Abstract
Cancer is the leading cause of death and the most important obstacle to increasing life expectancy. With the sophisticated design and research of anticancer drugs, multidrug resistance to chemotherapy has become more and more common. After the emergence of multidrug resistance, the development of a new drug is beset with difficulties. The repurposing of non-anticancer drugs is thus a timely strategy for cancer therapy. Here, we highlight the potential of repurposing siramesine, a central nervous system drug for antitumor research and we construct a metal organic framework-based nanoplatform for effective intracellular accumulation and pH-response siramesine release. The released drug induces lysosome membrane permeabilization, leading to lysosomal cathepsins leakage and then results in cell apoptosis. Due to the modification of folic acids, the constructed drug delivery nanosystem shows good biocompatibility and efficient cancer cell targeting. Importantly, the drug delivery system shows enhanced anticancer efficacy in vitro, which not only effectively kills cancer cells but also kills multidrug resistant cells. Thus, the drug delivery nanosystem constructed in this study is thought to become a promising anticancer agent for cancer therapy and even overcoming multidrug resistance, which provides good prospects for biomedical applications.
Highlights
Malignant tumors are still a huge threat to human health and well-being.[1]
Cells were incubated in Dulbecco's Modi ed Eagle's Medium (DMEM; MCF-7) or Roswell Park Memorial Institute (RPMI) 1640 medium (MCF-7/ADR, MCF-10A) with 10% fetal bovine serum (FBS) and 100 U mLÀ1 of penicillin and streptomycin
A er the material synthesis, transmission electron microscope (TEM) characterization was carried out to observe the morphology of zeolitic imidazolate framework-8 (ZIF-8), ZIF-8@Sira and ZIF-8@Sira/FA
Summary
Lysosomes were regarded as the cell's recycling bin, because they were involved in multiple cellular processes such as membrane repair, pathogen resistance and autophagy.[7,8] Later, the concept of lysosome cell death was presented and the role of lysosomal cathepsin leakage as a signi cant mediator of cell decease was proposed.[6]. Folate (FA)-mediated targeting has been widely used because that FA can be recognized by FA receptors overexpressed on the surfaces of the cancer cells and the receptor mediated endocytosis can increase the intracellular accumulation of drugs.[20,21,22] Polyethylene glycol (PEG) was thought to be the safest material to modify nanoparticles to improve the biocompatibility and prolong the circulation time.[23] PEG–FA was coated on ZIF-8, which enables the better stability and tumor targeting of nanomaterials. A er that, the pH-sensitive ZIF-8 was able to release drugs in the acidic endo/lysosomal environment and the efflux of siramesine trended to kill cancer cells by Scheme 1 Schematic illustration of the synthetic process and therapeutic functions of the ZIF-8@Sira/FA. This work offers the great potential applications of nonanticancer drugs for cancer therapy and broadens the utilization of ZIF-8 in the biomedical eld with higher anticancer activity and lower side effects
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