Bifunctional polymeric conjugates for contrast-enhanced magnetic resonance imaging-guided noninvasive photodynamic therapy of cancer.

摘要

Photodynamic therapy (PDT) is a minimally invasive clinical cancer treatment modality. It involves the delivery of photosensitive drugs to target tissues, followed by their light irradiation. Upon irradiation, excited photo sensitizers react with biomolecules to produce toxic singlet oxygen species that cause cell death and tumor necrosis. Currently available photosensitizers are low molecular weight compounds, which show poor tumor specificity and low accumulation, leading to low efficacy phototoxicity. High molecular weight polymer-photosensitizer systems show increased accumulation in tumors due to enhanced permeation and retention (EPR) effect, leading to improved tumor specificity and lower toxicity. Effective therapy also requires efficient detection of tumors and determination of the timing of maximal accumulation of drugs in tumors. Contrast-enhanced magnetic resonance imaging (CE-MRI) is routinely used in clinics for tumor detection as MRI provides anatomic images with high spatial resolution. A bifunctional polymeric conjugate with both photosensitizer and MRI contrast agent will confer dual functionality of noninvasive detection of tumors using MRI and minimally invasive photodynamic treatment of cancer lesions. However, such systems for dual imaging and photodynamic therapy are currently unavailable in clinics. For this thesis research, we designed bifunctional polymeric conjugates containing photosensitizing drugs and MRI contrast agents. Such conjugates would provide efficient tumor detection and assist in determining the timing of maximal accumulation of the conjugates in tumors. Image acquisition would further allow guiding the site-directed irradiation of tumor tissues. The bifunctional conjugate, PGA-(Gd-DO3A)-Mce 6 was synthesized by covalent conjugation of Gd-DO3A and mesochlorin e6 onto high molecular weight poly(L-glutamic acid). Furthermore, PGA-(Gd-DO3A)-Mce6 was modified via conjugation of poly(ethylene glycol) (PEG) onto polymer backbone, yielding PEG-PGA(Gd-DO3A)-Mce6. Contrast-enhanced MRI studies in mice bearing MDA-MB-231 human breast carcinoma xenografts showed a higher tumor and a lower liver accumulation for PEGylated bifunctional polymeric conjugates as compared to non-PEGylated conjugates. Site-directed irradiation based upon contrast-enhanced MR images led to a significantly higher therapeutic efficacy of PDT in mice receiving PEG-PGA-(Gd-DO3A)-Mce 6 as compared to the unmodified conjugate. The bifunctional polymeric conjugates are promising for safe and effective site-directed, MRI-guided minimally invasive photodynamic therapy of cancer.