Ding, Hui and Portilla-Arias, Jose and Patil, Rameshwar and Black, Keith L. and Ljubimova, Julia Y. and Holler, Eggehard (2011) The optimization of polymalic acid peptide copolymers for endosomolytic drug delivery. BIOMATERIALS, 32 (22). pp. 5269-5278. ISSN 0142-9612,
Full text not available from this repository. (Request a copy)Abstract
Membranolytic macromolecules are promising vehicles for cytoplasmic drug delivery, but their efficiency and safety remains primary concerns. To address those concerns, membranolytic properties of various poly(beta-L-malic acid) (PMLA) copolymers were extensively investigated as a function of concentration and pH. PMLA, a naturally occurring biodegradable polymer, acquires membranolytic activities after substitution of pendent carboxylates with hydrophobic amino acid derivatives. Ruled by hydrophobization and charge neutralization, membranolysis of PMLA copolymers increased as a function of polymer molecular weight and demonstrated a maximum with 50% substitution of carboxylates. Charge neutralization was achieved either conditionally by pH-dependent protonation or permanently by masking carboxylates. Membranolysis of PMLA copolymers containing tripeptides of leucine, tryptophan and phenylalanine were pH-dependent in contrast to pH-independent copolymers of Leucine ethyl ester and Leu-Leu-Leu-NH(2) with permanent charge neutralization. PMLA and tripeptides seemed a unique combination for pH-dependent membranolysis. In contrast to nontoxic pH-dependent PMLA copolymers, pH-independent copolymers were found toxic at high concentration, which is ascribed to their nonspecific disruption of plasma membrane at physiological pH. pH-Dependent copolymers were membranolytically active only at acidic pH typical of maturating endosomes, and are thus devoid of cytotoxicity. The PMLA tripeptide copolymers are useful for safe and efficient cytoplasmic delivery routed through endosome. (C) 2011 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CELL-PENETRATING PEPTIDES; L-ASPARTIC ACID; POLY(BETA-L-MALIC ACID); INTRACELLULAR DELIVERY; AMINO-ACIDS; POLYMER; SHIFTS; TRYPTOPHAN; INHIBITION; ANTIBODIES; pH-dependent copolymer; Polymalic acid; Drug delivery; Membranolysis; Endosome escape; Cytoplasmic delivery |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Alumni or Retired > Prof. Dr. Eggehard Holler |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Jun 2020 05:22 |
| Last Modified: | 05 Jun 2020 05:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20513 |
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