX > o(LA)₄-PTX > o(LA)₆-PTX. Bile metabolite profiles of the o(LA)₈-PTX prodrug is similar to plasma metabolite profiles. In comparison to equivalent doses of Abraxane®, plasma PTX exposure is two orders of magnitude higher for Abraxane® than PTX from o(LA)₈-PTX prodrug loaded PEG-b-PLA micelles, and plasma o(LA)₁-PTX exposure is fivefold higher than PTX from Abraxane®, demonstrating heightened plasma metabolite exposure for enhanced antitumor efficacy.

SUBMITTER: Repp L

PROVIDER: S-EPMC10141660 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Plasma Stability and Plasma Metabolite Concentration-Time Profiles of Oligo(Lactic Acid)8-Paclitaxel Prodrug Loaded Polymeric Micelles.

Repp Lauren L Skoczen Sarah L SL Rasoulianboroujeni Morteza M Stern Stephan T ST Kwon Glen S GS

The AAPS journal 20230411 3

Paclitaxel (PTX) is a frequently prescribed chemotherapy drug used to treat a wide variety of solid tumors. Oligo(lactic acid)8-PTX prodrug (o(LA)8-PTX) loaded poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles have higher loading, slower release and higher antitumor efficacy in murine tumor models over PTX-loaded PEG-b-PLA micelles. The goal of this work is to study plasma stability of o(LA)8-PTX-loaded PEG-b-PLA micelles and its pharmacokinetics aft ...[more]

PMID: 37041376

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Project description:BackgroundThe prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy.MethodsAmphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo.ResultsFibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC.ConclusionTPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC.

Dataset Information

Plasma Stability and Plasma Metabolite Concentration-Time Profiles of Oligo(Lactic Acid)₈-Paclitaxel Prodrug Loaded Polymeric Micelles.

Publications

Plasma Stability and Plasma Metabolite Concentration-Time Profiles of Oligo(Lactic Acid)<sub>8</sub>-Paclitaxel Prodrug Loaded Polymeric Micelles.

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