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Kaihui Nan, Tong Li, Peiling Xie, Yihong Tang, Sen Lin; Hyaluronic acid based legumain responsive nano-carrier for the targeted delivery of doxorubicin. Invest. Ophthalmol. Vis. Sci. 2016;57(12):767.
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Doxorubicin (DOX) is a potent chemotherapy agent for various cancers; however, its severe side effects limit its application. Current study aimed to develop a legumain-triggered DOX release system to selectively target cancer cells, reduing off-target toxicity.
Legumain substrate peptide was synthesized using solid phase method. DOX was conjugated to the legumain using O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) and Diisopropylethylamine (DIPEA) as the coupling agent. The conjugate (DOX-PEP-NH2) was then grafted onto hyaluronic acid (HA) in the presence of EDC/NHS to form HA-PEP-DOX. The HA-PEP-DOX was cross-linked to adipic dihydrazide in a water-in-oil emulsion to form Hyaluronic nano-spheres. The hyaluronic nano-spheres containing HA-PEP-DOX were evaluated on Y-79 cell line as well as normal ocular cell line using Cell Counting Kit (CCK-8).
Successful conjugation of DOX-PEP-NH2 with the HA nanospheres was confirmed by 1H-nuclear magnetic resonance spectra (1H-NMR). High resolution transmission electron microscope (HR-TEM) revealed the nano-sphere had an average size of 365 ± 28 nm with zeta potential value of -25 mV detected using a dynamic light scattering (DLS) analyzer. The amount of DOX grafted on HA nano-spheres ranged from 0.3 µg/mg to 3.5 µg/mg depending on the feeding of DOX-PEP-NH2. The IC50 of HA-PEP-DOX nano-spheres against Y-79 cells was approximately 3 µg/mL that was significantly lower than 7.5 µg/mL for free DOX. This formulation was well tolerated on cultured retinal pigmented epithelium (RPE) cells or L929 fibroblast cells even at the concentration of 4 µg/mL (DOX equivalent).
HA-PEP-DOX nano-spheres can selectively inhibit cancer cell (Y-79) viability while exhibiting benign cytotoxicity on the normal cell (RPE or L929). This formulation of DOX may enhance specificity of this potent therapeutics and reduce the off-target side effects significantly when applied on ocular drug targeted delivery.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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