摘要：

Triple negative breast cancer (TNBC) is aggressive, has a very poor prognosis with a high rate of reoccurrence and is refractory to standard chemo- and radiotherapy. Still, chemotherapy is an effective option to treat recurrent or metastatic cancers if the debilitating side effects limiting the dose and time of exposure can be diminished. The use of pro-drugs that can be activated locally by a prodrug enzyme can minimize collateral damage since the presence of the enzyme in the tumor and clearance from normal tissue can be verified noninvasively with imaging, which allows for optimal timing of prodrug administration (1). We previously demonstrated the efficacy of the prodrug 5-fluorocytosine (5-FC) in primary triple negative MDA-MB-231 xenografts following administration of a poly-L-lysine based theranostic nanoplex containing bacterial cytosine deaminase (bCD) that converts 5-FC to the chemotherapeutic agent 5-fluorouracil. The size of the bCD-nanoplex of ∼ 300 kD allowed its delivery into the tumor interstitium through leaky tumor vasculature but not through normal vasculature (1). Here we used a more effective variant of bCD (2) to target metastatic MDA-MB-231 cells. We injected 2 × 106 td-tomato fluorescent protein expressing MDA-MB-231 cells intravenously and monitored metastases formation in the lungs for 5 weeks by which time metastatic nodules were detected. We then treated the animals with the bCD-nanoplex (300 mg/kg i.v.). Twenty-four hours later, we injected a first dose of 5-FC (200 mg/kg i.v. and 250 mg/kg i.p.), repeated at 72 hours. The animals were followed for 2 weeks with weekly optical imaging at the end of which mice were euthanized and the lungs excised. We histologically evaluated metastatic burden (area occupied by metastatic cells/total lung area) in mice treated with bCD-nanoplex + 5-FC (n = 5) and in mice injected with the bCD-nanoplex only (n = 6). We observed a 32% decrease in metastatic burden in the pro-drug treated group vs the control group (14.8% + 1.5% in treated mice vs 22.0% + 2.6% in control mice, p = 0.03). These results are a first step towards the longitudinal evaluation of such a strategy with multiple doses. Additionally, the nanoplex can be coupled to multimodal imaging reporters (1) to time prodrug administration and improve the detection and treatment of triple negative, hormone refractory metastatic cancers.

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