L-Glucose-Modified Mirror-Image Zinc Phthalocyanine Photosensitizers for Enhanced Tumor-Targeted Photodynamic Therapy

Photodynamic therapy (PDT), a non-invasive treatment, has attracted significant attention in the field of cancer therapy. However, its clinical efficacy is largely restricted by the targeted retention ability of photosensitizers (PSs) in tumor tissues. Currently, a well-recognized strategy to enhance drug targeting is to conjugate targeting molecules to anti-cancer drugs. Due to the high demand for rapid proliferation, cancer cells take up D-Glucose at a much higher rate than normal cells. This characteristic has made D-Glucose a widely used targeting molecule in clinical applications. In recent years, the field of mirror-image biology has witnessed a surge in research. Studies have shown that mirror-image molecules are resistant to decomposition by natural enzymes. Mirror-image drugs developed based on this principle are expected to have longer half-lives, enabling more desirable lesion enrichment. To date, there has been limited research on the effects of L-Glucose modification on drug properties. Therefore, in this paper, we synthesized D-glucose and L-Glucose modified mirror-image zinc phthalocyanine PSs, D-GluPc and L-GluPc. Preliminary investigations indicated that the modification of D-GluPc and L-GluPc improved the targeting ability of zinc phthalocyanine. Moreover, changing the chirality of glucose did not affect the spectral, photophysical, and photochemical properties, sub-organelle distribution, or in vitro anti-tumor activity of phthalocyanine. Nevertheless, compared with D-GluPc, L-GluPc exhibited a significantly enhanced targeted retention ability in in-vivo tumor tissues, leading to superior anti-tumor activity in PDT. This may be attributed to the unique advantages of the mirror-image drug L-GluPc.