Self-Assembly of Intelligent Nanoplatform for Endogenous H2S-Triggered Multimodal Cascade Therapy of Colon Cancer.

The specific in situ generation and activation of therapeutic agents with high spatiotemporal precision is expected to revolutionize cancer treatment. Here, we develop an intelligent nanoplatform (termed as NP-Cu), which is constructed by assembling photosensitizer chlorin e6 (Ce6), hypoxia-responsive prodrug banoxantrone (AQ4N) with clickable dibenzocyclooctyne (DIBO) functionalized lysine (D-K), and cyclen-Cu2+ complex, for improving combination anticancer therapy. Cyclen-Cu2+ complex-induced photodynamic therapy (PDT) quenching in NP-Cu can be effectively and selectively activated by tumor-overproduced hydrogen sulfide (H2S). More importantly, the reaction of endogenous H2S with Cu2+ can generate photothermal agent copper sulfide (CuS) for photothermal therapy (PTT). Furthermore, with the activation of PTT and PDT, intracellular hypoxic stress is amplified to trigger AQ4N-associated chemodynamic therapy (CDT), leading to light-enhanced cascade therapy of PDT, PTT and CDT. Therefore, we present a simple and practical strategy for developing pathological stimuli responsive combination therapy, which has the potential of advancing precision cancer medicine.

Clickable amino acid derivative tuned self-assembly of antigen and adjuvant for cancer immunotherapy.

Amino acid-tuned self-assembly has become an attractive strategy for constructing various functional materials. Here, a series of dibenzocyclooctyne (DIBO) functionalized amphiphilic amino acid derivatives are designed and screened as building blocks of functional supramolecular self-assembly nanoparticles for cancer immunotherapy. One top-performing supramolecular self-assembly material (named DA6C1) is identified through combinatorial screening, and spherical nanoparticles can be easily prepared by this material tuned multicomponent synergistic self-assembly of ovalbumin (OVA) and CpG oligonucleotide. DA6C1 based nanovaccine can significantly enhance the cellular uptake of OVA and CpG into the same bone marrow derived dendritic cells (BMDCs) and greatly improve the activation of DCs. Moreover, after subcutaneous injection, this nanovaccine flows rapidly to the lymph nodes and elicits strong immune responses to achieve effective prophylactic and therapeutic effect. Therefore, our work highlights the great potential of clickable amino acid derivatives as a convenient and powerful tool to construct nanovaccine for effective immunotherapy.

Quantitative and high drug loading of self-assembled prodrug with defined molecular structures for effective cancer therapy.

Nanomedicines have made significant progress in the delivery of small molecular drugs, many challenges, however, still remain to be overcome, such as unsatisfactory drug loading, formulation instability, premature drug leakage, and poor blood circulation. Herein, an innovative glutathione (GSH)-sensitive amphiphilic dendritic prodrug with quantitative and high drug loading (>30 wt%) is reported. The multi-armed structure of prepared prodrug can self-assemble into nanoparticles in aqueous solution without the introduction of any organic solvents. The self-assembled prodrug nanoparticle is composed of the following key components: (i) polyethylene glycol (PEG) outer shell ensuring biocompatibility and prolonging blood circulation, (ii) prodrug inner core responding to GSH for triggered release of intact drug, (iii) multi-armed dendritic structure facilitating self-assembly and enhancing drug loading content, (iv) covalent drug conjugation avoiding drug leakage and improving stability, (v) defined chemical structures and quantitative drug loading easy for reproduction. Both in vitro and in vivo results show that these GSH-responsive prodrug nanoparticle exhibits significant inhibition of tumor cell growth, and is promising for efficient and safe chemotherapeutic delivery.

Enhanced gene delivery of low molecular weight PEI by flower-like ZnO microparticles.

Low molecular weight (1.8 kDa) branched polyethylenimine (PEI) has been used as non-viral vector for gene delivery because of its low toxicity, however, its further application in biomedical field has been restricted due to its low gene transfection efficiency. Herein, ZnO microflowers were prepared to increase the gene expression level mediated by PEI. Four methods have been applied to tune the shape of ZnO microstructures. Scanning electron microscopy (SEM) demonstrated the successful preparation of four kinds of flower like ZnO microparticles. By loading PEI/pDNA into ZnO microparticles, the formed new complexes showed enhanced gene transfection compared to PEI/pDNA alone. Cell uptaking experiments explained a possible mechanism that the tips of ZnO microflowers penetrated into the surface of cells, thus facilitating the entry of gene cargo into cells. These findings highlight the potential of needle like microstructure as adjuvant for efficient biomacromolecular delivery.

Biocompatible anionic polyelectrolyte for improved liposome based gene transfection.

Cationic liposomes have been widely used as efficient gene carriers. However, the serious cytotoxicity caused by exposed positive charges restricts the further application of those kinds of gene vectors. Thus, it is challenging to develop biocompatiable non-positive charge carriers to achieve high gene transfection efficiencies. Herein, we report a novel design by pasting biocompatible anionic polyelectrolyte, namely alginic acid, hyaluronic acid, pectin and polyglutamic acid, to the positive charge surface of liposome/pDNA complex. Through shielding the positive charges, the new gene carriers show decreased cytotoxicity while still maintaining high transfection efficiency. To be noted, the complex formed by coating polyglutamic acid to the surface of liposome/pDNA greatly enhanced the transfection efficiency in HepG2 cells, and the use of pectin shows increased transfection in MCF-7 cells. Hemolysis assay proved a possible mechanism that when the new gene complex was internalized into cells, as acidity increases, more side chains become hydrophobic, and thus destabilizing the endosomal membrane to accelerate DNA escape. The present results suggest that such anionic polyelectrolyte covered liposome based carrier possess promising application for clinical gene delivery.