Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic

Abstract

Despite the therapeutic potential of sphingolipids, the ability to develop this class of compounds as active pharmaceutical ingredients has been hampered by issues of solubility and delivery. Beyond these technical hurdles, significant challenges in completing the necessary preclinical studies to support regulatory review are necessary for commercialization. This review seeks to identify the obstacles and potential solutions in the translation of a novel liposomal technology from the academic bench to investigational new drug (IND) stage by discussing the preclinical development of the Ceramide NanoLiposome (CNL), which is currently being developed as an anticancer drug for the initial indication of hepatocellular carcinoma (HCC).

Delivery of long chain C16 and C24 ceramide in HeLa cells using oxidized graphene nanoribbons

“…Since the discovery of its bioactive properties over two decades ago (Dobrowsky, Kamibayashi, Mumby, & Hannun, ), there has been great interest in developing ceramide for therapeutic purposes. However, much of this focus has been on the short‐chain ceramide analogs such as C 6 ceramide, which have seen several different approaches to deliver it to cancer cells and induce apoptosis (Dhule et al, ; Kester et al, ; Kester et al, ; Shabbits & Mayer, ; Shabbits & Mayer, ; Zhai et al, ; Zou et al, ). There has been considerably less attention devoted to the longer chain ceramides in the realm of therapeutic delivery, mostly due to the difficulties associated with these ceramides in aqueous solution.…”

“…Many of these methods have centered around the use of the short chain C 6 ceramide, a synthetic ceramide analog which is a potent inducer of apoptosis (Zhai, Sun, Han, Jin, & Zhang, 2015). One of the more common methods of short chain ceramide delivery is liposomes, which incorporate C 6 ceramide or other short chain ceramides into constructs containing other co-factors (Kester et al, 2015;Shabbits & Mayer, 2003a;Zou et al, 2014). However, when introduced into an aqueous environment, ceramide rapidly releases from the liposomes, limiting their systemic delivery (Zolnik et al, 2008).…”

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

“…C 6 ceramide has been utilized for the development of a novel nanoliposome formulation termed ceramide nanoliposomes (CNLs). These CNLs can deliver C 6 ceramides effectively as well as synergizing with current chemotherapeuitcs by encapsulating them within the same nanoliposomes (Adiseshaiah et al, 2013; Kester et al, 2015; Ma, Mou, Ding, Zou, & Huang, 2016; Sun, Fox, Adhikary, Kester, & Pearlman, 2008). The efficacy of these CNLs is currently being investigated in a phase 1 clinical trial in patients with solid tumors.…”

“…The trial found that while the C 2 and C 6 ceramides had little to no toxicity, patients yielded only a 4% response rate, shelving topical administration of short chain ceramides as a potential chemotherapeutic (Jatoi et al, 2003). However, by encapsulating a C 6 ceramide into stable nontoxic nanoliposomes, researchers found that they could increase chemotoxicity as compared to free ceramide alone in in vivo models (Kester et al, 2015; Sun et al, 2008). These CNLs entered a phase I study beginning in 2017 for patients with advanced solid tumors at the University of Maryland, the University of Virginia, and the Medical University of South Carolina (Clinical trial #: NCT02834611) (ClinicalTrials.gov).…”

Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia

“…Nanoliposomal C6-ceramide has been investigated as a single agent and in combinatorial therapies (46), and recent work discusses preclinical development of C6-ceramide nanoliposomes (47). Of note, alterations in sphingolipid metabolism may play a crucial role in the regulation of cancer glycolytic capacity (48).…”