title: The nature of peptide interactions with acid end-group PLGAs and facile aqueous-based microencapsulation of therapeutic peptides.
abstract: An important poorly understood phenomenon in controlled-release depots involves the strong interaction between common cationic peptides and low Mw free acid end-group poly(lactic-co-glycolic acids) (PLGAs) used to achieve continuous peptide release kinetics. The kinetics of peptide sorption to PLGA was examined by incubating peptide solutions of 0.2-4mM octreotide or leuprolide acetate salts in a 0.1M HEPES buffer, pH7.4, with polymer particles or films at 4-37°C for 24h. The extent of absorption/loading of peptides in PLGA particles/films was assayed by two-phase extraction and amino acid analysis. Confocal Raman microspectroscopy, stimulated Raman scattering (SRS) and laser scanning confocal imaging, and microtome sectioning techniques were used to examine peptide penetration into the polymer phase. The release of sorbed peptide from leuprolide-PLGA particles was evaluated both in vitro (PBST+0.02% sodium azide, 37°C) and in vivo (male Sprague-Dawley rats). We found that when the PLGA-COOH chains are sufficiently mobilized, therapeutic peptides not only bind at the surface, a common belief to date, but also can be internalized and distributed throughout the polymer phase at physiological temperature forming a salt with low-molecular weight PLGA-COOH. Importantly, absorption of leuprolide into low MW PLGA-COOH particles yielded ~17 wt.% leuprolide loading in the polymer (i.e., ~70% of PLGA-COOH acids occupied), and the absorbed peptide was released from the polymer for >2 weeks in a controlled fashion in vitro and as indicated by sustained testosterone suppression in male Sprague-Dawley rats. This new approach, which bypasses the traditional encapsulation method and associated production cost, opens up the potential for facile production of low-cost controlled-release injectable depots for leuprolide and related peptides.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor 48109, USA.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Sophocleous
authors.forename: Kashappa-Goud H
authors.initials: KG
authors.lastname: Desai
authors.forename: J Maxwell
authors.initials: JM
authors.lastname: Mazzara
authors.forename: Ling
authors.initials: L
authors.lastname: Tong
authors.forename: Ji-Xin
authors.initials: JX
authors.lastname: Cheng
authors.forename: Karl F
authors.initials: KF
authors.lastname: Olsen
authors.forename: Steven P
authors.initials: SP
authors.lastname: Schwendeman
mesh_terms: D000327:Adsorption; D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004339:Drug Compounding; D019344:Lactic Acid / Q000737:chemistry*; D016729:Leuprolide / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D015282:Octreotide / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016729:Leuprolide; D015282:Octreotide
keywords: Controlled release; Kinetics; Microencapsulation; PLGA; Peptide; Sorption
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