Cross-linked Micelles Research Articles

Disulfide crosslinking and helical coiling of peptide micelles facilitate the formation of a printable hydrogel

Tripeptides self-assembled into aligned micelles which transformed into nanohelices via covalent and noncovalent interactions to give a printable hydrogel.

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

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).

PH-Responsive reversibly cross-linked micelles by phenol–yne click via curcumin as a drug delivery system in cancer chemotherapy

pH-sensitive reversibly cross-linked micelles by phenol–yne click via curcumin (Cur) using mPEG-b-PHEMA-5HA are developed by combining drug loading and cross-linking as a drug delivery system.

Amphiphilic Glycopolypeptide Star Copolymer-Based Cross-Linked Nanocarriers for Targeted and Dual-Stimuli-Responsive Drug Delivery.

Glycopolypeptide-based nanocarriers are an attractive class of drug delivery vehicles because of the involvement of carbohydrates in the receptor-mediated endocytosis process. To enhance their efficacy toward controlled and programmable drug delivery, we have prepared stable glycopolypeptide-based bioactive dual-stimuli-responsive (redox and enzyme) micelles for delivery of anticancer drugs specifically to the cancer cells. The amphiphilic biocompatible miktoarm star copolymer, which comprises two hydrophobic poly(ε-caprolactone) blocks, a short poly(propargyl glycine) middle block, and a hydrophilic galactose glycopolypeptide block, was designed and synthesized. The star copolymer is initially self-assembled into un-cross-linked (UCL) micelles, and free alkyne groups at the core-shell interface of the UCL micelles, which were cross-linked by bis(azidoethyl) disulfide (BADS) via click chemistry to form interface cross-linked (ICL) micelles. ICL micelles were found to be stable against dilution. BADS imparted redox-responsive properties to the micelles, while PCL rendered them enzyme-degradable. Dual-stimuli-responsive release behavior with Dox as model drug was studied individually as well as synergistically by applying two stimuli in different sequences. The galactose-containing UCL and ICL micelles were shown to be nontoxic. Intracellular Dox release from UCL and ICL micelles was demonstrated in liver cancer cells (HepG2) by time-dependent cellular uptake studies, and controlled release from ICL micelles compared to UCL micelles was observed. The present report opens a new approach toward targeted and programmable drug delivery in tumor tissues via a specifically targeted (receptor-mediated), dual-responsive, and stable cross-linked nanocarrier system.

Codelivery of miR-4638–5p and Docetaxel Based on Redox-Sensitive Polypeptide Micelles as an Improved Strategy for the Treatment of Castration-Resistant Prostate Cancer

In this work, we have developed a reducible, self-assembling disulfide cross-linked and peptide-based micelle system for codelivery of miR-4638-5p and DTX to improve the efficacy of castration-resistant prostate cancer (CRPC) therapy. The result showed that DTX in micelles (DTX-VPs) inhibited cell growth and induced apoptosis more effectively than free DTX both in vitro and in vivo. In addition, the DTX and miR-4638-5p loaded micelles (Co-VPs) achieved the most pronounced anticancer effect of all groups. Immunohistochemical analysis indicated that miR-4638-5p in micelle system could effectively downregulate the expression of Kidins220 and further improve the anticancer effect by enhancing tumor cell apoptosis and suppressing tumor cell proliferation. Finally, the bioimaging analysis demonstrated that DIR in micelles (DIR-VPs) showed a higher concentration and a longer retention time in tumor tissue than did free DIR, which indicated an excellent tumor-targeting ability of the micelle system. All these results suggest that codelivery of miR-4638-5p and DTX via polypeptide micelle system has a potential for CRPC treatment.

Photo-cross-linkable mixed micelles with dual response to pH and temperature

Two photo-cross-linkable star amphiphilic triblock copolymers with thermo- and pH-responsive properties, respectively, star poly(ε-caprolactone)-b- poly(2-cinnamoyloxyethyl methacrylate)-b-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [SPCL-b-PCEMA-b-P(NIPAAm-co-DMAAm)] and star poly(ε-caprolactone)-b-poly(2-cinnamoyloxyethyl methacrylate)-b-poly(2-(diethyl-amino)ethyl methacrylate) (SPCL-b-PCEMA-b-PDMAEMA), were synthesized by stepwise reversible addition-fragment chain transfer (RAFT) polymerization of 2-hydroxyethyl methacrylate and 2-dimethylaminoethyl methacrylate or N-isopropylacrylamide monomers using star PCL macro-RAFT agent (SPCL-DDAT), followed by carbodiimide-mediated coupling of photo-cross-linkable cinnamate groups. The obtained two cinnamate-functionalized star copolymers with different weight ratios were used to construct mixed micelles with dual thermores and pH-responsive properties. Photo-cross-linking was performed by UV irradiation, resulting in the stabilization of the cross-linked mixed micelles. Dual stimuli–responsive behavior was investigated by combination of dynamic light scattering and optical transmittance. The results showed that the stimuli responses were tunable by varying the content of two star copolymers and cross-linking density. The structure stability and dual thermo- and pH-responsive properties endowed the mixed micelle with potential applications in biomedical fields, such as controlled drug release.

Reduction-responsive shell cross-linked micelles derived from amphiphilic triblock copolymer as anticancer drug delivery carrier

Stimuli-responsive crosslinked micelles are attractive carriers for in vivo delivery of water-insoluble therapeutic drugs due to their excellent stability during the blood circulation and high therapeutic effect resulting from the intelligent break-up of the crosslinked structure triggered by intracellular conditions as well as the subsequent fast drug release. Herein, novel amphiphilic triblock copolymer poly(l-lactide)-b-poly(allyl glycidyl ether/propanedithiol)-b-poly(ethylene glycol) (PLLA-b-P(AGE-SH)-b-PEG) was designed and synthesized by combining two successive ring-opening polymerizations and subsequent “thio-ene” reaction. Due to their unique amphiphilic architecture, copolymer PLLA-b-P(AGE-SH)-b-PEG could self-assemble into core-shell micelles, and the stimuli-responsive crosslinked micelles (SCMs) were obtained by crosslinking the P(AGE-SH) segments in the micellar shell under redox condition. The SCMs exhibited good stability against extensive dilution and slow sustained drug release in a simulated normal physiologycal environment, but fast release in the presence of GSH. As revealed by the cytotoxicity assay, the micelles from the copolymer PLLA-b-P(AGE-SH)-b-PEG showed excellent biocompatibility against HEK293T cells. Due to these combined good properties, the stimuli-responsive crosslinked micelles from PLLA-b-P(AGE-SH)-b-PEG are proposed to be an ideal carrier for the in vivo delivery of water-insoluble therapeutics.

Shell Cross-Linked Micelles as Nanoreactors for Enantioselective Three-Step Tandem Catalysis.

Functionalized amphiphilic poly(2-oxazoline)-based triblock copolymers that assemble into shell cross-linked micelles (SCMs) are described. These micelles permit the site isolation of three incompatible catalysts through compartmentalization, thereby enabling three-step non-orthogonal tandem processes in one pot. In particular, the acid-catalyzed ketal hydrolysis to prochiral ketones proceeded in the hydrophilic corona, followed by the Rh-catalyzed asymmetric transfer hydrogenation to enantio-enriched alcohols in the cross-linked shell, and nucleophilic base-catalyzed acylation in the hydrophobic core. The catalysts are positioned in close proximity on a single micelle support to take advantage of the intramicellar substrate diffusion, yet they are sufficiently spaced apart from each other in physically distinct microenvironments. These compartmentalized micelles are substrate selective and, on a basic level, mimic compartmentalized catalytic architectures found in nature.

High Drug Loading, Reversible Disulfide Core-Cross-Linked Multifunctional Micelles for Triggered Release of Camptothecin.

Nanomedicines in polymeric therapeutics present a potential treatment for cancers. However, their clinical effectiveness still has room to be improved. Herein, reduction-responsive reversibly core-cross-linked micelles based on the poly(ethylene glycol)-dihydrolipoic acid (MeO-PEG2k-DHLA) conjugate were developed for triggered intracellular release of camptothecin (CPT). Coupling two molecules of dihydrolipoic acid (DHLA) to methyl-terminated PEG (Mw 2000) through a labile ester bond was performed by solution-phase condensation reaction. Due to the amphiphilic property, the MeO-PEG2k-DHLA conjugate formed micelles that were readily cross-linked with disulfide formation dispersed in water. These sole cross-linked micelles were 74.9 nm in hydrodiameter, as analyzed by dynamic light scattering (DLS). The nanostructures demonstrated excellent stability against extensive dilution, while rapidly dissociating under 10 mM glutathione (GSH), highlighting their potential for drug delivery. Interestingly, CPT was modified with a disulfide linkage and subsequently conjugated to the MeO-PEG2k-DHLA polymer scaffold. Core-cross-linking of the micelles achieved high drug loading of CPT (31.81%, wt %) and demonstrated that CPT release at pH 7.4 was significantly declined by cross-linking (i.e., less than 15% release in 24 h), whereas more than 90% of CPT was released under 10 mM GSH condition. In vitro cellular uptake and MTT assays showed that CPT-conjugated MeO-PEG2k-DHLA micelles were effectively internalized into tumor cells to induce the cytotoxic effects against HepG-2 and MCF-7 cells. Importantly, in vivo pharmacokinetics analysis demonstrated the nanoscale feature of micelles makes CPT to present longer retention time, resulting in a higher accumulation at tumor sites. Taken together, the disulfide core-cross-linked MeO-PEG2k-DHLA multifunctional micelles with high drug loading and excellent stability are potential candidates for tumor-targeting drug delivery.

Reassembling of Alkali-Treated Casein Micelles by Microbial Transglutaminase.

In milk, caseins interact to form nanoparticles called casein micelles. Under weak alkaline conditions, casein micelles swell reversibly and are disrupted at pH values above 8.5. The enzyme microbial transglutaminase (mTG) is widely used in food industry to modify the functional properties of proteins. Here, we evaluated the potential of mTG as a stabilizer for alkaline disrupted casein micelles. Hence, enzymatic cross-linking of casein micelles as well as sodium caseinate was studied at the natural milk pH 6.8 and under alkaline conditions at pH 7.9 by analyzing oligomerization via size exclusion chromatography, monomeric caseins via RP-HPLC-UV, and extra-micellar protein via Bradford assay. Additionally, alkaline swelling as well as enzymatic reconstruction of casein micelles was observed via scanning electron microscopy and dynamic light scattering. The results showed that the extent of cross-linking is mainly influenced by protein conformation and not by pH value. However, micellar αs2-casein was much more cross-linked at pH 7.9 compared to pH 6.8, whereas an opposite tendency was determined for micellar κ-casein. This leads to the conclusion that αs2-casein is mainly located in the inner center of casein micelles and is only accessible for enzymatic cross-linking after alkaline swelling of the micelle. Alkaline disrupted casein micelles are reassembled due to intramicellar cross-linking by mTG. On the basis of the results, an enhanced model of the structure of casein micelles was developed.

Self-assembly of DCPD-loaded cross-linked micelle from triblock copolymers and its pH-responsive behavior: A dissipative particle dynamics study

Dissipative particle dynamics (DPD) simulations were applied to investigate the solution self-assembly and pH-responsive behavior of hydrophobic DCPD (dicyclopentadiene)-loaded microcapsules from triblock copolymers poly (1,2-ethanediol, homopolymer-b-2-Diethylaminoethylmethacrylate-b-methyl methacrylate) (PEG-b-PDMAEMA-b-PMMA). Results indicate that micelles with longer hydrophilic PEG blocks and shorter hydrophobic PMMA blocks were in favor of encapsulating hydrophobic DCPD. Cross-linking at the core/shell interface generates a chemically bonded network structure in the micelle and leads to a significant decrease of their thermodynamic mobility (i.e., the increase of stability). Both non cross-linked and cross-linked micelles show a good pH-responsive behavior. In particular, cross-linked micelles still have the ability to carry DCPD due to the incomplete dispersion even completely protonation of PDMAEMA, which indicates that the cross-linked micelles could be expected to realize the slow release of encapsulated DCPD agent.

DOTA Functionalized Cross-Linked Small-Molecule Micelles for Theranostics Combining Magnetic Resonance Imaging and Chemotherapy.

Herein, a new theranostic nanoplatform was built by introducing DOTA on the surface of the cross-linked small molecular micelles. This nanoplatform consisted of three parts: (1) Hydrophobic alkyl chain functioned with alkenes as cross-linkable part to ensure the robust stability in vivo; (2) Hydrophilic DOTA for not only gadolinium ions complexion as MR imaging contrast agents but also platinum ions complexion as drug carriers; (3) Cisplatin as antitumor drug and MR imaging amplifier simultaneously. The metal loading content of the resulting Pt/Gd@DOTA-CSMs was up to 12 and 14 wt % for Gd(III) and Pt(II), respectively. The longitudinal relaxation rate of Gd@DOTA-CSMs (8.46 mM-1 s-1) was 2.6 times than that of the clinical Gd-DTPA (3.23 mM-1 s-1). When cisplatin was involved, not only great antitumor efficiency was achieved, but higher longitudinal relaxation rate of Pt/Gd@DOTA-CSMs (11.17 mM-1 s-1) was carried out due to the extension of rotational correlation time. The experiments of Balb/c mice bearing 4T1 xenograft indicated that Pt/Gd@DOTA-CSMs had better antitumor activity, lower side effect than clinically used cisplatin, and greater MR imaging than Gd-DTPA. All the results proved that the nanoplatform of DOTA-CSMs held remarkable potential in the field of therapeutics.

Iono-Elastomer-Based Wearable Strain Sensor with Real-Time Thermomechanical Dual Response

An ultrastretchable iono-elastomer with resistance sensitive to both elongation strain and temperature has been developed by hierarchical self-assembly of an end functionalized triblock copolymer in a protic ionic liquid (ethylammonium nitrate) followed by cross-linking. Small-angle X-ray scattering experiments in situ with uniaxial elongation reveal a nanoscale microstructural transition of the hierarchically self-assembled cross-linked micelles that is responsible for the material's remarkable mechanical and ionic conductivity responses. The results show that the intermicelle distance extends along the deformation direction while the micelles organize into a long-range ordered face-centered-cubic structure during the uniaxial elongation. Besides good cyclability and resistance to selected physical damage, the iono-elastomer simultaneously achieves an unprecedented combination of high stretchability (340%), highly linear resistance vs elongation strain ( R2 = 0.998), and large temperature gauge factor (Δ R/ R = 3.24%/°C@30 °C). Human subject testing demonstrates that the iono-elastomer-based wearable thermomechanical sensor is able to effectively and accurately register both body motion and skin temperature simultaneously.

Antibacterial adhesive injectable hydrogels with rapid self-healing, extensibility and compressibility as wound dressing for joints skin wound healing

Designing wound dressing materials with outstanding therapeutic effects, self-healing, adhesiveness and suitable mechanical property has great practical significance in healthcare, especially for joints skin wound healing. Here, we designed a kind of self-healing injectable micelle/hydrogel composites with multi-functions as wound dressing for joint skin damage. By combining the dynamic Schiff base and copolymer micelle cross-linking in one system, a series of hydrogels were prepared by mixing quaternized chitosan (QCS) and benzaldehyde-terminated Pluronic®F127 (PF127-CHO) under physiological conditions. The inherent antibacterial property, pH-dependent biodegradation and release behavior were investigated to confirm multi-functions of wound dressing. The hydrogel dressings showed suitable stretchable and compressive property, comparable modulus with human skin, good adhesiveness and fast self-healing ability to bear deformation. The hydrogels exhibited efficient hemostatic performance and biocompatibility. Moreover, the curcumin loaded hydrogel showed good antioxidant ability and pH responsive release profiles. In vivo experiments indicated that curcumin loaded hydrogels significantly accelerated wound healing rate with higher granulation tissue thickness and collagen disposition and upregulated vascular endothelial growth factor (VEGF) in a full-thickness skin defect model. Taken together, the antibacterial adhesive hydrogels with self-healing and good mechanical property offer significant promise as dressing materials for joints skin wound healing.

Synthesis of Redox-Responsive Core Cross-Linked Micelles Carrying Optically Active Helical Poly(phenyl isocyanide) Arms and Their Applications in Drug Delivery.

In this manuscript, we designed and synthesized three core cross-linked micelles (M-5L, P-5L, and P-5D) with redox-responsive disulfide bonds in the core and carrying optically active helical polyisocyanide arms. Their arms were different in the helicity of the main chain and the chirality of the side groups. These micelles showed excellent redox-responsiveness to reducing agent. However, because of the different chiralities of the arms, the three micelles exhibited different performances in drug delivery and controlled release. The M-5L micelle carrying left-handed helical arms showed better therapeutic effect than the other two due to the rapid cell membrane permeability.

Cross-Linked Aptamer-Lipid Micelles for Excellent Stability and Specificity in Target-Cell Recognition.

The specific binding ability of DNA-lipid micelles (DLMs) can be increased by the introduction of an aptamer. However, supramolecular micellar structures based on self-assemblies of amphiphilic DLMs are expected to demonstrate low stability when interacting with cell membranes under certain conditions, which could lead to a reduction in selectivity for targeting cancer cells. We herein report a straightforward cross-linking strategy that relies on a methacrylamide branch to link aptamer and lipid segments. By an efficient photoinduced polymerization process, covalently linked aptamer-lipid units help stabilize the micelle structure and enhance aptamer probe stability, further improving the targeting ability of the resulting nanoassembly. Besides the development of a facile cross-linking method, this study clarifies the relationship between aptamer-lipid concentration and the corresponding binding ability.

Artificial Zinc Enzymes with Fine-Tuned Active Sites for Highly Selective Hydrolysis of Activated Esters

Zinc enzymes are ubiquitous in nature and are frequently used to catalyze the hydrolysis of carboxylic acid esters, phosphate esters, and amides. Although many models and mimics of zinc enzymes have been reported, it remains difficult to construct active sites with accurately positioned catalytic groups and tunable substrate selectivity. By imprinting a substrate-like amino template coordinated to a polymerizable zinc complex inside cross-linked micelles, we prepared water-soluble nanoparticles with well-defined active sites. The position of the zinc ion could be tuned systematically with respect to the ester bond to be cleaved in the substrate (p-nitrophenyl esters), as well as the rigidity of the active site. Our imprinted zinc catalysts were able to distinguish substrates that differed by the position of a single methyl group, chain length of the acyl chain, and substitution of the phenyl ring. The turnover number (>460 at pH 7) was 1 order of magnitude higher than those previously reported for artific...

Surface ligands in the imprinting and binding of molecularly imprinted cross-linked micelles

ABSTRACTMolecular recognition in water is challenging but water-soluble molecularly imprinted nanoparticle (MINP) receptors were produced readily by double cross-linking of surfactant micelles in the presence of suitable template molecules. When the micellar surface was decorated with different polyhydroxylated ligands, significant interactions could be introduced between the surface ligands and the template. Flexible surface ligands worked better than rigid ones to interact with the polar moiety of the template, especially for those template molecules whose water-exposed surface is not properly solvated by water. The importance of these hydrophilic interactions was examined in the context of different substrates, density of the surface ligands, and surface-cross-linking density of the MINP. Together with the hydrophobic interactions in the core, the surface hydrophilic interactions can be used to enhance the binding of guest molecules in water.

One-Pot Synthesis of pH/Redox Responsive Polymeric Prodrug and Fabrication of Shell Cross-Linked Prodrug Micelles for Antitumor Drug Transportation.

Shell cross-linked (SCL) polymeric prodrug micelles have the advantages of good blood circulation stability and high drug content. Herein, we report on a new kind of pH/redox responsive dynamic covalent SCL micelle, which was fabricated by self-assembly of a multifunctional polymeric prodrug. At first, a macroinitiator PBYP- ss- iBuBr was prepared via ring-opening polymerization (ROP), wherein PBYP represents poly[2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane]. Subsequently, PBYP- hyd-DOX- ss-P(DMAEMA- co-FBEMA) prodrug was synthesized by a one-pot method with a combination of atom transfer radical polymerization (ATRP) and a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using a doxorubicin (DOX) derivative containing an azide group to react with the alkynyl group of the side chain in the PBYP block, while DMAEMA and FBEMA are the abbriviations of N, N-(2-dimethylamino)ethyl methacrylate and 2-(4-formylbenzoyloxy)ethyl methacrylate, respectively. The chemical structures of the polymer precursors and the prodrugs have been fully characterized. The SCL prodrug micelles were obtained by self-assembly of the prodrug and adding cross-linker dithiol bis(propanoic dihydrazide) (DTP). Compared with the shell un-cross-linked prodrug micelles, the SCL prodrug micelles can enhance the stability and prevent the drug from leaking in the body during blood circulation. The average size and morphology of the SCL prodrug micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The SCL micelles can be dissociated under a moderately acidic and/or reductive microenvironment, that is, endosomal/lysosomal pH medium or high GSH level in the tumorous cytosol. The results of DOX release also confirmed that the SCL prodrug micelles possessed pH/reduction responsive properties. Cytotoxicity and cellular uptake analyses further revealed that the SCL prodrug micelles could be rapidly internalized into tumor cells through endocytosis and efficiently release DOX into the HeLa and HepG2 cells, which could efficiently inhibit the cell proliferation. This study provides a fast and precise synthesis method for preparing multifunctional polymer prodrugs, which hold great potential for optimal antitumor therapy.

“pH-triggered” drug release using shell cross-linked micelles from aqueous RAFT-synthesized PAPMA-b-PNIPAM copolymers

A new polymer namely poly (N-(3-aminopropyl) methacrylamide)-b-poly(N-isopropylacrylamide) (PAPMA-b-PNIPAM) was made for pH-triggered drug delivery by means of aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. PAPMA-b-PNIPAM was hydrophilic at 25 °C, and micelles were formed at 39 °C. The PAPMA chain was crosslinked with terephthaldicarboxaldehyde at pH = 9.0 and shell cross-linking (SCL) micelles were prepared. The sizes of the SCL micelles were 45~65 nm which can be reversible dissociated under acidic conditions. The formation of temperature-responsive SCL micelles and their cleavage behaviours were characterized.