In vitro and in vivo degradation studies of a novel linear copolymer of lactide and ethylphosphate

Abstract

Poly(lactide-co-ethylphosphate)s, a new class of linear phosphorus-containing copolymers made by chain-extending low-molecular-weight polylactide prepolymers with ethyl dichlorophosphate, were investigated for their in vitro and in vivo degradation mechanism and kinetics. Microspheres made from poly(lactide-co-ethylphosphate) were studied under both accelerated and normal in vitro degradation conditions. Gel permeation chromatography (GPC), 1H- and 31P-NMR, weight loss measurements, and differential scanning calorimetry (DSC) techniques were used to characterize the change of molecular weight (M(w)), chemical composition, and glass transition temperature (T(g)) of the degrading polymers. The results indicated that the copolymers degraded in a two-stage fashion, with cleavage of the phosphate-lactide linkages contributing mostly to the initial more rapid degradation phase and cleavage of the lactide-lactide bonds being responsible for the slower latter stage degradation. The decrease in the copolymer M(w) was accompanied by a continuous mass loss. Results from the accelerated degradation studies confirmed that the copolymers degraded into various monomers of the copolymers, which were non-toxic and biocompatible. A two-stage hydrolysis pathway was thus proposed to explain the degradation behavior of the copolymers. In vivo degradation studies performed in mice demonstrated a good in vitro and in vivo correlation for the degradation rates. In vivo clearance of the polymer was faster and without any lag phase. These copolymers are potentially advantageous for drug delivery and other biomedical applications where rapid clearance of the polymer carrier and repeated dosing capability are essential to the success of the treatment.

Characterization of polyphosphoesters by fourier transform ion cyclotron resonance mass spectrometry

“…Species I appears to be formed as a result of hydrolysis of the phosphate-[1,4-bis(hydroxyethyl)terephthalate] bond (route 1 in Scheme 3) and the phosphate--ethoxy bond (route 2 in Scheme 3) in the PPE. Similar degradation pathways have been reported for poly(lactide-co-ethylphosphate) [22]. The peak observed at m/z 581.1436 (m/z calc 581.1424) corresponds to the loss of a water molecule from I.…”

“…Zhao and coworkers studied the in vitro and in vivo degradation of a poly(lactide-coethylphosphate) copolymer, the bulk of which was PDLA [poly(D,L-lactide)], using gel permeation chromatography, 1 H and 31 P NMR weight loss measure-ments, and differential scanning calorimetry [22]. Their results indicated a two stage degradation of the PPE: In the first (fast) stage, degradation predominantly occurs at the phosphate-lactide bonds with minor degradation at phosphate-ethoxy bonds.…”

Hydrolytic Degradation

“…As stated below, in regard to the triblock copolymer of PLLA and poly(ethylene oxide) (PEO) (abbreviated as PLLA-b-PEO-b-PLLA), the ester groups connecting PLLA and PEO rather than those connecting the lactyl units were preferentially hydrolytically degraded at an early stage. Chaubal et al [217] showed that in the NHD of poly(DLlactide)-b-poly(ethylphosphate) (PDLLA-b-PEP), the cleavage of the ethylphosphate-lactyl linkage first occurs and then Solid [17,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Solid (crystalline residues) [41,42] Solid (porous) [43] Ringer solution Solid (including fibers) [44][45][46] Simulated body fluid Solid [ [57] HCl solution, DL-lactic acid solution (pH 2.0) Solid [58] HCl solution (pH À0.9, 0.2), NaOH solution (pH 11.8, 12 Solid [190] PLLA-PCL multiblock copolymer Not specified Phosphate-buffered solution Solid [191] PLLA-b-poly(1,5-dioxepan-2-one)-b-PLLA and multiblock copolymer 37 Phosphate-buffered solution (pH 7.4) Solid [192,193] (continued ) the cleavage of the lactyl-lactyl linkage takes place. For this reason, the hydrolytic degradation of PLLA-b-PEO-b-PLLA and PDLLA-b-PEP was faster at an early stage than at a late stage.…”

Understanding the Enzymatic Degradation of Biodegradable Polymers and Strategies to Control Their Degradation Rate

“…48,86 HPLC and MS techniques have been successfully used on the isolation and identification of the degradation products of biodegradation of polyurethanes by cholesterol esterase. 50,56,57 Chaubal and coworkers 69 followed the generation of water-soluble degradation products during the in vitro degradation of a linear copolymer of lactide and ethylphosphate by NMR.…”