Abstract
Combination chemotherapy has become the primary strategy against cancer multidrug resistance; however, accomplishing optimal pharmacokinetic delivery of multiple drugs is still challenging. Herein, we report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. In acidic tumour environments, the positive charge generated by the protonation of the diisopropylamine moiety facilitated the cellular uptake of the particles. Upon internalization, the acidic endosomal pH condition and intracellular glutathione regulated the sequential release of the drugs in a time-dependent manner, providing a promising therapeutic approach to overcoming drug resistance during cancer treatment.
Highlights
Drug delivery systems using nanocarriers, such as polymeric and inorganic nanoparticles, are promising tools for providing sequential drug release in a one-tablet format owing to their tunable drug loading and release capabilities[17,18,19,20]
Hydrophilic drugs can be loaded to the inner space of the hollow silica nanoparticles with a high loading efficiency, and hydrophobic drugs can be loaded on the mesoporous surface of Hollow mesoporous silica nanoparticles (HMSNs) by physical adsorption[1,29,30,31,32]
Upon internalization, a higher density of the cationic charge on the polymer shell is further generated at more acidic milieu of endosomes, resulting in the swelling of the polymer gatekeepers that induces the release of a hydrophilic drug, verapamil hydrochloride (Ver), and blocks the drug efflux pump P-glycoprotein which is the major protein for drug resistance[35,36,37,38]
Summary
Polymer Gatekeeper–Hollow Silica received: 28 September 2016 accepted: 22 March 2017 Published: 24 April 2017. We report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. We present a new class of drug delivery strategy for spatiotemporal release of different multiple drugs in a sequential manner by exploiting a pH- and redox-triggered release system using polymer-gated HMSNs (Fig. 1). At the acidic pH of tumour environments, the protonated DPA generates a positive surface charge on the HMSN that enhances the opportunity for tumour-targeted cellular uptake. Each drug was loaded into HMSNs without any chemical modifications, using a simple and robust method of combination of two different drugs
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