Institute of Chemistry for Functionalized Materials, School of Chemistry and Chemical Engineering, Liaoning Normal University, 850 Huanghe Road, Dalian 116029, China.
Inorg Chem. 2013 Feb 4;52(3):1388-97. doi: 10.1021/ic3020942. Epub 2013 Jan 24.
The bifunctional mesoporous zirconium phosphonates (ZrBFs) were synthesized through surfactant-assisted co-condensation of ZrCl(4) with two different phosphonic acids, both 1-phosphomethylproline (H(3)PMP) and 1,4-bis(phosphomethyl)piperazine (BPMP), in a one-pot procedure. The L-proline group of H(3)PMP and piperazine group of BPMP in the frameworks endow ZrBFs with pH-controllable release function and high cell penetration capability, which was derived from the reversible protonation-deprotonation of L-proline groups and piperazine groups on the mesoporous walls under different pH values (pH sensitivity) as well as further functionalization with biological modifiers via the carboxyls in L-proline groups on the outer surface (functionalizability), respectively. ZrBFs, possessing cationic frameworks once formed, exhibit high payload for salmon sperm DNA as model nucleic acid owing to strong electrostatic attraction between them. On the basis of pH-sensitive ZrBFs carriers and assisted by lag-time films coating, the time- and pH-controlled oral colon-targeted nucleic acid delivery systems have been developed, which can carry most of the loaded salmon sperm DNA to the colon under dual control, time control and pH value control. Furthermore, salmon sperm DNA can remain intact during delivery, as evidenced by the fact that the released salmon sperm DNA in the pH transition release experiment still retain its structural integrity and native conformation. Also, fluorescence spectra demonstrate that ZrBFs can be further functionalized with a cell-penetrating peptide of octaarginine (R8) via the carboxyls in L-proline groups of H(3)PMP on the outer surface using a coupling agent, which will enhance the penetration capability of ZrBFs through biomembranes. ZrBFs have a potential application as a new kind of carrier in oral delivery of nucleic acids targeting the colon for gene therapy of colon-related diseases due to their unique bifunctionality.
介孔锆膦酸盐（ZrBFs）是通过在一个反应釜中，用两种不同的膦酸，即 1-膦甲基脯氨酸（H3PMP）和 1,4-双（膦甲基）哌嗪（BPMP），与 ZrCl4 进行表面活性剂辅助共聚合成的。H3PMP 中的 L-脯氨酸基团和 BPMP 中的哌嗪基团赋予 ZrBFs 具有 pH 可控释放功能和高细胞穿透能力，这是源于在不同 pH 值下（pH 敏感性），介孔壁上的 L-脯氨酸基团和哌嗪基团的可逆质子化-去质子化，以及通过外表面上的 L-脯氨酸基团上的羧基进一步与生物修饰物进行功能化（功能化能力）。ZrBFs 一旦形成阳离子骨架，由于它们之间的强静电吸引力，对鲑鱼精子 DNA 等模型核酸具有高载药量。基于 pH 敏感的 ZrBFs 载体，并在滞后时间薄膜涂层的辅助下，开发了时间和 pH 双重控制的口服结肠靶向核酸递药系统，该系统可以在双重控制、时间控制和 pH 值控制下，将大部分负载的鲑鱼精子 DNA 递送到结肠。此外，在递药过程中鲑鱼精子 DNA 可以保持完整，这可以从 pH 转换释放实验中释放的鲑鱼精子 DNA 仍保留其结构完整性和天然构象这一事实得到证明。此外，荧光光谱表明，ZrBFs 可以通过外表面上 H3PMP 的 L-脯氨酸基团上的羧基，使用偶联剂进一步与穿膜肽八精氨酸（R8）进行功能化，这将增强 ZrBFs 通过生物膜的穿透能力。由于其独特的双功能性，ZrBFs 有望作为一种新型载体，用于针对结肠的口服核酸递药，用于结肠相关疾病的基因治疗。
