15 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

    Multifunctional Polymeric Micelles with Amplified Fenton Reaction for Tumor Ablation

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    Relative to normal cells, tumor cells lack adequate capability of reactive oxygen scavenging. Thus, tumor cells can be selectively killed by increasing the concentration of reactive oxygen species in tumor tissue. In this report, we construct an integrated multifunctional polymeric nanoparticle which can selectively improve hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) levels in tumor tissue and convert them into more active hydroxyl radicals by Fenton reaction. First, the diblock copolymers containing polyethylene glycol (PEG) and poly­(glutamic acid) modified by <i>β-</i>cyclodextrin (β-CD) were synthesized. The block copolymer, ferrocenecarboxylic acid hexadecyl ester (DFc), and ascorbyl palmitate (PA) were coassembled in aqueous solution to obtain stable core–shell micelles through the inclusion complexation between β-CD moieties in the block copolymer and ferrocene (Fc) groups from DFc. After intravenous injection, the particles achieved significant accumulation in tumor tissue where ascorbic acid at the pharmacological concentration promotes the production of H<sub>2</sub>O<sub>2</sub>, and subsequently Fenton reaction was catalyzed by Fc groups to produce hydroxyl radicals to efficiently kill cancer cells and suppress tumor growth. The micellar systems possess great potentials toward cancer therapy through synergistic H<sub>2</sub>O<sub>2</sub> production and conversion into hydroxyl radicals specifically in tumor tissue

    Facile Preparation and Radiotherapy Application of an Amphiphilic Block Copolymer Radiosensitizer

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    Radiosensitizer plays an important role in the cancer radiotherapy for efficient killing of hypoxic cancer cells at a low radiation dose. However, the commercially available small molecular radiosensitizers show low efficiency due to poor bioavailability in tumor tissues. In this report, we develop a novel amphiphilic block copolymer radiosensitizer, metronidazole-conjugated poly­(ethylene glycol)-<i>b</i>-poly­(γ-propargyl-l-glutamate) (PEG-<i>b</i>-P­(PLG-<i>g</i>-MN)), which can be self-assembled into core–shell micelles (MN-Micelle) with an optimal size of ∼60 nm in aqueous solution. In vitro cytotoxicity evaluation indicated that MN-Micelle sensitized the hypoxic cancer cells more efficiently under radiation with the sensitization enhancement ratio (SER) of 1.62 as compared with that of commercially available sodium glycididazole (GS; SER = 1.17) at the metronidazole-equivalent concentration of 180 μg/mL. Upon intravenous injection of MN-Micelle into the tumor-bearing mice, high tumor deposition was achieved, which finally suppressed tumor growth completely after electron beam radiation at a low radiation dose of 4 Gy. MN-Micelle with outstanding performance as an in vivo radiosensitizer holds great potentials for translation into radiotherapy application

    Multifunctional Mesoporous Hollow Cobalt Sulfide Nanoreactors for Synergistic Chemodynamic/Photodynamic/Photothermal Therapy with Enhanced Efficacy

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    The unique tumor microenvironment (TME) characteristic of severe hypoxia, overexpressed intracellular glutathione (GSH), and elevated hydrogen peroxide (H2O2) concentration limit the anticancer effect by monotherapy. In this report, glucose oxidase (GOx)-encapsulated mesoporous hollow Co9S8 nanoreactors are constructed with the coverage of polyphenol diblock polymers containing poly(oligo(ethylene glycol) methacrylate) and dopamine moieties containing methacrylate polymeric block, which are termed as GOx@PCoS. After intravenous injection, tumor accumulation, and cellular uptake, GOx@PCoS deplete GSH by Co3+ ions. GOx inside the nanoreactors produce H2O2 via oxidation of glucose to enhance •OH-based chemodynamic therapy (CDT) through the Fenton-like reaction under the catalysis of Co2+. Moreover, Co3+ ions possess catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia. Upon 808 nm laser irradiation, GOx@PCoS exhibit photothermal and photodynamic effects with a high photothermal conversion efficiency (45.06%) and generation capacity of the toxic superoxide anion (•O2–) for photothermal therapy (PTT) and photodynamic therapy (PDT). The synergetic antitumor effects can be realized by GSH depletion, starvation, and combined CDT, PTT, and PDT with enhanced efficacy. Notably, GOx@PCoS can also be used as a magnetic resonance imaging (MRI) contrast agent to monitor the antitumor performance. Thus, GOx@PCoS show great potentials to effectively modulate TME and perform synergistic multimodal therapy

    Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified Oxidation-Triggered Drug Release

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    The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (∼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (∼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release

    Polyplex Micelles with Thermoresponsive Heterogeneous Coronas for Prolonged Blood Retention and Promoted Gene Transfection

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    Adequate retention in blood circulation is a prerequisite for construction of gene delivery carriers for systemic applications. The stability of gene carriers in the bloodstream requires them to effectively resist protein adsorption and maintain small size in the bloodstream avoiding dissociation, aggregation, and nuclease digestion under salty and proteinous medium. Herein, a mixture of two block catiomers consisting of the same cationic block, poly­{<i>N</i>-[<i>N</i>-(2-aminoethyl)-2-aminoethyl]­aspartamide} (PAsp­(DET)), but varying shell-forming blocks, poly­[2-(2-methoxyethoxy) ethyl methacrylate] (PMEO<sub>2</sub>MA), and poly­[oligo­(ethylene glycol) methyl ether methacrylate] (POEGMA), was used to complex with plasmid DNA (pDNA) to fabricate polyplex micelles with mixed shells (MPMs) at 20 °C. The thermoresponsive property of PMEO<sub>2</sub>MA allows distinct phase transition from hydrophilic to hydrophobic by increasing incubation temperature from 20 to 37 °C, which results in a distinct heterogeneous corona containing hydrophilic and hydrophobic regions at the surface of the MPMs. Subsequent study verified that this transition promoted further condensation of pDNA, thereby giving rise to improved complex and colloidal stability. The proposed system has shown remarkable stability in salty and proteinous solution and superior tolerance to nuclease degradation. As compared with polyplex micelles formed from single POEGMA-<i>b</i>-PAsp­(DET) block copolymer, in vivo circulation experiments in the bloodstream further confirmed that the retention time of MPMs was prolonged significantly. Moreover, the proposed system exhibited remarkably high cell transfection activity especially at low N/P ratios and negligible cytotoxicity and thus portends promising utility for systemic gene therapy applications

    Polyprodrug Amphiphiles: Hierarchical Assemblies for Shape-Regulated Cellular Internalization, Trafficking, and Drug Delivery

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    Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-<i>b</i>-PCPTM polyprodrug amphiphiles, where PEG is poly­(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy

    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
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