Background: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties. Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH). Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells. Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.

Numerous nanoparticles drug delivery systems for therapeutic implications in cancer treatment are in preclinical development as conventional chemotherapy has several drawbacks. A chemotherapeutic approach requires high doses of chemotherapeutic agents with low bioavailability, non-specific targeting, and above all, development of multiple drug resistance. In recent years, inorganic nano-drug delivery platforms (NDDPs; with a metal core) have emerged as potential chemotherapeutic systems in oncology. One of the major goals of developing inorganic NDDPs is to effectively address the targeted anti-cancer drug(s) delivery related problems by carrying the therapeutic agents to desired tumors sites. In this current review, we delve into summarizing the recent developments in targeted release of anti-cancer drugs loaded in inorganic NDDPs such as mesoporous silica nanoparticles, carbon nanotubes, layered double hydroxides, superparamagnetic iron oxide nanoparticles and calcium phosphate nanoparticles together with highlighting their therapeutic performance at tumor sites.