A next generation theranostic nano-platform for sustained and enhanced inhibition of cancer stem cells

Cancer stem cell;STAT3 inhibition;Drug Delivery;Drug Repurposing;Carbon nanoparticles;Host guest chemistry;Cucurbitruil[6];Niclosamide

Ostadhossein, Fatemeh ; Pan ; Dipanjan

关键词: Cancer stem cell;    STAT3 inhibition;    Drug Delivery;    Drug Repurposing;    Carbon nanoparticles;    Host guest chemistry;    Cucurbitruil[6];    Niclosamide;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/89162/OSTADHOSSEIN-THESIS-2015.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Primary tumor extermination and conventional chemotherapy are proved to be inefficient in cancer therapy in that they preferentially abolish differentiated cells whilst leaving behind treatment resistant, tumorigenic cancer stem cells (CSCs). CSCs are validated to be the root cause of therapeutic resistance, recurrence, and tumor progression. CSCs are considered to be modulated by overexpression of certain pathways,including signal transducer and activator of transcription 3 (STAT3). The aberrant activity of STAT3 has been identified in clinical inspection of > 70% of breast and prostate cancer and its inhibition by various mechanisms holds unprecedented significance in modern medicine. Niclosamide (Nic), an FDA approved anthelmintic drug, has recently been reported as potent inhibitor of STAT3 and it is seen toandtriggered the activation of cancer cell apoptotic mechanism. Despite its promising cancer treatment capabilities, lack of solubility is a major bottleneck limiting its bio-availability. To circumvent the issue, we adopted a nanomedicine approach integrated with a surface decorated cucurbituril (CB[6]) host-guest chemistry using luminescent carbon nanoparticles (Nano-Carbobitaceae) for sustained and enhanced delivery of niclosamide traceable with vibrational spectroscopic methods. Carbon nanoparticles (Hydrodynamic dynamic size=55±1 nm) were obtained via the environmentally benign hydrothermal synthetic route using food grade Agave nectar as the carbohydrate source. The particles were either prefunctionalized (hHydrodynamic dynamic size= 76±13 nm) or postfunctionalized (Hydrodynamic hydrodynamic dynamic size= 93±4 nm) with CB[6] and were further loaded with STAT3 inhibitor Nic. Extensive physiochemical characterizations were subsequently carried out to confirm the binding of Nic and CB. FT-IR results indicated the a 2:3 binding complexation model. Furthermore, the 1H NMR results showed shifts in the characteristic peaks of Nic upon encapsulation in CB[6] cavity.The potential of the developed particle for the in vitro applications was evaluated. Interestingly, the hydrodynamic size of the particles was mostly preserved in various physiologically relevant media. Approximately two-fold enhancement in IIC50 values were observed for the encapsulated drug versus free drug. The IC50 value of Nic, CB[6] Nic and CB[6] CNP Nic (post functionalized) was determined to be (45±04)×10-6 M, (28±03)×10-6 M and (21±02)×10-6 M, respectively. HenceOur results indicated that, this novel nanoplatform holds promise for sustained and enhanced chemotherapeutic delivery of sparingly soluble Nic for modulation of stem cell signaling pathways.