Abstract
There is great interest in repurposing disulfiram (DSF), a rapidly metabolizing nontoxic drug, for brain cancers and other cancers. To overcome the instability and low therapeutic efficacy, we engineered passively-targeted DSF-nanoparticles (DSFNPs) using biodegradable monomethoxy (polyethylene glycol) d,l-lactic-co-glycolic acid (mPEG-PLGA) matrix. The physicochemical properties, cellular uptake and the blood brain-barrier permeability of DSFNPs were investigated. The DSFNPs were highly stable with a size of ∼70 nm with a >90% entrapment. Injection of the nanoparticles labeled with HITC, a near-infrared dye into normal mice and tumor-bearing nude mice followed by in vivo imaging showed a selective accumulation of the formulation within the brain and subcutaneous tumors for >24 h, indicating an increased plasma half-life and entry of DSF into desired sites. The DSFNPs induced a potent and preferential killing of many brain tumor cell lines in cytotoxicity assays. Confocal microscopy showed a quick internalization of the nanoparticles in tumor cells followed by initial accumulation in lysosomes and subsequently in mitochondria. DSFNPs induced high levels of ROS and led to a marked loss of mitochondrial membrane potential. Activation of the MAP-kinase pathway leading to a nuclear translocation of apoptosis-inducing factor and altered expression of apoptotic and anti-apoptotic proteins were also observed. DSFNPs induced a powerful and significant regression of intracranial medulloblastoma xenografts compared to the marginal efficacy of unencapsulated DSF. Together, we show that passively targeted DSFNPs can affect multiple targets, trigger potent anticancer effects, and can offer a sustained drug supply for brain cancer treatment through an enhanced permeability retention (EPR).
Highlights
Disulfiram (DSF, Antabuse) was the first drug approved by the U.S Food and Drug Administration to treat chronic alcohol dependence [1]
While the smaller size of the particles may facilitate the transport across the blood-brain barrier (BBB), an enhanced permeability retention in the tumor vasculature [24, 54] may aid a preferential accumulation of these formulations in cancer tissues
A hypervascularity, incomplete vascular architecture, secretion of vascular permeability factors leading to extravasation within the malignant tissues and absence of lymphatic drainage for clearance may all contribute a greater accumulation of DSFNPs in brain cancers
Summary
Disulfiram (DSF, Antabuse) was the first drug approved by the U.S Food and Drug Administration to treat chronic alcohol dependence [1]. The higher MGMT content in gliomas serves to remove the mutagenic and cytotoxic O6-alkylguanines and confer tumor drug resistance and therapy failure [11]. Consistent with this observation, we have found that different dithiocarbamates retained the ability to inactivate MGMT [12]. Because DSF bears several properties, including the ability to cross the blood-brain barrier (BBB) [13], cytotoxicity against glioma stem cells [14], inhibition of various targets, including the MGMT and ALDH [15], there is significant interest in developing DSF for brain tumor treatment; a clinical trial has already been listed [16]. DSF with or without soluble copper (Cugluconate) is undergoing clinical trials in liver cancer and other cancer types [17, 18]
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