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Molecular Features Influencing the Release of Peptides from Amphiphilic Polymeric Reverse Micelles.

ABSTRACT: Efficient and controlled release of peptides bound to polymeric reverse micelle assemblies can be achieved through the cooperative effects of disassembly and disruption of charge-charge interactions. Through the examination of various peptides and polymer architectures, we have identified the factors that affect the release efficiency of the electrostatically bound peptides. Peptide guests and polymers with a greater number of complementary charges result in less efficient release than peptides and polymers with lower numbers of charges. Interestingly, we find that the presence of adjacent charged groups on the monomeric unit of the polymer exhibits exceptionally low release efficiency, perhaps because of a chelate-like effect, even when the total polymer charge is lower. Overall, our findings inform the design principles for catch-and-release systems based on polymeric reverse micelles, which offer great versatility and tunability.

SUBMITTER: Serrano MAC

PROVIDER: S-EPMC6173316 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Molecular Features Influencing the Release of Peptides from Amphiphilic Polymeric Reverse Micelles.

Serrano Mahalia A C MAC Zhao Bo B He Huan H Thayumanavan S S Vachet Richard W RW

Langmuir : the ACS journal of surfaces and colloids 20180402 15

Efficient and controlled release of peptides bound to polymeric reverse micelle assemblies can be achieved through the cooperative effects of disassembly and disruption of charge-charge interactions. Through the examination of various peptides and polymer architectures, we have identified the factors that affect the release efficiency of the electrostatically bound peptides. Peptide guests and polymers with a greater number of complementary charges result in less efficient release than peptides ...[more]

PMID: 29561150

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Project description:BackgroundThe ubiquitous nature of bacterial biofilms combined with the enhanced resistance towards antimicrobials has led to the development of an increasing number of strategies for biofilm eradication. Such strategies must take into account the existence of extracellular polymeric substances, which obstruct the diffusion of antibiofilm agents and assists in the maintenance of a well-defended microbial community. Within this context, nanoparticles have been studied for their drug delivery efficacy and easily customised surface. Nevertheless, there usually is a requirement for nanocarriers to be used in association with an antimicrobial agent; the intrinsically antimicrobial nanoparticles are most often made of metals or metal oxides, which is not ideal from ecological and biomedical perspectives. Based on this, the use of polymeric micelles as nanocarriers is appealing as they can be easily prepared using biodegradable organic materials.ResultsIn the present work, micelles comprised of poly(lactic-co-glycolic acid) and dextran are prepared and then functionalised with curcumin. The effect of the functionalisation in the micelle's physical properties was elucidated, and the antibacterial and antibiofilm activities were assessed for the prepared polymeric nanoparticles against Pseudomonas spp. cells and biofilms. It was found that the nanoparticles have good penetration into the biofilms, which resulted in enhanced antibacterial activity of the conjugated micelles when compared to free curcumin. Furthermore, the curcumin-functionalised micelles were efficient at disrupting mature biofilms and demonstrated antibacterial activity towards biofilm-embedded cells.ConclusionCurcumin-functionalised poly(lactic-co-glycolic acid)-dextran micelles are novel nanostructures with an intrinsic antibacterial activity tested against two Pseudomonas spp. strains that have the potential to be further exploited to deliver a secondary bioactive molecule within its core.

Project description:Peptides derived from the third Bcl-2 homology domain (BH3) renormalize apoptotic signaling by antagonizing prosurvival Bcl-2 family members. These potential peptide drugs exhibit therapeutic activities but are limited by barriers including short circulation half-lives and poor penetration into cells. A diblock polymeric micelle carrier for the BIM BH3 peptide was recently described that demonstrated antitumor activity in a B-cell lymphoma xenograft model [Berguig et al., Mol. Ther. 2015, 23, 907-917]. However, the disulfide linkage used to conjugate the BIM peptide was shown to have nonoptimal blood stability. Here we describe a peptide macromonomer composed of BIM capped with a four amino acid cathepsin B substrate (FKFL) that possesses high blood stability and is cleaved to release the drug inside of target cells. Employing RAFT polymerization, the peptide macromonomer was directly integrated into a multifunctional diblock copolymer tailored for peptide delivery. The first polymer block was made as a macro-chain transfer agent (CTA) and composed of a pH-responsive endosomolytic formulation of N,N-diethylaminoethyl methacrylate (DEAEMA) and butyl methacrylate (BMA). The second polymer block was a copolymer of the peptide and polyethylene glycol methacrylate (PEGMA). PEGMA monomers of two sizes were investigated (300 Da and 950 Da). Protein gel analysis, high performance liquid chromatography, and coupled mass spectrometry (MS) showed that incubation with cathepsin B specifically cleaved the FKFL linker and released active BIM peptide with PEGMA300 but not with PEGMA950. MALDI-TOF MS showed that incubation of the peptide monomers alone in human serum resulted in partial cleavage at the FKFL linker after 12 h. However, formulation of the peptides into polymers protected against serum-mediated peptide degradation. Dynamic light scattering (DLS) demonstrated pH-dependent micelle disassembly (25 nm polymer micelles at pH 7.4 versus 6 nm unimers at pH 6.6), and a red blood cell lysis assay showed a corresponding increase in membrane destabilizing activity (<1% lysis at pH 7.4 versus 95% lysis at pH 6.6). The full carrier-drug system successfully induced apoptosis in SKOV3 ovarian cancer cells in a dose-dependent manner, in comparison to a control polymer containing a scrambled BIM peptide sequence. Mechanistic analysis verified target-dependent activation of caspase 3/7 activity (8.1-fold increase), and positive annexin V staining (72% increase). The increased blood stability of this enzyme-cleavable peptide polymer design, together with the direct polymerization approach that eliminated postsynthetic conjugation steps, suggests that this new carrier design could provide important benefits for intracellular peptide drug delivery.

Dataset Information

Molecular Features Influencing the Release of Peptides from Amphiphilic Polymeric Reverse Micelles.

Publications

Molecular Features Influencing the Release of Peptides from Amphiphilic Polymeric Reverse Micelles.

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