Bile Acid Tethered Docetaxel‐Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes
Vedagopuram Sreekanth, Animesh Kar, Sandeep Kumar, Sanjay Pal, Poonam Yadav, Yamini Sharma, Varsha Komalla, Harsh Sharma, Radhey Shyam, Ravi Datta Sharma, Arnab Mukhopadhyay, Sagar Sengupta, Ujjaini Dasgupta, Avinash Bajaj
Abstract
In this study, we describe the engineering of sub-100 nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates. We further demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next-generation chemotherapeutic.