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The critical time window between the incidence of frostbite injury and the initiation of treatment in remote snowbound areas is a determining factor for an effective therapeutic response. It is an emergency condition and challenging to treat due to the poor vascularity of affected body parts, and it requires immediate action. In addition to cold trauma-induced tissue damage, the inflammatory mediators majorly contribute to pathologic aggravations. We have designed and evaluated a topical “nano-spray gel (NSG)” formulation, which is based on a combination of liposomal heparin sodium (Hp) and ibuprofen (Ibu) for rapid relief of frostbite injury in extremely low temperatures. The scientific literature suggests that heparin is associated with rapid endothelial cell repair, normalizing blood circulation in capillaries, and has a potential role in wound healing. Hp-containing liposomes were prepared by the extruder method, which suitably formulated an ibuprofen-containing gel to obtain a nano-Spray formulation (HLp-Ibu-NSG) applicable for topical delivery. A single spray puff of the formulation delivers ∼154 mg of the gel, which corresponds to ∼205 U of heparin. In this study, heparin liposomes exhibited significant healing of wound in vitro (scratch assay, fibroblast cells) and in vivo (wound healing in Sprague Dawley rats) at a low dose. In the rat model of frostbite injury, the HLp-Ibu-NSG formulation demonstrated significant reduction in the wound area (up to ∼96%) and improvement of histopathology in 14 days as compared to the control groups. No edema and erythema were detected post-treatment of HLp-Ibu-NSG in the affected area. The underlying mechanism was delineated as a modulation of the inflammatory cytokine (IL-6, TNF-α, IL-10, IL-4) mediators at the wound site and blood circulation to foster frostbite healing. Future clinical studies on the nano-spray gel are required to evaluate its efficacy for the treatment of frostbite symptoms. The instant on-site application of this formulation might be helpful in saving extremities of soldiers, mountaineers, and pilgrims having frostbite.

The tumour site-specific stimulus responsiveness of smart drug delivery systems gives a unique system for effective therapeutic delivery with reduced toxic effects of conventional chemotherapeutic drugs. In this work, matrix metalloproteinase-2 (MMP-2)-responsive mesoporous silica nanoparticles (MSNs) were synthesized and assessed for "self-actuating" on-demand controlled drug delivery for cancer therapy. MMPs are members of protease enzymes that are generally overexpressed in cancerous tissues in all stages of cancer. MSNs have attracted significant consideration as a potential delivery system because of their robust and versatile physicochemical properties suitable to deliver the therapeutic payload. Cisplatin (Cis) was used as a model drug, which was incorporated into MSNs to evaluate targeting of lung cancer cells and their release kinetics. In this delivery system, collagen was coated on the surface of Cis-loaded MSNs (Cis-MSN) to form a capping layer, resulting in collagen-coated MSNs (Cis-col-MSN). Under normal cell conditions, a collagen-capping coat efficiently forbids the release of Cis molecules from Cis-col-MSN. The tumor microenvironment would lead to augmented drug release because of the uncapping of collagen from MSN pores due to the presence of overexpressed MMP-2 enzyme and the ensuing controlled drug release. MMP-responsive experiments have shown augmented enzyme triggered drug release. The cellular uptake and cytocompatibility studies in A549 adenocarcinomic lung cancer cell lines demonstrated that this nanocarrier could be efficiently endocytosed in 24 h and have shown favorable biocompatibility with the cells. Cytotoxicity results of Cis-col-MSN demonstrated dose-dependent toxicity. The efficacy of the Cis-col-MSN significantly enhanced with the supplementation of MMP-2 enzyme with increasing concentrations in the cell culture milieu. The efficacy of formulation was attributed to significantly enhance reactive oxygen species, cell cycle arrest, and apoptosis. It is expected that Cis-col-MSN promises a pragmatic approach to constructing an "on-demand" smart drug delivery system to deliver a therapeutic payload at the tumor site only.

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