Abstract 491: Encapsulation of the stem cell inhibitor Salinomycin in novel QUATRAMER sustained injectable suspension (HSB-1216) for the treatment of small cell lung cancer

Abstract

Small cell lung cancer (SCLC) represents approximately 15% of all cases of lung cancer. SCLC patients have a poor prognosis and limited treatment options. Conventional chemotherapy can reduce the bulk of SCLC lesions, but cancer stem cells (CSCs) survive, reconstitute the tumor and contribute to metastases. Thus, targeting CSCs, which are resistant to many current treatments, may significantly improve outcomes of SCLC patients. Salinomycin (SAL), a potassium ionophore, preferentially targets CSCs. However, SAL is extensively metabolized in animal models and is associated with substantial toxicity at higher doses, limiting its potential for anti-cancer activity in patients In this study, we report a novel QUATRAMER polymeric nanoparticle (NP)-based formulation, that potentially overcomes toxicity of SAL. SAL was encapsulated in polymeric NPs comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG-modified PLA-tetra-block copolymer (SAL-NPs; HSB-1216). SAL release from the NPs was controlled by both PEG/PEG-PPG-PEG chain length and the PLA molecular weight, permitting time-dependent release over sustained periods. Treatment of the human SCLC cell line NCI-H69 with HSB-1216 demonstrated an IC50 of 0.5 uM. Once weekly treatment of BALB/c nu/nu mice harboring NCI-H69 xenografts with HSB-1216 at a dose of 5 mg/kg resulted in substantial tumor growth inhibition The tumor growth inhibition was without any effect on the body weights of the mice. These results demonstrate that a novel formulation for sustained delivery of SAL in a sustained injectable suspension represents an approach for targeting CSCs in SCLCs and potentially other cancer types. Citation Format: Surender M. Kharbanda, Anees Mohammad, Sireesh Appajosyula, Mark Rosenberg, James Hill, Sandeep Laumas, Donald W. Kufe, Harpal Singh. Encapsulation of the stem cell inhibitor Salinomycin in novel QUATRAMER sustained injectable suspension (HSB-1216) for the treatment of small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 491.

Salinomycin-Based Drug Delivery Systems: Overcoming the Hurdles in Cancer Therapy

“…Since these studies represent the foundation for new product development, Hillstream BioPharma designed a polymeric nanosystem with Sali (HSB-1216) for the treatment of small cell lung cancer and triple negative breast cancer. The novel QUATRAMER technology entails the incorporation of Sali in polymeric nanoparticles composed of PEG-polypropylene glycol (PPG)-PEG-modified PLA tetra-block copolymer [ 112 , 113 , 114 , 115 ]. Preclinical studies highlighted that in the case of lung cancer, once/week administration of the formulation in a xenograft model at a dose of 5 mg/kg inhibited the tumor growth with no evident side effects, while the in vitro studies performed on MDA-MB-231 triple negative breast cancer cell line evidenced a near total inhibition of mammosphere formation compared to paclitaxel by selectively binding to the CD44 marker [ 112 , 113 , 116 ].…”

“…The novel QUATRAMER technology entails the incorporation of Sali in polymeric nanoparticles composed of PEG-polypropylene glycol (PPG)-PEG-modified PLA tetra-block copolymer [ 112 , 113 , 114 , 115 ]. Preclinical studies highlighted that in the case of lung cancer, once/week administration of the formulation in a xenograft model at a dose of 5 mg/kg inhibited the tumor growth with no evident side effects, while the in vitro studies performed on MDA-MB-231 triple negative breast cancer cell line evidenced a near total inhibition of mammosphere formation compared to paclitaxel by selectively binding to the CD44 marker [ 112 , 113 , 116 ]. These positive results constituted the basis of planning a phase I clinical trial in patients with metastatic small cell lung cancer that followed or are following a cancer therapy with platinum-based drugs [ 117 ].…”

Salinomycin as a potent anticancer stem cell agent: State of the art and future directions

“…219 , 220 HSB‐1216 is generated by encapsulating salinomycin within QUATRAMER delivery technology, which used a polyethylene glycol (PEG)‐polypropylene glycol (PPG)‐PEG modified polylactic acid (PLA)‐tetra‐block copolymer. The team reported that HSB‐1216 has strong effects on eliminating small cell lung CSCs in mice 221 and also displays potent inhibitory effects on tumor biopsy‐derived organoids from triple negative breast cancer patients. 222 …”