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Uniform segmented platelet micelles with compositionally distinct and selectively degradable cores.

ABSTRACT: The creation of nanoparticles with controlled and uniform dimensions and spatially defined functionality is a key challenge. The recently developed living crystallization-driven self-assembly (CDSA) method has emerged as a promising route to one-dimensional (1D) and 2D core-shell micellar assemblies by seeded growth of polymeric and molecular amphiphiles. However, the general limitation of the epitaxial growth process to a single core-forming chemistry is an important obstacle to the creation of complex nanoparticles with segmented cores of spatially varied composition that can be subsequently exploited in selective transformations or responses to external stimuli. Here we report the successful use of a seeded growth approach that operates for a variety of different crystallizable polylactone homopolymer/block copolymer blend combinations to access 2D platelet micelles with compositionally distinct segmented cores. To illustrate the utility of controlling internal core chemistry, we demonstrate spatially selective hydrolytic degradation of the 2D platelets-a result that may be of interest for the design of complex stimuli-responsive particles for programmed-release and cargo-delivery applications.

SUBMITTER: Tong Z

PROVIDER: S-EPMC10239731 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Uniform segmented platelet micelles with compositionally distinct and selectively degradable cores.

Tong Zaizai Z Xie Yujie Y Arno Maria C MC Zhang Yifan Y Manners Ian I O'Reilly Rachel K RK Dove Andrew P AP

Nature chemistry 20230420 6

The creation of nanoparticles with controlled and uniform dimensions and spatially defined functionality is a key challenge. The recently developed living crystallization-driven self-assembly (CDSA) method has emerged as a promising route to one-dimensional (1D) and 2D core-shell micellar assemblies by seeded growth of polymeric and molecular amphiphiles. However, the general limitation of the epitaxial growth process to a single core-forming chemistry is an important obstacle to the creation of ...[more]

PMID: 37081206

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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 ζ-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 ζ-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

Uniform segmented platelet micelles with compositionally distinct and selectively degradable cores.

Publications

Uniform segmented platelet micelles with compositionally distinct and selectively degradable cores.

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