Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors.
Poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(alpha-benzyl carboxylate epsilon-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30-0.44 and 0.65-0.68 mg/mL in the presence of 5000-5000 and 5000-24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anti-cancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anti-cancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Ommoleila
O
Molavi
Zengshuan
Z
Ma
Abdullah
A
Mahmud
Aws
A
Alshamsan
John
J
Samuel
Raymond
R
Lai
Glen S
GS
Kwon
Afsaneh
A
Lavasanifar
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001555:Benzene Derivatives / Q000737:chemistry; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054728:Cucurbitacins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D014315:Triterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D007783:Lactones; D008823:Micelles; D011091:Polyesters; D011108:Polymers; D050796:STAT3 Transcription Factor; D014315:Triterpenes; C473831:poly(ethylene oxide)-b-poly(caprolactone); C458722:polyethylene oxide-polycaprolactone copolymer; C041246:cucurbitacin B; D011092:Polyethylene Glycols; D054728:Cucurbitacins; C038106:cucurbitacin I