Pluronic F-127 Stabilised Docetaxel Nanocrystals Improve Apoptosis by Mitochondrial Depolarization in Breast Cancer Cells: Pharmacokinetics and Toxicity Assessment.
Docetaxel (DTX) is favoured option for breast cancer treatment; however its marketed formulation (Taxotere) generates therapeutic response at the cost of undue toxicity. In order to circumvent such limitations, DTX nanocrystals (DTX-NCs) were prepared through high pressure homogenization (HPH) technique using pluronic F-127 (PF-127) as a stabilizer. DTX-NCs presented higher efficacy against MCF-7 breast cancer cells with exposition of 1.75 and 2.13 fold lower inhibitory concentration (IC50) compared to free drug and Taxotere, respectively. DTX-NCs enhanced the DTX induce G2-M arrest by 1.24 and 1.79 fold compared to Taxotere and free DTX whereas highest apoptotic population (54.79%) of MCF-7 cells was also observed when cells were incubated with DTX-NCs for 24 h in comparison to free DTX (9.69%) and Taxotere (12.55%). The claims of improvement were substantiated by investigating the modulation in apoptotic mechanism induced by the subtle physical state variation of DTX in DTX-NCs. Results revealed that DTX-NCs induced apoptosis was linked to altered mitochondrial membrane potential. DTX-NCs caused highest (39.53%) depolarization of mitochondria compared to free DTX (9.34%) and Taxotere (18.72%). Further, safety of DTX-NCs was ascertained via haemolytic testing and in-vivo toxicity studies in mice. Developed formulation exhibited acceptable haemolytic potential which suggested its suitability towards parenteral administration. Moreover, in-vivo acute toxicity studies demonstrated that the developed NCs were safer than marketed Taxotere. These results elicit that DTX-NCs would be a viable alternative to commercial formulation for treatment of breast cancer.
Vivek K
VK
Pawar
Siddharth
S
Gupta
Yuvraj
Y
Singh
Jaya Gopal
JG
Meher
Komal
K
Sharma
Pankaj
P
Singh
Annie
A
Gupta
Himangshu K
HK
Bora
Mohini
M
Chaurasia
Manish K
MK
Chourasia
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004058:Diffusion; D000077143:Docetaxel; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D004357:Drug Synergism; D005079:Excipients / Q000737:chemistry; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008422:Materials Testing; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry* / Q000633:toxicity; D017208:Rats, Wistar; D043823:Taxoids / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005079:Excipients; D043823:Taxoids; D020442:Poloxamer; D000077143:Docetaxel