Shizhong Luo

Thiol and pH dual-responsive dynamic covalent shell cross-linked micelles for triggered release of chemotherapeutic drugs

We report on the fabrication of dynamic covalent shell cross-linked (SCL) micelles of amphiphilic diblock copolymers functionalized with aldehyde moieties in the hydrophilic block by utilizing difunctional crosslinkers cleavable in response to pH and thiols. Well-defined amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-MAEBA), was synthesized via ring opening polymerization (ROP) of e-caprolactone (CL) and atom transfer radical polymerization (ATRP) of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and p-(methacryloxyethoxy)benzaldehyde (MAEBA) comonomers. In aqueous solution, the diblock copolymer self-assembles into micelles consisting of hydrophobic PCL cores and hydrophilic P(OEGMA-co-MAEBA) coronas covalently anchored with aldehyde groups. The subsequent shell cross-linking reaction was conducted at pH 6.2 upon addition of difunctional dithiolbis(propanoic dihydrazide) (DTP). The formation of dynamic acylhydrazone cross-linking linkages was facilitated under the catalysis of aniline. The obtained SCL micelles can be de-crosslinked via two biologically relevant modes, namely, acidic pH-triggered cleavage of acylhydrazone bonds into aldehyde and hydrazide and thiol-triggered cleavage of disulfide linkages, which have been utilized for triggered release of physically encapsulated chemotherapeutic drugs. The dual-responsive dynamic covalent SCL micelles were examined by dynamic laser light scattering (LLS), 1H NMR, Ellmans assay, and enzymatic degradation tests. In addition, camptothecin (CPT)-loaded SCL micelles were used to investigate thiol and pH-modulated CPT release profiles. Compared with CPT-loaded non-cross-linked (NCL) micelles, CPT-loaded SCL micelles can largely minimize drug leakage under physiological conditions, whilst exhibiting accelerated drug release under mildly acidic or thiol-rich microenvironments, which are relevant to those of acidic organelles (endosomes and lysosomes) or cytosol within tumor cells. Cell cytotoxicity studies revealed that drug-free SCL micelles are almost nontoxic, whereas CPT-loaded SCL micelles can efficiently deliver chemotherapeutic drug (CPT) into HepG2 cells, leading to considerable nucleic accumulation at extended incubation duration. The reported dynamic covalent shell cross-linking strategy can exert intricate control concerning the micellar stability and the release profile of encapsulated drugs in response to biological microenvironments, which augurs well for their potential use as novel smart nanocarriers for drug delivery in cancer chemotherapy.

Dual pH-triggered multistage drug delivery systems based on host–guest interaction-associated polymeric nanogels

The polymeric nanogels were constructed via host-guest interactions for dual pH-triggered multistage drug delivery, which showed tumor acidity-triggered nanogel reorganization into smaller nanoparticles for deep tissue penetration, high-efficiency cellular uptake, and intracellular endo-lysosomal pH-responsive drug release.

Redox-responsive core cross-linked micelles based on cypate and cisplatin prodrugs-conjugated block copolymers for synergistic photothermal–chemotherapy of cancer

Responsive cross-linked block copolymer micelles which have emerged as promising drug delivery systems showed high stability and on-demand drug release. The combination therapy of cancer can be achieved via co-delivery of varying therapeutic molecules in one system. Here, we developed a redox-responsive core cross-linked (CCL) micelle conjugated with cypate and cisplatin prodrugs within the cores for synergistic photothermal and chemotherapy. The block copolymer, poly[(2-(2-methoxyethoxy)ethyl methacrylate)-co-(N-methacryloxy succinimide)]-block-poly(N-(2-hydroxypropyl) methacrylamide) (P(MEO2MA-co-MASI)-b-PHPMA), was synthesized via reversible addition–fragment chain transfer (RAFT) polymerization. After partial amidation reaction of succinimide with 3-azidopropylamine, the alkynyl-functionalized cypate and Pt(IV) complex were conjugated via click reaction. The CCL micelles were fabricated by core cross-linking at 37 °C in aqueous solution using cystamine as the cross-linker. P(Pt-Cy-MEO2MA)-b-PHPMA CCL micelles showed redox-responsive cross-linker cleavage and cisplatin drug release in the presence of reductants. The conjugated cypate moieties in the cores of CCL micelles resulted in photothermal temperature increase and reactive oxygen species (ROS) generation under 805 nm near infrared (NIR) laser irradiation. The cytotoxicity of CCL micelles was investigated with and without NIR irradiation. A significant synergistic effect of photothermal therapy and chemotherapy was demonstrated against cisplatin-resistant human lung cancer cells A549R under NIR irradiation.

Thermoresponsive unimolecular micelles with a hydrophobic dendritic core and a double hydrophilic block copolymer shell

Biocompatible stimuli-responsive unimolecular polymeric micelles have attracted much interest due to their unique structures and potential applications in biomedical fields such as drug delivery and tissue engineering. Here, we report the preparation of dendritic unimolecular polymeric micelles with temperature sensitive shells via reversible addition-fragmentation transfer (RAFT) technique. A multi-arm star amphiphilic copolymer (H40-PDEA) with a hydrophobic hyperbranched polyester (Boltorn H40) as the core and the grafted poly(N,N-diethylacrylamide) (PDEA) as the shell was prepared using H40 based macroRAFT agent. And a dendritic unimolecular polymer (H40-PDEA-PDMA) with a double hydrophilic block copolymer (DHBC) [PDEA-b-poly(2-(dimethylamino)ethyl methacrylate) (PDEA-b-PDMA)] as the dual thermoresponsive shells was synthesized by H40-PDEA based macroRAFT agent. Both H40-PDEA and H40-PDEA-PDMA have a reversible phase transition behavior in aqueous solution. In particular, the unimolecular polymeric micelles H40-PDEA-PDMA with double thermoresponsive shells exhibit a two-stage phase transition behavior. Laser light scattering (LLS), UV-vis transmittance, excimer fluorescence measurements, and micro-differential scanning calorimetry (micro-DSC) were used in combination to probe the conformational changes of chains located at the inner layer and outer corona during the phase transition process.