title: Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy.
abstract: Endosomal pH-activatable paclitaxel (PTX) prodrug micellar nanoparticles were designed and prepared by conjugating PTX onto water-soluble poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acid-labile acetal bond to the PAA block and investigated for potent growth inhibition of human cancer cells in vitro. PTX was readily conjugated to PEG-PAA with high drug contents of 21.6, 27.0, and 42.8 wt % (denoted as PTX prodrugs 1, 2, and 3, respectively) using ethyl glycol vinyl ether (EGVE) as a linker. The resulting PTX conjugates had defined molecular weights and self-assembled in phosphate buffer (PB, pH 7.4, 10 mM) into monodisperse micellar nanoparticles with average sizes of 158.3-180.3 nm depending on PTX contents. The in vitro release studies showed that drug release from PTX prodrug nanoparticles was highly pH-dependent, in which ca. 86.9%, 66.4% and 29.0% of PTX was released from PTX prodrug 3 at 37 °C in 48 h at pH 5.0, 6.0, and pH 7.4, respectively. MTT assays showed that these pH-sensitive PTX prodrug nanoparticles exhibited high antitumor effect to KB and HeLa cells (IC(50) = 0.18 and 0.9 μg PTX equiv/mL, respectively) as well as PTX-resistant A549 cells. Notably, folate-decorated PTX prodrug micellar nanoparticles based on PTX prodrug 3 and 20 wt % folate-poly(ethylene glycol)-b-poly(D,L-lactide) (FA-PEG-PLA) displayed apparent targetability to folate receptor-overexpressing KB cells with IC(50) over 12 times lower than nontargeting PTX prodrug 3 under otherwise the same conditions. Furthermore, PTX prodrug nanoparticles could also load doxorubicin (DOX) to simultaneously release PTX and DOX under mildly acidic pH. These acetal-linked PTX prodrug micellar nanoparticles have appeared as a highly versatile and potent platform for cancer therapy.
authors.affiliation: Biomedical Polymers Laboratory, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, PR China.
authors.forename: Yudan
authors.initials: Y
authors.lastname: Gu
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhong
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000080:Acetals / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008823:Micelles; D053769:Nanocapsules / Q000737:chemistry*; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000080:Acetals; D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D053769:Nanocapsules; D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; D017239:Paclitaxel