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Effects of nano-confinement and conformational mobility on molecular imprinting of cross-linked micelles.

ABSTRACT: Molecular imprinting is a facile method to create guest-complementary binding sites in a cross-linked polymeric network. When performed within cross-linked micelles, the resulting molecularly imprinted nanoparticles (MINPs) exhibited an extraordinary ability to distinguish subtle structural changes in the guest, including the shift of a hydrophilic or hydrophobic group by 1 carbon and addition of a single methylene/methyl group. A high surface-cross-linking density prior to core-cross-linking was key to the high-fidelity imprinting, enhancing both the binding affinity of the imprinted micelle for the template and selectivity among structural analogues. Whereas the imprinted site closely complemented the hydrophilic surface anchoring group and rigid hydrophobic aromatic core, it was expanded significantly for a conformationally mobile small group (i.e., methoxy).

SUBMITTER: Chen K

PROVIDER: S-EPMC7474537 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Effects of nano-confinement and conformational mobility on molecular imprinting of cross-linked micelles.

Chen Kaiqian K Zhao Yan Y

Organic & biomolecular chemistry 20190901 37

Molecular imprinting is a facile method to create guest-complementary binding sites in a cross-linked polymeric network. When performed within cross-linked micelles, the resulting molecularly imprinted nanoparticles (MINPs) exhibited an extraordinary ability to distinguish subtle structural changes in the guest, including the shift of a hydrophilic or hydrophobic group by 1 carbon and addition of a single methylene/methyl group. A high surface-cross-linking density prior to core-cross-linking wa ...[more]

PMID: 31528942

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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.

Project description:To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross-linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti-tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N-acetylcysteine, after PTX-DCMs have reached the tumor site.

Dataset Information

Effects of nano-confinement and conformational mobility on molecular imprinting of cross-linked micelles.

Publications

Effects of nano-confinement and conformational mobility on molecular imprinting of cross-linked micelles.

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