title: Poly(ethylene oxide)-block-polyphosphoester-graft-paclitaxel conjugates with acid-labile linkages as a pH-sensitive and functional nanoscopic platform for paclitaxel delivery.
abstract: There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile poly(ethylene oxide)-block-polyphosphoester-graft-PTX drug conjugate (PEO-b-PPE-g-PTX G2) degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading is improved significantly, in this second-generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive β-thiopropionate linkage. The PEO-b-PPE-g-PTX G2 forms well-defined nanoparticles in an aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 114 ± 31 nm, and exhibits a PTX loading capacity as high as 53 wt%, with a maximum PTX concentration of 0.68 mg mL(-1) in water (vs 1.7 μg mL(-1) for free PTX). The PEO-b-PPE-g-PTX G2 shows accelerated drug release under acidic conditions (≈50 wt% PTX released in 8 d) compared with neutral conditions (≈20 wt% PTX released in 8 d). Compared to previously reported polyphosphoester-based PTX drug conjugates, PEO-b-PPE-g-PTX G1 without the β-thiopropionate linker, the PEO-b-PPE-g-PTX G2 shows pH-triggered drug release property and 5- to 8-fold enhanced in vitro cytotoxicity against two cancer cell lines.
authors.affiliation: Departments of Chemistry and Chemical Engineering, Laboratory for Synthetic-Biologic Interactions, Texas A&M University, P.O. Box 30012, 3255 TAMU, College Station, TX, 77842, USA.
authors.forename: Jiong
authors.initials: J
authors.lastname: Zou
authors.forename: Fuwu
authors.initials: F
authors.lastname: Zhang
authors.forename: Shiyi
authors.initials: S
authors.lastname: Zhang
authors.forename: Stephanie F
authors.initials: SF
authors.lastname: Pollack
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Elsabahy
authors.forename: Jingwei
authors.initials: J
authors.lastname: Fan
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wooley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010755:Organophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D010755:Organophosphates; D011108:Polymers; C000592762:poly(ethylene oxide)-block-polyphosphoester-graft-paclitaxel; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: pH-triggered release; paclitaxel; polymer-drug conjugates; polyphosphoester; thiol-ene