Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor (S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.
Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano-Pt) as a catalase-like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano-Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano-Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed "nano-Pt/VP@MLipo," is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano-Pt catalyzation improves the VP-mediated PDT, which in turn triggers the release of nano-Pt via membrane permeabilization. The ultrasmall 3-5 nm nano-Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano-Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.
Liposomal drug delivery for cancer therapy can be limited due to drug leakage in circulation. Here, we develop a new method to enhance the stability of actively loaded liposomal doxorubicin (DOX) through embedding a stiff nanobowl in the liposomal water cavity. Nanobowl-supported liposomal DOX (DOX@NbLipo) resists the influence of plasma protein and blood flow shear force to prevent drug leakage. This approach yields improved drug delivery to tumor sites and enhanced antitumor efficacy. Compared to alternative methods of modifying liposome surface and composition for stability, this approach designs a physical support for an all-aqueous nanoliposomal cavity. Nanobowl stabilization of liposomes is a simple and effective method to improve carrier stability and drug delivery.
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