pH-Controlled Gas-Generating Mineralized Nanoparticles: A Theranostic Agent for Ultrasound Imaging and Therapy of Cancers

We report a theranostic nanoparticle that can express ultrasound (US) imaging and simultaneous therapeutic functions for cancer treatment. We developed doxorubicin-loaded calcium carbonate (CaCO₃) hybrid nanoparticles (DOX-CaCO₃-MNPs) through a block copolymer templated <i>in situ</i> mineralization approach. The nanoparticles exhibited strong echogenic signals at tumoral acid pH by producing carbon dioxide (CO₂) bubbles and showed excellent echo persistence. <i>In vivo</i> results demonstrated that the DOX-CaCO₃-MNPs generated CO₂ bubbles at tumor tissues sufficient for echogenic reflectivity under a US field. In contrast, the DOX-CaCO₃-MNPs located in the liver or tumor-free subcutaneous area did not generate the CO₂ bubbles necessary for US contrast. The DOX-CaCO₃-MNPs could also trigger the DOX release simultaneously with CO₂ bubble generation at the acidic tumoral environment. The DOX-CaCO₃-MNPs displayed effective antitumor therapeutic activity in tumor-bearing mice. The concept described in this work may serve as a useful guide for development of various theranostic nanoparticles for US imaging and therapy of various cancers

Intracellular NO-Releasing Hyaluronic Acid-Based Nanocarriers: A Potential Chemosensitizing Agent for Cancer Chemotherapy

In this work, we investigate whether <i>S</i>-nitrosoglutathione (GSNO)-conjugated hyaluronic acid-based self-assembled nanoparticles (GSNO-HANPs) can be useful as a chemosensitizing agent to improve the anticancer activity of doxorubicin (DOX). The GSNO-HANPs were prepared by aqueous assembly of GSNO-conjugated HA with grafted poly­(lactide-<i>co</i>-glycolide). Aqueous GSNO stability shielded within the assembled environments of the GSNO-HANPs was greatly enhanced, compared to that of free GSNO. The NO release from the GSNO-HANPs was facilitated in the presence of hyaluronidase-1 (Hyal-1) and ascorbic acid at intracellular concentrations. Microscopic analysis showed GSNO-HANPs effectively generated NO within the cells. We observed that NO made the human MCF-7 breast cancer cells vulnerable to DOX. This chemosensitizing activity was supported by the observation of an increased level of ONOO^– (peroxynitrite), a highly reactive oxygen species, upon co-treatment with the GSNO-HANPs and DOX. Apoptosis assays showed that GSNO-HANP alone exhibited negligible cytotoxic effects and reinforced apoptotic activity of DOX. Animal experiments demonstrated the effective accumulation of GSNO-HANPs in solid MCF-7 tumors and effectively suppressed tumor growth in combination with DOX. This hyaluronic acid-based intracellularly NO-releasing nanoparticles may serve as a significant chemosensitizing agent in treatments of various cancers