Abstract
Cancer is a leading cause of death with rates expected to grow with life expectancy. Among leading treatments, cisplatin, widely used to combat cancer, suffers from low stability and selectivity. Here, we covalently conjugated an analog of cisplatin to biocompatible polydopamine nanoparticles (PDA-NPs) to increase both properties. Dynamic light scattering and electron microscopy studies suggest that the platinum-conjugated PDA particles (Pt–PDA-NPs) are monodispersed and spherical with a diameter of about 200 nm with platinum atoms mostly in the shell. Particles were also characterized with inductively coupled plasma mass atomic emission spectroscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy to determine the localization and amount of Pt atoms. The chelated metal did not leach from the conjugated particles under normal physiological conditions, while it was released only under acidic and oxidative conditions existing predominantly inside lysosomes and near cancer cells, suggesting their dual-stimuli responsiveness. Fluorescent microscopy confirmed that Pt–PDA-NPs are localized in the endoplasmic reticulum and internalized into cancer cells by endosomes. In cell survival experiments, particles are more toxic to human MCF-7 breast cancer cells compared to healthy NIH-3T3 cells. Mechanistic studies confirmed that the anticancer activity was induced by increased apoptosis. Field-dependent magnetization measurements suggest that Pt–PDA-NPs with a Gd3+-modified surface are paramagnetic and detectable by MRI, suggesting their promising theranostic application in cancer treatment.
Highlights
Cancer is one of the leading causes of mortality, with about 18 million deaths, and has an estimated financial cost of over 1 trillion USD.[1]
We demonstrated in this study that the release of the cisplatin analog from PDA-NPs is dual-stimuli responsive, requiring both acidic and oxidative conditions exist mainly inside lysosomes and near cancer cells
In order to produce a cisplatin-based therapeutic agent that can be used for selective targeting and imaging of cancer cells, an analog of cisplatin was synthesized (Figure 1)
Summary
Cancer is one of the leading causes of mortality, with about 18 million deaths, and has an estimated financial cost of over 1 trillion USD.[1]. Cisplatin is a square planar coordination complex of platinum with two chlorines and two ammonia groups in a cis conformation. It is hydrolyzed inside the cells to form the active monohydrated Pt complex, which interacts with guanine in the nuclear DNA, followed by displacement of another chlorine and binding to an adjacent nucleobase (guanine or cytosine).[7] This interaction causes distortion of the DNA helix, which triggers cellular processes to halt cellular division, leading to cell apoptosis. Cisplatin is effective in the treatment of a variety of cancers, disadvantages such as degradation in aqueous solutions and a high affinity for thiol-containing serum proteins limit its wide application.[8] Platinum drugs tend to develop resistance mainly due to reduced uptake, enhanced detoxification by increased production of cysteine-containing molecules, and increased
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