A Paramagnetic Metal-Organic Framework Enhances Mild Magnetic Hyperthermia Therapy by Downregulating Heat Shock Proteins and Promoting Ferroptosis via Aggravation of Two-Way Regulated Redox Dyshomeostasis.

Mild magnetic hyperthermia therapy (MMHT) holds great potential in treating deep-seated tumors, but its efficacy is impaired by the upregulation of heat shock proteins (HSPs) during the treatment process. Herein, Lac-FcMOF, a lactose derivative (Lac-NH2 ) modified paramagnetic metal-organic framework (FcMOF) with magnetic hyperthermia property and thermal stability, has been developed to enhance MMHT therapeutic efficacy. In vitro studies showed that Lac-FcMOF aggravates two-way regulated redox dyshomeostasis (RDH) via magnetothermal-accelerated ferricenium ions-mediated consumption of glutathione and ferrocene-catalyzed generation of ∙OH to induce oxidative damage and inhibit heat shock protein 70 (HSP70) synthesis, thus significantly enhancing the anti-cancer efficacy of MMHT. Aggravated RDH promotes glutathione peroxidase 4 inactivation and lipid peroxidation to promote ferroptosis, which further synergizes with MMHT. H22-tumor-bearing mice treated with Lac-FcMOF under alternating magnetic field (AMF) demonstrated a 90.4% inhibition of tumor growth. This work therefore provides a new strategy for the simple construction of a magnetic hyperthermia agent that enables efficient MMHT by downregulating HSPs and promoting ferroptosis through the aggravation of two-way regulated RDH.

A disulfide-induced supra-amphiphilic co-assembly for glycosylated pro-drug-photosensitizer nanoparticles in combination therapies.

A disulfide-induced supra-amphiphilic co-assembly strategy for hydrophobic drug co-delivery in combination therapies was proposed based on a disulfide bond containing hydrophobic pro-drug-photosensitizer (BG) and a hydrophilic/targeting dimer lactose molecule (Lac-SS-Lac). The anti-tumor efficiency was significantly enhanced by the combination therapies of epidermal growth factor receptor (EGFR) targeted therapy and phototherapy in EGFR-positive and/or galectin overexpressed tumors.

Nanococktail Based on Supramolecular Glyco-Assembly for Eradicating Tumors In Vivo.

The development of robust phototherapeutic strategies for eradicating tumors remains a significant challenge in the transfer of cancer phototherapy to clinical practice. Here, a phototherapeutic nanococktail atovaquone/17-dimethylaminoethylamino-17-demethoxygeldanamycin/glyco-BODIPY (ADB) was developed to enhance photodynamic therapy (PDT) and photothermal therapy (PTT) via alleviation of hypoxia and thermal resistance that was constructed using supramolecular self-assembly of glyco-BODIPY (BODIPY-SS-LAC, BSL-1), hypoxia reliever atovaquone (ATO), and heat shock protein inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). Benefiting from a glyco-targeting and glutathione (GSH) responsive units BSL-1, ADB can be rapidly taken up by hepatoma cells, furthermore the loaded ATO and 17-DMAG can be released in original form into the cytoplasm. Using in vitro and in vivo results, it was confirmed that ADB enhanced the synergetic PDT and PTT upon irradiation using 685 nm near-infrared light (NIR) under a hypoxic tumor microenvironment where ATO can reduce O2 consumption and 17-DMAG can down-regulate HSP90. Moreover, ADB exhibited good biosafety, and tumor eradication in vivo. Hence, this as-developed phototherapeutic nanococktail overcomes the substantial obstacles encountered by phototherapy in tumor treatment and offers a promising approach for the eradication of tumors.

Pillar[5]arene based glyco-targeting nitric oxide nanogenerator for hyperthermia-induced triple-mode cancer therapy.

Nitric oxide (NO)-mediated gas therapy (GT) and alkyl radical (R•) therapy (ART) are emerging cancer therapy modes, and multi-mode therapy has been recognized as an attractive strategy for enhancing anti-cancer efficacy. In this work, a thermal-responsive R• initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIBI)-loaded glycol-targeting NO nanogenerator was constructed by first the covalent conjugation of thermal-responsive NO donor of S-nitrosothiols (RSNO) on the surface of mesoporous silica-coated gold nanorods (AuNRs@MSN), then the coating of a supramolecular complex of amino pillar[5]arene (NP5) and galactose derivative (G), and finally the loading of AIBI. The glycol-targeting NO nanogenerator demonstrated specific targeting ability to HepG2 cells owing to the recognition between galactose residues and asialoglycoprotein receptors (ASGPR). Specially, upon 808 nm near-infrared (NIR) irradiation, the AIBI-loaded NO nanogenerator generated hyperthermia to achieve photothermal therapy (PTT), and further GT and ART resulted from the thermal responsiveness of RSNO and AIBI, respectively. In vitro experiments revealed that the AIBI-loaded glyco-targeting NO nanogenerator had good biocompatibility and exhibited effective inhibition to the proliferation of HepG2 cells. This work provides a novel way to supramolecular hybrid drug delivery systems for triple-mode targeting therapy of PTT/GT/ART.

Cancer-Mitochondria Dual-Targeting Glycol/Ferrocenium-Based Polydopamine Nanoparticles for Synergistic Photothermal and Photodynamic Therapy.

A cancer-mitochondria dual-targeting nanoparticle based on lactose and ferrocenium derivatives conjugated polydopamine (PDA@Lac/Fc/Hyp) was constructed, which exhibited cancer-targeting and mitochondria-targeting ability deriving from lactose and ferrocenium derivatives due to the specific carbohydrate-protein interaction and cationic species properties, respectively. Moreover, PDA@Lac/Fc/Hyp showed great biocompatibility and phototherapeutic efficiency. This work displays a good example of constructing cancer-mitochondria dual-targeting nanoparticle for synergistic phototherapy.

A multifunctional supramolecular vesicle based on complex of cystamine dihydrochloride capped pillar[5]arene and galactose derivative for targeted drug delivery.

Background: Supramolecular vesicles are a novel class of nanocarriers that have great potential in biomedicine.Methods: A multifunctional supramolecular vesicle (CAAP5G) based on the complex of CAAP5 and galactose derivative (G) assembled via host-guest interaction was constructed. Results: Using Human embryonic kidney T (293T) cells as experimental models, the cytotoxic effects of CAAP5G was investigated to 0-50 µmol/L for 24 h. Notably, the CAAP5G vesicles revealed low-toxicity to 293T cells, it was critical to designing drug nano-carriers. Simultaneously, we have evaluated doxorubicin hydrochloride (DOX)-loaded CAAP5G vesicles anticancer efficiency, where DOX-loaded CAAP5G vesicles and free DOX incubated with Human hepatocellular carcinoma cancer cell (HpeG2 cells) and 293T cells for 24 h, 48 h, 72 h. It turned out that CAAP5G vesicles encapsulated anticancer drug (DOX) could decrease DOX side-effect on 293T cells and increase DOX anticancer efficiency. More importantly, the cysteamine as an adjuvant chemotherapy drug was released from CAAP5G vesicles in HepG2 cells where a higher GSH concentration exists. The adjuvant chemotherapy efficiency was evaluated, where free DOX and DOX-loaded CAAP5G vesicles incubated with DOX-resistance HepG2 cells (HepG2-ADR cells) for 24, 48, 72 h, respectively. Conclusion: The results revealed that the DOX encapsulated by CAAP5G vesicles could enhance the cytotoxicity of DOX and provide insights for designing advanced nano-carriers toward adjuvant chemotherapies.