Long-Hai Wang,Sheng-Gang Ding,Jun-Jie Yan,Ye-Zi You
Encapsulation of negatively charged plasmid DNA into a small-sized nanocapsule without using any condensing agent is very challenging up to now. Here we report a versatile method for encapsulating large-sized plasmid DNAs into small-sized bioreducible nanocapsules in which shearing force and surfactant can fold large-sized plasmid DNAs into small-sized emulsion droplets containing bioreducible branched polymers. Subsequently, temperature triggers the bioreducible branched polymers to aggregate and cross-link at the water/oil interface of the emulsion nanodroplet, forming a bioreducible shell around the nanodroplet. Thus, a small-sized nanocapsule (∼110 nm) containing large-sized plasmid DNA (∼1900 nm long) forms by removal of the surfactant.
Amphiphilic diblock poly(ε-caprolactone)-b-glycopolypeptides (PCL–SS–GPPs) bearing disulfide bonds were synthesized from a clickable poly(ε-caprolactone)–SS–poly(2-azidoethyl-L-glutamate) diblock copolymer. Galactosyl and lactosyl sugar units as targeting ligands were conjugated to the polypeptide blocks via an efficient click reaction. The chemical structures of PCL–SS–GPPs were characterized by Fourier transform infrared spectroscopy and nuclear magnetic resonance analysis. Owing to their amphiphilic nature, these copolymers could self-assemble into spherical nano-sized micelles in an aqueous medium, as confirmed by fluorometry, transmission electron microscopy, and dynamic light scattering. The hydrophobic anticancer drug doxorubicin (DOX) and superparamagnetic iron oxide (SPIO) nanoparticles (NPs), as the magnetic resonance imaging (MRI) contrast agent, were simultaneously encapsulated in the hydrophobic core of the micelles via dialysis. The release profiles of encapsulated DOX from the SPIO/DOX-loaded PCL–SS–GPPs micelles were shown to be rapid in the presence of 10 mM glutathione (GSH) within 24 h, whereas in the absence of GSH, there was less than 35% DOX released from the PCL–SS–GPPs micelles in 24 h. Inverted fluorescence microscopy revealed the specific interaction between the sugars units on the PCL–SS–GPPs surface with the FITC-lectin. MTT assay demonstrated that the blank PCL–SS–GPPs micelles were nontoxic to the HepG2 cells, even for concentrations up to 500 μg mL−1, whereas the free DOX and DOX-loaded PCL–SS–GPPs micelles showed significant cytotoxicity against the HepG2 cells. The fluorescence images and flow cytometry tests revealed that DOX could be efficiently transported into HepG2 tumor cells by PCL–SS–GPPs micelles. The PCL–SS–GPPs micelles loaded with superparamagnetic iron oxide (SPIO) nanoparticles enabled excellent MRI contrast enhancement, thus confirming their effectiveness for MR imaging.
Ruthenium-based agents are promising in cancer chemotherapy but lack specific targeting and controlled release properties. Herein, a new class of bioreducible mer-[Ru(III)Cl 3 (dmso)(L)] prodrugs with highly DNA binding affinity were designed and synthesized for nucleus-targeted chemotherapy and selective activation in response to the tumor microenvironment. In this regard, ruthenium(III) prodrugs were reduced into highly active ruthenium(II) drugs in response to high intracellular glutathione levels, resulting in tumor apoptosis through synergistic intercalation that blocked DNA replication and coordination that cleaved nuclear DNA. In light of this, a multifunctional nanodrug (Ru-MSN-PLip) was constructed by integrating RuDPNI prodrug-loaded mesoporous silica nanoparticles (Ru-MSN) with a fusion protein-incorporated liposome (PLip) to achieve multiple targeting and eGFP-based fluorescence imaging of nonsmall cell lung cancer. Due to fusion protein-based cancer cell recognition and Ru(III) prodrug-mediated nuclear DNA targeting, Ru-MSN-PLip achieved sequential delivery and greater antitumor activity. In addition, Ru-MSN-PLip exhibited long-term blood circulation and selective accumulation in tumors, leading to significantly limited tumor growth in vivo without notable toxicity. Our findings indicated the potential applications of these types of bioreducible and traceable nanoprodrugs for efficient and safe nonsmall cell lung cancer therapy.
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