Degradable Cationic Shell Cross-Linked Knedel-like Nanoparticles: Synthesis, Degradation, Nucleic Acid Binding, and in Vitro Evaluation

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• 作者：Sandani Samarajeewa ; Aida Ibricevic ; Sean P. Gunsten ; Ritu Shrestha ; Mahmoud Elsabahy ; Steven L. Brody ; Karen L. Wooley
• 刊名：Biomacromolecules
• 出版年：2013
• 出版时间：April 8, 2013
• 年：2013
• 卷：14
• 期：4
• 页码：1018-1027
• 全文大小：550K
• 年卷期：v.14,no.4(April 8, 2013)
• ISSN：1526-4602

文摘

In this work, degradable cationic shell cross-linked knedel-like (deg-cSCK) nanoparticles were developed as an alternative platform to replace similar nondegradable cSCK nanoparticles that have been utilized for nucleic acids delivery. An amphiphilic diblock copolymer poly(acrylamidoethylamine)₉₀-block-poly(dl-lactide)₄₀ (PAEA₉₀-b-PDLLA₄₀) was synthesized, self-assembled in aqueous solution, and shell cross-linked using a hydrolyzable cross-linker to afford deg-cSCKs with an average core diameter of 45 卤 7 nm. These nanoparticles were fluorescently labeled for in vitro tracking. The enzymatic- and hydrolytic-degradability, siRNA binding affinity, cell uptake and cytotoxicity of the deg-cSCKs were evaluated. Esterase-catalyzed hydrolysis of the nanoparticles resulted in the degradation of ca. 24% of the PDLLA core into lactic acid within 5 d, as opposed to only ca. 9% degradation from aqueous solutions of the deg-cSCK nanoparticles in the absence of enzyme. Cellular uptake of deg-cSCKs was efficient, while exhibiting low cytotoxicity with LD50 values of ca. 90 and 30 渭g/mL in RAW 264.7 mouse macrophages and MLE 12 cell lines, respectively, ca. 5- to 6-fold lower than the cytotoxicity observed for nondegradable cSCK analogs. Additionally, deg-cSCKs were able to complex siRNA at an N/P ratio as low as 2, and were efficiently able to facilitate cellular uptake of the complexed nucleic acids.