Nano-Scale Targeting Of Pc 4 To Improve Drug Delivery, Accumulation, And Pdt Efficacy In Brain Tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Malignant gliomas are among the most lethal cancers with a median survival expectancy of only 6-12 months. Surgical resection is the mainstay of treatment. However, curative resection is often not possible due to infiltrating growth of the tumor into normal brain. Photodynamic therapy (PDT) has been suggested as an additional therapy to guide tumor resections and enhance the effect of surgery via photoreactive treatment during or at the cessation of surgical intervention. The most difficult challenge in treating malignant brain tumors may be delivering targeted therapies that preserve healthy tissue while effectively eradicating the cancer. Therefore, improving drug delivery rate and tumor selectivity of the photosensitizing agent will dramatically reduce systemic toxicity and enhance the success of PDT. EGFR amplification is the most common genetic alteration in gliomas and plays a critical role in stimulating glioma progression, making it an ideal target. Consequently, we have developed a highly efficient EGFR-targeted gold-nanoparticle (EGF-Au NP) to improve delivery of PDT cancer drugs to tumors in vivo. EGF peptides attached to PEGylated Au NPs deliver hydrophobic PDT drug, Pc 4, to brain tumors overexpressing EGFR better than either the non-targeted Au NPs or Pc 4 alone. The drug rapidly releases and penetrates deep within tumors within 1-4 hrs. In vivo small animal imaging experiments show targeted delivery of Pc 4 to tumor sites. Ex vivo imaging of the tumors confirmed as much as a 4-fold increase in the intrinsic fluorescence of Pc 4 over non-targeted conjugates after systemic administration. Moreover, in vitro experiments show a higher concentration of Pc 4 uptake per Au NP over non-targeted Au NPs per cancer cell. Histological analysis, including confocal microscopy, shows that, after targeting, the delivered Pc 4 localizes in the endosomes of the cancer cells. Transmission electron micrographs show that Au NPs cluster along the cell surface or within discrete vesicles within the cell. Localization within the endosomal pathway may be more effective for PDT and produce less off-target toxicity than free Pc 4, which preferentially accumulates in mitochondria. Further, glioma cells treated for 4 hrs with EGF-targeted Au NP-Pc 4 and then exposed to PDT show an enhanced killing effect, especially when compared to either non-targeted Au NP-Pc 4 or free Pc 4 controls. Systemic delivery of EGF-Au NP-Pc 4 to heterotopic brain tumors reveals increasing tumor necrosis after PDT. Biodistribution experiments also show that the Au NPs and Pc 4 are effectively excreted over time. This study suggests that the EGFR-targeted Au NPs improve drug delivery to tumors for PDT and are removed from the body safely after treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1685. doi:10.1158/1538-7445.AM2011-1685