Enzyme-powered Janus nanomotors launched from intratumoral depots to address drug delivery barriers

Abstract

The delivery of nanoparticles encounters a series of biological barriers from systemic clearance, tumor accumulation, cellular uptake and intracellular drug release. In this study we propose enzyme-powered nanomotors launched from intratumorally injected local depots to overcome these delivery barriers. Hydroxyapatite-embedded mesoporous silica nanoparticles (Hap@MSN) are prepared by formation of silica layers on CaCO3 nanoparticles, transformation of CaCO3 into Hap cores, and camptothecin (CPT) loading. Janus nanoparticles (JPs) are obtained by the selective deposition of gold layer on one side of Hap@MSN. Janus nanomotors (JNMs) are constructed by separately grafting hyaluronic acid (HA) and urease on the opposite sides of JPs as the targeting moiety and power source, respectively. JNMs indicate self-propelled motion under the physiological concentration of urea (5 mM), and the motion is less disturbed in the dense tumor matrix. Despite no influence on the endocytosis mechanism, the self-propelled motion and HA-mediated targeting enhance the cellular uptake and cytotoxicity of JNMs. JNMs rapidly release the encapsulated CPT in the acidic endo/lysosomes of tumor cells (pH 5.0) while maintaining their integrity (CTP release <10%) in physiological conditions (pH 7.4) and tumor matrix (pH 6.5). In addition, JNMs are loaded into electrospun fiber fragments (JNM@EF) for intratumoral administration to achieve a high retention and gradual release of JNMs in response to the slightly acidic tumor matrix (pH 6.5). The self-propelled motion promotes the deep penetration and even distribution of JNMs in tumors, dramatically enhancing the antitumor efficacy. Therefore, the launching of nanomotors from intratumoral depots is a feasible strategy to boost the antitumor efficacy via promoting the local accumulation, deep tumor penetration, tumor cell capture and intracellular release of chemotherapeutic drugs.