Dual-Programmable Semiconducting Polymer NanoPROTACs for Deep-Tissue Sonodynamic-Ferroptosis Activatable Immunotherapy.

Proteolysis-targeting chimeras (PROTACs) can provide promising opportunities for cancer treatment, while precise regulation of their activities remains challenging to achieve effective and safe therapeutic outcomes. A semiconducting polymer nanoPROTAC (SPNFeP ) is reported that can achieve ultrasound (US) and tumor microenvironment dual-programmable PROTAC activity for deep-tissue sonodynamic-ferroptosis activatable immunotherapy. SPNFeP is formed through a nano-precipitation of a sonodynamic semiconducting polymer, a ferroptosis inducer, and a newly synthesized PROTAC molecule. The semiconducting polymers work as sonosensitizers to produce singlet oxygen (1 O2 ) via sonodynamic effect under US irradiation, and ferroptosis inducers react with intratumoral hydrogen peroxide (H2 O2 ) to generate hydroxyl radical (·OH). Such a dual-programmable reactive oxygen species (ROS) generation not only triggers ferroptosis and immunogenic cell death (ICD), but also induces on-demand activatable delivery of PROTAC molecules into tumor sites. The effectively activated nanoPROTACs degrade nicotinamide phosphoribosyl transferase (NAMPT) to suppress tumor infiltration of myeloid-derived suppressive cells (MDSCs), thus promoting antitumor immunity. In such a way, SPNFeP mediates sonodynamic-ferroptosis activatable immunotherapy for entirely inhibiting tumor growths in both subcutaneous and 2-cm tissue-covered deep tumor mouse models. This study presents a dual-programmable activatable strategy based on PROTACs for effective and precise cancer combinational therapy.

Accompanying photocytotoxic activity of gold nanoechinus and zinc phthalocyanine on cancerous cell lines.

BACKGROUND: Near-infrared triggered photodynamic therapy (NIR-PDT) has been introduced as a relatively deep tumor treatment modality. The gold Nanoechinus (Au NE) is a rare type of nanostructures that act as a transducer to change NIR wavelength to ultraviolet (UV) and visible lights. During the photodynamic process, Au nanoechinus (Au NE) converts the irradiation of 980 nm to 674 nm which is absorbed by Zn(II) Phthalocyanine tetrasulfonic acid (ZnPcS). In this study the cooperation effect of Au NE and ZnPcS in PDT on MCF7 and Hela cells was investigated. METHODS: Cytotoxicity and phototoxicity of the composition having different concentrations of Au NE and ZnPcS upon irradiation of 980 nm NIR light were evaluated against MCF7 and Hela cells after two different incubation times and irradiating with two different power densities of laser. RESULTS: Among different experimental groups, in MCF7 cells, which were incubated for 48 h with 50 µg/mL Au NE+2µM ZnPcS and were treated by 980 nm laser with a power density of 200 mW cm-2 for 15 and 30 min, 48 and 38% cell viability were recorded. No appreciable result was observed due to PDT of Hela cells. CONCLUSIONS: Comparing to other PDT modalities against MCF7 cells, NIR-PDT procedure suggested in this study with the synergistic effect of Au NE and ZnPcS could be a secure promising modality in the treatment of deep-seated tumors. Carefully increasing the power density and ambient temperature, to the extent of skin tolerance threshold value, seems to be efficient in the treatment of Hela cells.