Oxygen tension regulating nanoformulation for the improved photodynamic therapy of hypoxic tumors

The clinical efficacy of photodynamic therapy (PDT) is hampered by the low oxygen tension highly prevalent in solid tumors. Hence, improving the oxygen tension by suppling hyperbaric oxygen (HBO), through oxygen delivery nanoarchitectures or by designing in situ oxygen-generating nanoenzymes is considered a robust approach for PDT that involves type II photosensitizers (PS). In this study, we successfully synthesized 4-arm chlorin-polylactide (CPLA) conjugates from meta-tetra-3-hydroxymethyl phenyl chlorin (m-THMPC) and D, L-lactide via ring opening polymerization (ROP), that could assemble into stable NPs, for the delivery of molecular oxygen into inner regions of hypoxic tumors (HTs). The monodispersed Air-CPLA-NPs prevented the PS, chlorin, from aggregation-induced quenching and loss of signal. Moreover, the Air-CPLA-NPs produced a marked level of intracellular ROS or ¹O₂ upon light irradiation (660 ± 10 nm, 20 J/cm²) which is indispensable for the prolonged and efficient PDT of HTs. The confocal laser scanning microscopy (CLSM) images revealed the gradual cellular internalization of Air-CPLA-NPs in hypoxic H1299 cells. It unveiled significant dose-dependent in vitro cytotoxicity towards normoxic and hypoxic H1299 cells. Furthermore, the in vivo anticancer study displayed the tumor growth inhibition (TGI) effect of Air-CPLA-NPs + PDT in normoxic and hypoxic xenograft mice models. Accordingly, the present architecture improved the PDT efficacy by overcoming the oxygen barrier in the inner tissues of HTs demonstrating the prospect of CPLA-NPs as an "oxygen shuttle" for the clinical PDT of solid tumors.