Light-Promoted Lysosomal Escape of a Phthalocyanine and Antisense Oligonucleotide-Complexed G‑Quadruplex for Dual Photodynamic and Antisense Therapy

• Published in: ACS pharmacology & translational science 2024-10, Vol.7 (10), p.3216-3227
• Main Authors: Tam, Dick Yan, Lau, Wendy K. M., Limanto, Yosephine Tania, Ng, Dennis K. P.
• Format: Article
• Language: English
• ISSN: 2575-9108; 2575-9108
• DOI: 10.1021/acsptsci.4c00384

Combination therapy has been proven as an effective strategy for cancer treatment. To this end, we report herein a self-assembled nucleic acid–based complex for dual photodynamic and antisense therapy. It contains a nucleolin-targeting As1411-based G-quadruplex platform, a partially hybridized antisense oligonucleotide 4625, which can inhibit the antiapoptotic protein B cell lymphoma-xL inducing apoptotic cell death, and a zinc­(II) phthalocyanine (ZnPc)-based photosensitizer held by noncovalent interactions. Through a series of in vitro experiments, we have demonstrated that this DNA complex can be internalized selectively to nucleolin-overexpressed MCF-7 and A549 cells through receptor-mediated endocytosis and is localized in the lysosomes. Upon light irradiation, the photosensitization of ZnPc triggers the formation of reactive oxygen species for cell killing and promotes the lysosomal escape of 4625 for antisense therapy. The combined therapeutic effect can eliminate the cancer cells effectively with a half maximal inhibitory concentration of ca. 0.5 μM.