RESUMO
BACKGROUND: Photodynamic therapy (PDT) is a promising technique for cancer treatment; however, low tissue permeability for irradiating light and insufficient photosensitizer (PS) accumulation in tumors limit its clinical potential. Nanoparticles are engineered to improve selective drug delivery to tumor sites, but its accumulation is highly variable between tumors and patients. Identifying PS accumulation peak in a personalized manner is crucial for therapeutic outcome. Magnetic nanoparticles (MNPs) provide opportunity for tracking drug accumulation in dynamics using non-invasive magnetic resonance imaging (MRI). The purpose of the study was to evaluate MNP loaded with PS as a theranostic tool for treating cancer in mice xenograft colon cancer models. METHODS: MNPs coated with human serum albumin (HSA) were loaded with bacteriochlorine a. MRI, atomic emission spectroscopy (AES) and fluorescent imaging were used to study MNP and drug accumulation rates and dynamics in CT26 tumors. Tumor growth curves were evaluated in animals that received PDT at different time points upon MNP systemic injection. RESULTS: Peak MNP accumulation in tumors was detected by MRI 60 min post injection (pi) and the data were verified by AES and fluorescent imaging. Up to 17% of injected dose/g of tissue was delivered to malignant tissues 24 h after injection. Consistent with MRI predicted drug accumulation peak PDT performed 60 min after intravenous injection was more efficient in inhibiting tumor growth than treatment scheduled 30 min and 240 min pi. CONCLUSIONS: PS loading on HAS-coated MNPs is a perspective approach to increase drug delivery to tumor site. Tracking for MNP accumulation by MRI can be used to predict drug concentration peak in tumors and to adjust PDT time scheduling for improved antitumor response.
RESUMO
Reactive oxygen species generated by photosensitizers are efficacious remedy for tumor eradication. Eleven cycloimide derivatives of bacteriochlorin p (CIBCs) with different N-substituents at the fused imide ring and various substituents replacing the 3-acetyl group were evaluated as photosensitizers with special emphasis on structure-activity relationships. The studied CIBCs absorb light within a tissue transparency window (780-830 nm) and possess high photostability at prolonged light irradiation. The most active derivatives are 300-fold more phototoxic toward HeLa and A549 cells than the clinically used photosensitizer Photogem due to the substituents that improve intracellular accumulation (distribution ratio of 8-13) and provide efficient photoinduced singlet oxygen generation (quantum yields of 0.54-0.57). The substituents predefine selective CIBC targeting to lipid droplets, Golgi apparatus, and lysosomes or provide mixed lipid droplets and Golgi apparatus localization in cancer cells. Lipid droplets and Golgi apparatus are critically sensitive to photoinduced damage. The average lethal dose of CIBC-generated singlet oxygen per volume unit of cell was estimated to be 0.22 mM. Confocal fluorescence analysis of tissue sections of tumor-bearing mice revealed the features of tissue distribution of selected CIBCs and, in particular, their ability to accumulate in tumor nodules and surrounding connective tissues. Considering the short-range action of singlet oxygen, these properties of CIBCs are prerequisite to efficient antitumor photodynamic therapy.
