Development of Mitotane Lipid Nanocarriers and Enantiomers: Two-in-One Solution to Efficiently Treat Adreno-Cortical Carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren(®) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano-carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid-based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods.

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

“…Nanoformulations have emerged as an attractive strategy for incorporation of molecules that have poor water solubility, such as mitotane. Mitotane nanoformulations are expected to improve the therapeutic effect, enhance bioavailability, and reduce the toxic effects of mitotane 93 . Three formulations are being developed: (i) self‐microemulsifying drug delivery system (SMEDDS); (ii) lipid‐based nanocarriers; and (iii) micelles.…”

“…Nevertheless, SMEDDS can be considered as a new tool for optimizing the administration of mitotane and additional studies should be performed in this regard. Lipid‐based nanocarriers: solid lipid nanoparticles or nanostructured lipid carriers (NLCs) consist of either solid or lipid nanoparticles. NLCs are a novel type of lipid nanoparticles that use a solid matrix 93 . In fact, mitotane was efficiently loaded in solid lipid nanoparticles and in NLCs, as potential delivery systems for enhancing the therapeutic effects of mitotane, improving bioavailability, and controlling drug release 96 .…”

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“…In general, it is well accepted that administration of appropriate nanodrug formulations can contribute to enhance the duration response, the response rate, the OS, and PFS in patients with a given type of cancer [83, 84]. In this regard and based on a recent study announcing the preparation of nanoliposomes-encapsulated bevacizumab with beneficial effects in prolonging the residency of bevacizumab in the vitreous [85], it might be interesting to test ipilimumab plus nanoencapsulated bevacizumab in patients with unresectable stage III or stage IV melanoma.…”

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“…different shapes and surface properties) that includes, but not limited to, lipid-based nano-molecules (e.g. liposomes, solid lipid NPs (SLN) and nanostructured lipid carriers (NLC)) [6], carbon nanotubes (e.g. single-walled or multi-walled-CNTs) [7,8], fullerenes (i.e.…”