Near-Infrared Activatable Phthalocyanine–Poly‑L‑Glutamic Acid Conjugate: Enhanced in Vivo Safety and Antitumor Efficacy toward an Effective Photodynamic Cancer Therapy

We previously developed a new zinc­(II) phthalocyanine (ZnPc) derivative (<b>Pc 1</b>) conjugated to poly-L-glutamic acid (PGA) (<b>1-PG</b>) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that <b>1-PG</b> possessed high near-infrared (NIR) light absorptivity (λ_max = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that <b>1-PG</b> accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose <b>1-PG</b> (2 mg of <b>Pc 1</b> equivalent/kg) induced a greater tumor volume reduction (−74 ± 5%) when compared to high dose <b>ZnPc</b> (8 mg/kg, −50 ± 12%). At higher treatment doses (8 mg of <b>Pc 1</b> equivalent/kg), <b>1-PG</b> reduced tumor volume maximally (−91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with <b>1-PG</b> (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of <b>1-PG</b> as a useful photosensitizer candidate for clinical PDT