Autophagy inhibitors for cancer therapy: Small molecules and nanomedicines.

Autophagy is a conserved process in which the cytosolic materials are degraded and eventually recycled for cellular metabolism to maintain homeostasis. The dichotomous role of autophagy in pathogenesis is complicated. Accumulating reports have suggested that cytoprotective autophagy is responsible for tumor growth and progression. Autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), are promising for treating malignancies or overcoming drug resistance in chemotherapy. With the rapid development of nanotechnology, nanomaterials also show autophagy-inhibitory effects or are reported as the carriers delivering autophagy inhibitors. In this review, we summarize the small-molecule compounds and nanomaterials inhibiting autophagic flux as well as the mechanisms involved. The nanocarrier-based drug delivery systems for autophagy inhibitors and their distinct advantages are also described. The progress of autophagy inhibitors for clinical applications is finally introduced, and their future perspectives are discussed.

Chemo-Phototherapy with Carfilzomib-Encapsulated TiN Nanoshells Suppressing Tumor Growth and Lymphatic Metastasis.

The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.