Phosphatidylinositol 3-kinase inhibitor (PIK75) containing surface functionalized nanoemulsion for enhanced drug delivery, cytotoxicity and pro-apoptotic activity in ovarian cancer cells.
OBJECTIVE
Ovarian cancer is a debilitating disease, which needs multi-pronged approach of targeted drug delivery and enhanced efficacy with the use of combination therapeutics. In this study, we have examined the anticancer activity of PIK75 incorporated in surface functionalized nanoemulsions for targeted delivery to SKOV-3 cells. A pro-apoptotic molecule C(6)-ceramide was also co-delivered to augment therapeutic efficacy.


METHODS
EGFR and FR functionalized nanoemulsions incorporating PIK75 and C(6)-ceramide were characterized for particle size, surface charge, entrapment efficiency and morphology. Fluorescence and quantitative uptake studies were conducted in SKOV-3 cells to determine intracellular distribution. Cell viability was assessed using MTT assay while mechanism of cytotoxicity was evaluated using capsase-3/7, TUNEL and hROS assay.


RESULTS
Cytotoxicity assay showed 57% decrease in IC(50) value of PIK75 following treatment with EGFR targeted nanoemulsion and 40% decrease following treatment with FR targeted nanoemulsion. Combination therapy with PIK75 and ceramide enhanced the cytotoxicity of PIK75 compared to therapy with individual formulations. The increase in cytotoxicity was attributed to increase in cellular apoptosis and hROS activity.


CONCLUSIONS
The results of this study showed that the targeted system improved cytotoxicity of PIK75 compared to the non-targeted system. Combination therapy with ceramide augmented PIK75's therapeutic activity.
School of Pharmacy, Faculty of Medical & Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Meghna
M
Talekar
Srinivas
S
Ganta
Amit
A
Singh
Mansoor
M
Amiji
Jackie
J
Kendall
William A
WA
Denny
Sanjay
S
Garg
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D004655:Emulsions / Q000008:administration & dosage / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism
D002518:Ceramides; D004655:Emulsions; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C101954:N-caproylsphingosine; C512478:EGFR protein, human; D066246:ErbB Receptors; D053148:Caspase 3; D053179:Caspase 7