Bile Acid Tethered Docetaxel‐Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes. Issue 10 (19th January 2021)

• Record Type: Journal Article
• Authors: Sreekanth, Vedagopuram; Kar, Animesh; Kumar, Sandeep; Pal, Sanjay; Yadav, Poonam; Sharma, Yamini; Komalla, Varsha; Sharma, Harsh; Shyam, Radhey; Sharma, Ravi Datta; Mukhopadhyay, Arnab; Sengupta, Sagar; Dasgupta, Ujjaini; Bajaj, Avinash
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 10(2021)
• Page Start: 5394
• Page End: 5399
• Publication Date: 2021-01-19
• Subjects: cancer therapy -- docetaxel -- epigenetic changes -- nanomicelles -- toxicity; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202015173
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Phosphocholine derivative of docetaxel‐conjugated lithocholic acid can form stable sub‐100 nm nanomicelles (DTX‐PC NMs). DTX‐PC NMs exhibit superior tolerance and pharmacokinetics over FDA‐approved formulation. DTX‐PC NMs can retard tumor progression in murine models and induce upregulation of tumor suppressor genes. Superior pharmacokinetic profiling in non‐human primates makes them an ideal platform for clinical applications.