In the present study, a series of copolymers (PAMD-Ch) was synthesized by grafting polymeric Plerixafor/AMD3100 (PAMD) with different amounts of cholesterol and the effect of cholesterol modification on siRNA delivery was investigated. PAMD-Ch/siRNA polyplexes exhibited improved colloidal and enzymatic stability when compared with PAMD/siRNA polyplexes containing no cholesterol. PAMD-Ch with low (17 wt%) and medium (25 wt%) cholesterol content exhibited CXCR4 antagonism comparable to unmodified PAMD. Cholesterol modification increased cell uptake of siRNA polyplexes and significantly decreased sensitivity of siRNA transfection to the presence of serum. When used to deliver anticancer siRNA against polo-like kinase 1 (PLK1), polyplexes based on PAMD-Ch with 17 wt% cholesterol exhibited the highest cancer cell killing activity both in serum-free and serum-containing conditions. Overall, the results of this study validate cholesterol modified PAMD as dual-function delivery vectors suitable for efficient delivery of anticancer siRNA and simultaneous CXCR4 inhibition for combined anticancer therapies.
Elastin associated microfibrils (EAMF) are ubiquitous connective tissue structures that are believed to provide tensile strength and flexibility to numerous tissues. In this study the ontogeny of EAMF in normal human aorta was examined using immunohistochemical analysis of fibrillin, an EAMF component, and mRNA levels of fibrillin and elastin. Specimens of infra-renal aorta from ages 11 months to 44 years were obtained following organ procurement. Decreasing amounts, as judged by computer digitized image analysis, of immunoreactive fibrillin when compared to elastin auto-fluorescence were observed in aortic sections with increasing age. Elastase treatment would un-mask the anti-fibrillin reactive epitope reinforcing the suggestion that EAMF act as a "scaffold" for elastin deposition. Northern and dot blot hybridizations demonstrated a decrease in relative fibrillin message levels with increasing age. The abundance of fibrillin in relation to elastin may suggest a role for EAMF independent of their association with elastin.
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