6 research outputs found

    Endosomal-Escape Polymers Based on Multicomponent Reaction-Synthesized Monomers Integrating Alkyl and Imidazolyl Moieties for Efficient Gene Delivery

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    As one of the toughest tasks in the course of intracellular therapeutics delivery, endosomal escape must be effectively achieved, particularly for intracellular gene transport. In this report, novel endosomal-escape polymers were designed and synthesized from monomers by integrating alkyl and imidazolyl via Passerini reaction and reversible addition–fragmentation chain transfer polymerization (RAFT). After introducing the endosomal-escape polymers with proper degrees of polymerization (DPs) into poly­(2-dimethylaminoethyl methacrylate) (PDMAEMA) as the gene delivery vectors, the block copolymers exhibited significantly enhanced hemolytic activity at endosomal pH, and the plasmid DNA (pDNA)-loaded polyplexes showed efficient endosomal escape compared with PDMAEMA, ultimately achieving dramatically increased gene transfection efficacy. These results suggest that the polymers that integrate alkyl and imidazolyl moieties for efficient endosomal escape have wide potential applications for intracellular gene delivery

    Integrated Nanoparticles To Synergistically Elevate Tumor Oxidative Stress and Suppress Antioxidative Capability for Amplified Oxidation Therapy

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    The improved antioxidant system of cancer cells renders them well-adaptive to the intrinsic oxidative stress in tumor tissues. On the other hand, cancer cells are more sensitive to elevated tumor oxidative stress as compared with normal cells due to their deficient reactive oxygen species-eliminating systems. Oxidation therapy of cancers refers to the strategy of killing cancer cells through selectively increasing the oxidative stress in tumor tissues. In this article, to amplify the oxidation therapy, we develop integrated nanoparticles with the properties to elevate tumor oxidative stress and concurrently suppress the antioxidative capability of cancer cells. The amphiphilic block copolymer micelles of poly­(ethylene glycol)-<i>b</i>-poly­[2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)­benzyl)­oxy)­carbonyl)­oxy)­ethyl methacrylate] (PEG-<i>b</i>-PBEMA) are integrated with palmitoyl ascorbate (PA) to form hybrid micelles (PA-Micelle). PA molecules at pharmacologic concentrations serve as a prooxidant to upregulate the hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) level in tumor sites and the PBEMA segment exhibits H<sub>2</sub>O<sub>2</sub>-triggered release of quinone methide for glutathione depletion to suppress the antioxidative capability of cancer cells, which synergistically and selectively kill cancer cells for tumor growth suppression. Given the significantly low side toxicity against normal tissues, this novel integrated nanoparticle design represents a novel class of nanomedicine systems for high-efficiency oxidation therapy with the potentials to be translated to clinical applications

    Matrix Metalloproteinase-Responsive Multifunctional Peptide-Linked Amphiphilic Block Copolymers for Intelligent Systemic Anticancer Drug Delivery

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    The amphiphilic block copolymer anticancer drug nanocarriers clinically used or in the progress of clinical trials frequently suffer from modest final therapeutic efficacy due to a lack of intelligent features. For example, the biodegradable amphiphilic block copolymer, poly­(ethylene glycol)-<i>b</i>-poly­(d,l-lactide) (PEG–PDLLA) has been approved for clinical applications as a paclitaxel (PTX) nanocarrier (Genexol–PM) due to the optimized pharmacokinetics and biodistribution; however, a lack of intelligent features limits the intracellular delivery in tumor tissue. To endow the mediocre polymer with smart properties via a safe and facile method, we introduced a matrix metalloproteinase (MMP)-responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG–<i>GPLGVRGDG</i>–PDLLA (<b>P1</b>). <b>P1</b> was further self-assembled into micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered dePEGylation due to cleavage of the peptide linkage. Moreover, the residual VRGDG sequences are retained on the surface of the NPs after dePEGylation, which can serve as ligands to facilitate the cellular uptake. The cytotoxicity of PTX loaded in <b>P1</b> NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG–<i>GPLGVRG</i>–PDLLA (<b>P2</b>) and PEG–PDLLA (<b>P3</b>) NPs. In vivo studies confirmed that PTX-loaded <b>P1</b> NPs show prolonged blood circulation, which are similar to <b>P2</b> and <b>P3</b> NPs but exhibit more-efficient accumulation in the tumor site. Ultimately, PTX-loaded <b>P1</b> NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration. Therefore, the strategy by facile incorporation of a responsive peptide linkage between PEG and PDLLA is a promising approach to improving the therapeutic efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles

    Thiolactone Chemistry-Based Combinatorial Methodology to Construct Multifunctional Polymers for Efficacious Gene Delivery

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    Hydrophobic segments and amino moieties in polymeric nonviral gene vectors play important roles in overcoming a cascade of barriers for efficient gene delivery. However, it remains a great challenge to facilely construct well-defined multifunctional polymers through optimization of the amino and hydrophobic groups. Herein, we choose thiolactone chemistry to perform the ring opening reaction of varying hydrophobic groups-modified thiolactones by various amines to generate mercapto groups for further Michael addition reaction with poly­[2-(acryloyloxy)­ethyl methacrylate] (PAOEMA). Based on the combinatorial methodology, a series of multifunctional polymers were prepared and screened. The polymer (P3D) from tetraethylenepentamine and heptafluorobutyric acid-functionalized thiolactone is the most efficacious one with significantly higher gene transfection efficiency and lower cytotoxicity compared with polyethylenimine (PEI) (branched average <i>M</i><sub>w</sub> ∼ 25 000 Da) and Lipofectamine 2000. Cellular uptake and intracellular distribution studies indicate that P3D complexes show high-efficiency endocytosis and excellent endosomal escape. Accordingly, thiolactone chemistry-based combinatorial methodology allows for facile integration of multifunctional groups to prepare simultaneous efficacious and low-cytotoxic gene delivery vectors

    Smart Asymmetric Vesicles with Triggered Availability of Inner Cell-Penetrating Shells for Specific Intracellular Drug Delivery

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    Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nanocarriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly­(ethylene glycol)-<i>GPLGVRG</i>-<i>b</i>-poly­(ε-caprolactone)-<i>b</i>-poly­(3-guanidinopropyl methacrylamide) (PEG-<i>GPLGVRG</i>-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9% and 91%, respectively. Upon treatment with MMP-2 to cleave the stealthy PEG shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76% exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (∼10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors

    Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin

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    Construction of efficient doxorubicin (DOX) delivery systems addressing a cascade of physiological barriers remains a great challenge for better therapeutic efficacy of tumors. Herein, we design well-defined enzyme-responsive peptide-linked block copolymer, PEG-<i>GPLG­VRGDG</i>-P­(BLA-<i>co</i>-Asp) [PEG and P­(BLA-<i>co</i>-Asp) are poly­(ethylene glycol) and partially hydrolyzed poly­(β-benzyl l-aspartate) (PBLA), respectively] (<b>P3</b>), with modular functionality for efficient delivery of DOX. The block copolymers were successfully obtained via click reaction to introduce peptide (<i>alkynyl</i>-GPLGVRGDG) into the end of PEG for initiating ring-opening polymerization of β-benzyl l-aspartate <i>N</i>-carboxyanhydride (BLA-NCA) by terminal amino groups followed by partial hydrolysis of PBLA segments. <b>P3</b> micelle was demonstrated to encapsulate DOX efficiently through synergistic effect of benzyl group-based hydrophobic and carboxyl moiety-based electrostatic interactions. Effective matrix metalloproteinase-2 (MMP-2)-triggered cleavage of peptide for dePEGylation of <b>P3</b> micelles was confirmed and residual RGD ligands were retained on the surfaces. Against HT1080 cells overexpressing MMP-2, DOX-loaded <b>P3</b> micelles showed approximately 4-fold increase of the cellular internalization amount as compared with free DOX and half maximal inhibitory concentration (IC<sub>50</sub>) value of DOX-loaded <b>P3</b> micelles was determined to be 0.38 μg/mL compared with 0.66 μg/mL of free DOX due to MMP-triggered dePEGylation, RGD-mediated cellular uptake, and rapid drug release inside cells. Binding and penetration evaluation toward HT1080 multicellular tumor spheroids (MCTs) confirmed high affinity and deep penetration of <b>P3</b> micelles in tumor tissues. This modular design of enzyme-responsive block copolymers represents an effective strategy to construct intelligent drug delivery vehicles for addressing a cascade of delivery barriers
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