Rational vivo giving a higher efficiency of ND-based therapeutics

        Rational design of the ND surface is paramount in producing and optimizing drug adsorption/release strategies. Adsorption/desorption mechanisms of drugs with differently modified NDs have been studied. Combination chemotherapy using drug cocktails is currently the most effective treatment of mutated and multidrug-resistant tumors223 . As a step toward clinical implementation of ND chemotherapeutic platform, the Feedback System Control (FSC—a technology for rapid search of optimal compositions among numerous combinations of drugs in different concentrations) was recently used to optimize millions of possible formulations with ND-DOX, ND-bleomycin, ND-mitoxantrone, and unmodified paclitaxel. The FSC picked up 57 different optimal combinations, which were tested on three different breast cancer cell lines in order to determine the global optimum of ND-drugs ratios; It turned out that these optimized ND-drugcombinations outperformed single drugs in every cell line tested224.The migration of cancer stem cells is the main reason of metastasis. As a rule, cancer stem cells are chemoresistant to conventional drug treatment. ND-epirubicin complex has been shown to kill cancer stem cells in vitro and in vivo giving a higher efficiency of ND-based therapeutics in comparison to neat epirubicin. The ND-epirubicin complex showed no toxicity to chemoresistant tumor-bearing mice 12 days post-treatment, while at the same time eliminating tumor cells involving cancer stem cells. On the contradictory, epirubicin alone was toxic to mice, resulting the loss in body weight and lower percent of survival. ND-DOX was efficient in killing tetracycline-resistant leukemia cells K562  and brain tumors in C6 and U251 MG orthotopic xenograft mice225. Normally, to get the ND-DOX across the blood-brain barrier (BBB), the material is injected intracranially. However, it will be more exciting in the future to see ND-mediated DOX delivery to brain by direct penetration through the BBB. For example, in a recent work researchers indicates that the potential of F-HPHTND-alum (where alum is aluminum oxyhydroxide) complex of 2930 ± 230 nm to penetrate through the BBB. A small fraction of injected FND-alum was observed in mice brain along with a larger fraction found in liver, spleen,and lymph nodes. ND-mediated drug delivery across the BBB can be used to treat a wider spectrum of central neural system diseases besides cancer. In particular, ND was shown to suppress the activity of the Alzheimer disease-associated amyloid-ß, BACE-1, and p-tau receptors.

       Apart from desorption, several publications studied the covalent bond cleavage mediated release in response to environment pH. In particular cis-platin, DOX, and paclitaxel liberate from their covalent conjugates with NDs, through this mechanism suppresses the proliferation of different cancer cells226. For further improvement in vivophysiological stability, silica, polymer or silica/polymer ND composites have been designed. These composites suppress the cancer cell proliferation in vitro and in vivo, desorbing the anticancer drug inside the cells in response to a slightly acidic pH in endosomes. Another recent research topic in this area is the use of ND-metal hybrid particles for photothermal ablation of tumors. The photothermal effect, also known as hyperthermia, is the conversion of the light energy into heat attain by certain nanomaterials, e.g., gold nanoparticles. As a result, high temperatures can be reached locally, leading to cell death. A new generation of theranostic photothermal agents combines fluorescent HPHTND and gold nanorods. Due to its fluorescence, ND in these mate-rials helps to locate the photothermal particles. After the particles are localized in the tumor, precise and tuned laser treatment can be applied to selectively destroy tumor lesions227.To 

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