Imaging-guided stimuli-responsive delivery systems based on nanomaterials for cancer theranostics have been recognized as promising alternatives to traditional therapies in clinic. How to integrate multiple response-mediated nanoproperty (i.e., charge, size, or stability) transitions into a cascaded manner to overcome multistage biological barriers which usually demand different and even opposing nanoproperties in each stage is still a challenge. Herein, a multistage and cascaded responsive theranostic nanoplatform for imaging-traceable TRAIL gene precise delivery was prepared by a cleavable PEGylated shell and a fluorescent carbon dot (CD)-based core. The CDs as the core were prefunctionalized with polyethylenimine end-capped disulfide-bond-bearing hyperbranched poly(amido amine) (HPAP), endowing the CDs with enhanced fluorescent quantum yield (27%), intracellular degradability, and efficient gene delivery capability. The shell was fabricated by dimethylmaleic acid modification of mPEG-PEI600 copolymer and exhibited tumor microenvironment-triggered charge reversal, leading to the shell detachment from the core at the tumor site. The nanoplatform with cascaded responsive property displays prolonged blood circulation time benefiting from PEGylated shielding once being injected into blood, subsequently effective accumulation at tumor tissues from blood induced by the elevated EPR effect resulting from the microenvironment-driven synchronous charge conversion and size shrinkage, and finally controlled gene release in tumor cell cytosol facilitated by glutathione-triggered HPAP degradability. In vitro and in vivo assays demonstrated that such a blood–tissue–cell cascaded responsive nanoplatform not only possessed imaging-trackable tumor-specific delivery ability but also exhibited enhanced and selective antitumor activity through TRAIL-mediated apoptosis as well as excellent biocompatibility. This study provides a multifunctional integration strategy, paving the way for designing novel theranostic nanomedicines on the basis of precision medicine.
For cancer gene therapy, a safe and high-efficient gene carrier is a must. To resolve the contradiction between gene transfection efficiency and cytotoxicity, many polymers with complex topological structures have been synthesized, although their synthesis processes and structure control are difficult as well as the high molecular weight also bring high cytotoxicity. We proposed an alternative strategy that uses supramolecular inclusion to construct the aggregate from the small molecules for gene delivery, and to further explore the relationship between the topological assembly structure and their ability to deliver gene. Herein, PEI-1.8k-conjugating β-CD through 6-hydroxyl (PEI-6-CD) and 2-hydroxyl (PEI-2-CD) have been synthesized respectively and then assembled with diferrocene (Fc)-ended polyethylene glycol (PEG-Fc). The obtained aggregates were then used to deliver MMP-9 shRNA plasmid for MCF-7 cancer therapy. It was found that the higher gene transfection efficiency can be obtained by selecting PEI-2-CD as the host and tuning the host/guest molar ratios. With the rational modulation of supramolecular architectures, the aggregate played the functions similar to macromolecules which exhibit higher transfection efficiency than PEI-25k, but show much lower cytotoxicity because of the nature of small/low molecules. In vitro and in vivo assays confirmed that the aggregate could deliver MMP-9 shRNA plasmid effectively into MCF-7 cells and then downregulate MMP-9 expression, which induced the significant MCF-7 cell apoptosis, as well inhibit MCF-7 tumor growth with low toxicity. The supramolecular aggregates maybe become a promising carrier for cancer gene therapy and also provided an alternative strategy for designing new gene carriers.
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