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Theranostics 2017; 7(17):4229-4239. doi:10.7150/thno.21688 This issue Cite

Research Paper

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

Stephanie J. Blocker¹, Kirk A. Douglas¹, Lisa Anne Polin^{1, 3}, Helen Lee², Bart S. Hendriks², Enxhi Lalo¹, Wei Chen^{1, 3}, Anthony F. Shields^{1, 3✉}

1. Department of Oncology, Wayne State University, Detroit, MI, USA;
2. Merrimack Pharmaceuticals, Cambridge, MA, USA;
3. Karmanos Cancer Institute, Detroit, MI, USA.

✉ Corresponding author: E-mail: shieldsaorg

Abstract

Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with ⁶⁴Cu 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 ⁶⁴Cu-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 ⁶⁴CuCl₂ chelated with 4-DEAP-ATSC. Tumor-bearing mice received ~200-300 μCi of ⁶⁴Cu-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 ⁶⁴Cu-MM-DX-929, with a mean change in tumor SUV_max 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 SUV_max of 7.6%±4.8% (n=12). Changes in tumor SUV_max 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 ⁶⁴Cu-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to untreated controls. Imaging with ⁶⁴Cu-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.

Keywords: PET, liposomes, bevacizumab, EPR, colon cancer, irinotecan.

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