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Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart.

ABSTRACT: Injectable hydrogels have significant therapeutic potential for treatment of myocardial infarction (MI) through tissue bulking and local drug delivery, including the delivery of small interfering RNAs (siRNAs). As siRNA targets are identified as potential treatments for MI, hydrogels may bolster efficacy through local and sustained release. Here, we designed an injectable hydrogel to respond to local upregulation in proteolytic activity after MI to erode and release siRNA against MMP2 (siMMP2), a target implicated in deleterious remodeling. Specifically, hyaluronic acid (HA) was modified with hydrazides or aldehydes and mixed to form shear-thinning and self-healing hydrogels through dynamic hydrazone bonds and with peptide crosslinkers that degrade in response to protease activity. HA was further modified with ?-cyclodextrin to sequester cholesterol-modified siRNA, limiting passive diffusion. Hydrogels eroded in response to proteases and released active siRNA that knocked down MMP2 in primary cardiac fibroblasts. In a rat model of MI, hydrogels delivering siMMP2 attenuated hydrogel erosion by ~46% at 4?weeks when compared to hydrogels delivering control siRNA, ultimately improving myocardial thickness in the infarct. Delivery of the siMMP2 hydrogel led to significant functional improvements, including increased ejection fraction (27%, 66%), stroke volume (32%, 120%), and cardiac output (20%, 128%) when compared to controls (% increase versus hydrogels with control siRNA, % increase versus saline injection alone). This report demonstrates the utility of biomaterial-based RNA delivery systems for cardiac applications.

SUBMITTER: Wang LL

PROVIDER: S-EPMC6134398 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart.

Wang Leo L LL Chung Jennifer J JJ Li Elizabeth C EC Uman Selen S Atluri Pavan P Burdick Jason A JA

Journal of controlled release : official journal of the Controlled Release Society 20180704

Injectable hydrogels have significant therapeutic potential for treatment of myocardial infarction (MI) through tissue bulking and local drug delivery, including the delivery of small interfering RNAs (siRNAs). As siRNA targets are identified as potential treatments for MI, hydrogels may bolster efficacy through local and sustained release. Here, we designed an injectable hydrogel to respond to local upregulation in proteolytic activity after MI to erode and release siRNA against MMP2 (siMMP2), ...[more]

PMID: 29981357

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Project description:In this study, a new type of injectable hydrogel called "HyMic" that can convert into core cross-linked (CCL) micelles upon exposure to matrix metalloproteinases (MMP's), was designed and developed for drug delivery applications. HyMic is composed of CCL micelles connected via an enzyme cleavable linker. To this end, two complementary ABA block copolymers with polyethylene glycol (PEG) as B block were synthesized using atom transfer radical polymerization (ATRP). The A blocks were composed of a random copolymer of N-isopropylacrylamide (NIPAM) and either N-(2-hydroxypropyl)methacrylamide-cysteine (HPMA-Cys) or N-(2-hydroxypropyl) methacrylamide-ethylthioglycolate succinic acid (HPMA-ETSA). Mixing the aqueous solutions of the obtained polymers and rising the temperature above the cloud point of the PNIPAM block resulted in the self-assembly of these polymers into flower-like micelles composed of a hydrophilic PEG shell and hydrophobic core. The micellar core was cross-linked by native chemical ligation between the cysteine (in HPMA-Cys) and thioester (in HPMA-ETSA) functionalities. A slight excess of thioester to cysteine groups (molar ratio 3:2) was used to allow further chemical reactions exploiting the unreacted thioester groups. The obtained micelles displayed a Z-average diameter of 80 ± 1 nm (PDI 0.1), and ?-potential of -4.2 ± 0.4 mV and were linked using two types of pentablock copolymers of P(NIPAM-co-HPMA-Cys)-PEG-peptide-PEG-P(NIPAM-co-HPMA-Cys) (Pep-NC) to yield hydrogels. The pentablock copolymers were synthesized using a PEG-peptide-PEG ATRP macroinitiator and the peptide midblock (lysine-glycine-proline-glutamine-isoleucine-phenylalanine-glycine-glutamine-lysine (Lys-Gly-Pro-Gln-Gly-Ile-Phe-Gly-Gln-Lys)) consisted of either l- or d-amino acids (l-Pep-NC or d-Pep-NC), of which the l-amino acid sequence is a substrate for matrix metalloproteases 2 and 9 (MMPs 2 and 9). Upon mixing of the CCL micelles and the linker (l/d-Pep-NC), the cysteine functionalities of the l/d-Pep-NC reacted with remaining thioester moieties in the micellar core via native chemical ligation yielding a hydrogel within 160 min as demonstrated by rheological measurements. As anticipated, the gel cross-linked with l-Pep-NC was degraded in 7-45 days upon exposure to metalloproteases in a concentration-dependent manner, while the gel cross-linked with the d-Pep-NC remained intact even after 2 months. Dynamic light scattering analysis of the release medium revealed the presence of nanoparticles with a Z-average diameter of ?120 nm (PDI < 0.3) and ?-potential of ?-3 mV, indicating release of core cross-linked micelles upon HyMic exposure to metalloproteases. An in vitro study demonstrated that the released CCL micelles were taken up by HeLa cells. Therefore, HyMic as an injectable and enzyme degradable hydrogel displaying controlled and on-demand release of CCL micelles has potential for intracellular drug delivery in tissues with upregulation of MMPs, for example, in cancer tissues.

Dataset Information

Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart.

Publications

Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart.

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