In this study,w ed escribe 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,D TX-PC NMs do not cause any systemic toxicity and slowthe decayrate of plasma DTX concentration in rodents and non-rodent species including non-human primates.W ef urther demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNAm ethyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore,t his unique system has the potential to improve the quality of life in cancer patients and can be translated as anext-generation chemotherapeutic.
We report a structure-activity relationship of lithocholic acid amphiphiles for their anticancer activities against colon cancer. We synthesized ten cationic amphiphiles differing in nature of cationic charged head groups using lithocholic acid. We observed that anticancer activities of these amphiphiles against colon cancer cell lines are contingent on nature of charged head group. Lithocholic acid based amphiphile possessing piperidine head group (LCA-PIP1) is ~10 times more cytotoxic as compared to its precursor. Biochemical studies revealed that enhanced activity of LCA-PIP1 as compared to lithocholic acid is due to greater activation of apoptosis.LCA-PIP1 induces sub G0 arrest and causes cleavage of caspases. A single dose of lithocholic acid-piperidine derivative is enough to reduce the tumor burden by 75% in tumor xenograft model.
Herein, we present the engineering of a supramolecular nanomicellar system that is composed of self-assembled units of PEGylated lithocholic acid (LCA)-Docetaxel (DTX) conjugate (LCA-DTX-PEG). We tethered a short polyethylene glycol...
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