Chimeric Nanoparticle: A Platform for Simultaneous Targeting of Phosphatidylinositol-3-Kinase Signaling and Damaging DNA in Cancer Cells.
Phosphatidylinositol-3-kinase (PI3K) signaling has been hijacked in different types of cancers. Hence, PI3K inhibitors have emerged as novel targeted therapeutics in cancer treatment as mono and combination therapy along with other DNA damaging drugs. However, targeting PI3K signaling with small molecules leads to the emergence of drug resistance and severe side effects to the cancer patients. To address these, we have developed a biocompatible, biodegradable cholesterol-based chimeric nanoparticle (CNP), which can simultaneously load PI103, doxorubicin, and cisplatin in a controlled ratiometric manner. Size, shape, and morphology of these CNPs were characterized by dynamic light scattering (DLS), field-emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), and transmission electron microscopy (TEM). Increased amounts of PI103, doxorubicin, and cisplatin were released from CNPs through controlled and continuous manner over 120 h at pH = 5.5 compared to neutral pH. The CNPs showed much enhanced in vitro cytotoxicity in HeLa, HL60, MCF7, and MDA-MB-231 cancer cells compared to a free drug cocktail at 24 and 48 h by inducing apoptosis. Confocal laser scanning microscopy (CLSM) imaging revealed that indeed these CNPs were internalized into subcellular lysosomes through endocytosis in a time dependent mode over 6 h and retained inside for 48 h in HeLa, MDA-MB-231, and MCF7 cells. These CNPs showed their efficacy by damaging DNA and inhibiting Akt as a downstream modulator of PI3K signaling in HeLa cervical cancer cells. These CNPs have the potential to open up new directions in next-generation nanomedicine by simultaneous targeting of multiple oncogenic signaling pathways and inducing DNA damage for augmented therapeutic outcome by reducing toxic side effects and overcoming drug resistance.
['Palvai|Sandeep|S|', 'More|Piyush|P|', 'Mapara|Nikunj|N|', 'Basu|Sudipta|S|']
D000970:Antineoplastic Agents D017209:Apoptosis D001672:Biocompatible Materials D045744:Cell Line, Tumor D002784:Cholesterol D002945:Cisplatin D004249:DNA Damage D004317:Doxorubicin D004337:Drug Carriers D000067493:Dynamic Light Scattering D005663:Furans D006367:HeLa Cells D006801:Humans D006863:Hydrogen-Ion Concentration D061986:MCF-7 Cells D018625:Microscopy, Atomic Force D053758:Nanoparticles D019869:Phosphatidylinositol 3-Kinases D011725:Pyridines D011743:Pyrimidines D015398:Signal Transduction
chimeric nanoparticle cancer DNA damage PI3K signaling PI103 doxorubicin cisplatin