Zhijun Zhang

Bioinspired Therapeutic Dendrimers as Efficient Peptide Drugs Based on Supramolecular Interactions for Tumor Inhibition

Bioinspired tryptophan-rich peptide dendrimers (TRPDs) are designed as a new type of dendritic peptide drugs for efficient tumor therapy. The TRPDs feature a precise molecular structure and excellent water solubility and are obtained in a facile process. Based on the unique features of peptide dendrimers, including highly branched structures, abundant terminal groups, and globular-protein-like architectures, the therapeutic dendrimers show significant supramolecular interactions with DNA through the tryptophan residues (indole rings and amino groups). Further experimental results indicate that TRPDs are efficient antitumor agents both in vitro and in vivo.

Tumor-Specific Multiple Stimuli-Activated Dendrimeric Nanoassemblies with Metabolic Blockade Surmount Chemotherapy Resistance

Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs. In the meantime, we proposed a versatile tactic of a tumor-specific metabolism blockade for provoking several pathways (ATP restriction, apoptotic activation, and anti-apoptotic inhibition) to restrain multiple cellular factors of drug resistance. The highly efficient antitumor activity to drug-resistant MCF-7R tumor in vitro and in vivo supports this design and strongly defeats both physiological barriers and cellular factors of chemotherapy resistance. This work sets up an innovative dendrimeric nanosystem to surmount multidrug resistance, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications.

Supramolecular PEGylated Dendritic Systems as pH/Redox Dual-Responsive Theranostic Nanoplatforms for Platinum Drug Delivery and NIR Imaging

Recently, self-assembling small dendrimers into supramolecular dendritic systems offers an alternative strategy to develop multifunctional nanoplatforms for biomedical applications. We herein report a dual-responsive supramolecular PEGylated dendritic system for efficient platinum-based drug delivery and near-infrared (NIR) tracking. With a refined molecular/supramolecular engineering, supramolecular dendritic systems were stabilized by bioreducible disulfide bonds and endowed with NIR fluorescence probes, and PEGylated platinum derivatives coordinated onto the abundant peripheral groups of supramolecular dendritic templates to generate pH/redox dual-responsive theranostic supramolecular PEGylated dendritic systems (TSPDSs). TSPDSs markedly improved the pharmacokinetics and biodistribution of platinum-based drugs, owing to their stable nanostructures and PEGylated shells during the blood circulation. Tumor intracellular environment (low pH value and high glutathione concentration) could trigger the rapid disintegration of TSPDSs due to acid-labile coordination bonds and redox-cleavable disulfide linkages, and then platinum-based drugs were delivered into the nuclei to exert antitumor activity. In vivo antitumor treatments indicated TSPDSs not only provided high antitumor efficiency which was comparable to clinical cisplatin, but also reduced renal toxicity of platinum-based drugs. Moreover, NIR fluorescence of TSPDSs successfully visualized in vitro and in vivo fate of nanoplatforms and disclosed the intracellular platinum delivery and pharmacokinetics. These results confirm tailor-made supramolecular dendritic system with sophisticated nanostructure and excellent performance is a promising candidate as smart theranostic nanoplatforms.

Virus-inspired mimics: self-assembly of dendritic lipopeptides into arginine-rich nanovectors for improving gene delivery

With inspirations from natural viruses, arginine-containing dendritic lipopeptides were designed for bioinspired fabrication. Self-assembling the defined amphiphilic lipopeptides generated virus-inspired nanovectors with an arginine-rich corona. These nanovectors provided some remarkable benefits for gene delivery, including well-defined nanostructure, high transfection efficiency, serum resistance and low cytotoxicity.

Virion‐Like Membrane‐Breaking Nanoparticles with Tumor‐Activated Cell‐and‐Tissue Dual‐Penetration Conquer Impermeable Cancer

Poor drug penetration into tumor cells and tissues is a worldwide difficulty in cancer therapy. A strategy is developed for virion-like membrane-breaking nanoparticles (MBNs) to smoothly accomplish tumor-activated cell-and-tissue dual-penetration for surmounting impermeable drug-resistant cancer. Tailor-made dendritic arginine-rich peptide prodrugs are designed to mimic viral protein transduction domains and globular protein architectures. Attractively, these protein mimics self-assemble into virion-like nanoparticles in aqueous solution, having highly ordered secondary structure. Tumor-specific acidity conditions would activate the membrane-breaking ability of these virion-like nanoparticles to perforate artificial and natural membrane systems. As expected, MBNs achieve highly efficient drug penetration into drug-resistant human ovarian (SKOV3/R) cancer cells. Most importantly, the well-organized MBNs can pass through endothelial/tumor cells and spread from one cell to another one. Intravenous injection of MBNs into nude mice bearing impermeable SKOV3/R tumors suggests that the MBNs can recognize the tumor tissue after prolonged blood circulation, evoke the membrane-breaking function for robust transvascular extravasation, and penetrate into the deep tumor tissue. This work provides the first demonstration of sophisticated molecular and supramolecular engineering of virion-like MBNs to realize the long-awaited cell-and-tissue dual-penetration, contributing to the development of a brand-new avenue for dealing with incurable cancers.

Tumor-adapting and tumor-remodeling AuNR@dendrimer-assembly nanohybrids overcome impermeable multidrug-resistant cancer

Herein, smart Au nanorod@dendrimer-assembly nanohybrids (AuNR@DA NHs) were developed for adapting sequential biological barriers and remodeling tumor permeability, thereby achieving multimodal enhancement of penetration and internalization in multidrug-resistant poorly-permeable tumors. The AuNR@DA NHs possessed well-defined hybrid nanostructures, high dimensional stability, improved photothermal conversion efficiency, multistage transformations and on-demand therapeutic delivery. The tumor-adapting NHs could surmount complicated physiological barriers through enzyme/redox/pH triple-responsive features with tumor-tunable size, interface and disintegration, allowing for tumor site-specific photothermal conversion. More importantly, locally NIR-induced hyperthermia production would remodel the permeability of the tumor tissue and cell membrane to further facilitate penetration and internalization of organic drugs and inorganic nanoparticles. Encouragingly, in vitro and in vivo antitumor treatments suggested that supramolecular hybrid fabrication of theranostic AuNR@DA NHs successfully provided overwhelming chemo-photothermal effects against impermeable multidrug-resistant cancer.