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

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.