Liposomal Cu-64-PET Imaging of Anti-VEGF Drug Effects on Liposomal Delivery to Colon Cancer Xenografts

Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with Cu-64 for positron emission tomography (PET) to image tumor localization. Bevacizumab (bev), a VEGF targeted antibody, may modify LP delivery by altering tumor EPR and this change can also be imaged. Objective: Assess the utility of Cu-64-labeled LP for PET in measuring altered LP delivery early after treatment with bev. Methods: HT-29 human colorectal adenocarcinoma tumors were grown subcutaneously in SCID mice. Empty LP MM-DX-929 (Merrimack Pharmaceuticals, Inc.Cambridge, MA) were labeled with (CuCl2)-Cu-64 chelated with 4-DEAP-ATSC. Tumor-bearing mice received similar to 200-300 mu Ci of Cu-64-MM-DX-929 and imaged with microPET. All mice were scanned before and after the treatment period, in which half of the mice received bev for one week. Scans were compared for changes in LP accumulation during this time. Initially, tissues were collected after the second PET for biodistribution measurements and histological analysis. Subsequent groups were divided for further treatment. Tumor growth following bev treatment, with or without LP-I, was assessed compared to untreated controls. Results: PET scans of untreated mice showed increased uptake of Cu-64-MM-DX-929, with a mean change in tumor SUVmax of 43.9%+/- 6.6% (n=10) after 7 days. Conversely, images of treated mice showed that liposome delivery did not increase, with changes in SUVmax of 7.6%+/- 4.8% (n=12). Changes in tumor SUVmax were significantly different between both groups (p=0.0003). Histology of tumor tissues indicated that short-term bev was able to alter vessel size. Therapeutically, while bev monotherapy, LP-I monotherapy, and treatment with bev followed by LP-I all slowed HT-29 tumor growth compared to controls, combination provided no therapeutic benefit. Conclusions: PET with tracer LP Cu-64-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to untreated controls. Imaging with Cu-64-MM-DX-929 is sensitive enough to measure drug-induced changes in LP localization which can have an effect on outcomes of treatment with LP.