Potent peptide-conjugated silicon phthalocyanines for tumor photodynamic therapy

Abstract

Phthalocyanines (Pcs) are a group of promising photosensitizers for use in photodynamic therapy (PDT). However, their extremely low solubility and their strong tendency to aggregate in aqueous solution greatly restrict their application. Conjugation of Pc macrocycles with peptide ligands could be a very useful strategy to optimize the physical properties of Pcs not only by increasing their water solubility and reducing their aggregation but also by endowing the conjugates with a tumor-targeting capability. To develop highly potent photosensitizers for tumor PDT, we prepared new peptide-conjugated photosensitizers using silicon Pc (SiPc), which has much higher photodynamic activity than zinc Pcs, as the light activation moiety and the cRGDfK peptide (or simply cRGD) as the peptide moiety. A polyethylene glycol linker and an extra carboxylic acid group were also tested for introduction into the conjugates to optimize the conjugate structure. The conjugates' photophysical and photodynamic behaviors were then carefully evaluated and compared using in vitro and in vivo experiments. One of the prepared conjugates, RGD-(Linker)2-Glu-SiPc, showed excellent physical properties and photodynamic activity, with an EC50 (half maximal effective concentration) of 10-20 nM toward various cancer cells. This conjugate eradicated human glioblastoma U87-MG tumors in a xenograft murine tumor model after only one dose of photodynamic treatment, with no tumor regrowth during observation for up to 35 days. The conjugate RGD-(Linker)2-Glu-SiPc thus showed highly promising potential for use in tumor treatment.

Silicon phthalocyanines: synthesis and resurgent applications

“…In a recent example, only one of the axial carboxylic acid groups in a symmetrical SiPc was subjected to a typical amide coupling reaction to form a series of unsymmetrical SiPc-peptide conjugates. 62 Symmetrical and unsymmetrical SiPcs with axial Si-C bonds. The formation and isolation of SiPcs with direct Si-C axial bonds have been comparatively difficult because of two prime reasons: i) cationic nature of hexa-coordinated silicon which instead prefers bonding with electronegative elements such as oxygen and chloride and ii) photo-instability of Si-C bonds.…”

Targeting Integrins in Cancer Nanomedicine: Applications in Cancer Diagnosis and Therapy

“…Li et al used c[RGDfK(Ac-SCH 2 CO)] peptides conjugated with albumin-based NPs with a photosensitizer IRDye 700DX to treat ovarian cancer in three dimensional (3D) culture, and the results showed a significant cytotoxic effect in cancer cells [210]. Other studies have also shown promising results regarding the use of integrin-targeted NPs to deliver photosensitizing agents to cancer cells [211][212][213].…”

Nano-Mediated Photodynamic Therapy for Cancer: Enhancement of Cancer Specificity and Therapeutic Effects

“…This family of tetrapyrrolic structures with incorporated central metal ions is also used for the treatment of non-invasive cancers, and designated as a second generation of PSs with improved photophysical and photodynamic properties over those of porphyrins. These tetrapyrrolic macrocycles strongly absorb light in the near-infrared region of the visible spectrum and are proven to effectively kill malignant tumors during PDT [ 42 , 43 , 44 ]. One of the major downfalls of this family of PSs is the lack of adequate water solubility.…”

“…One of the major downfalls of this family of PSs is the lack of adequate water solubility. This issue can be overcome by adding charged particles, carbohydrates, or peptide ligands to the periphery of phthalocyanines to give rise to third generation PSs [ 44 ].…”