Inhibition of the transport of HIV in vitro using a pH-responsive synthetic mucin-like polymer system.
Inhibition of the transport of HIV in vitro using a pH-responsive synthetic mucin-like polymer system.
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DOI：
10.1016/j.biomaterials.2011.05.001
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发表时间：
2011-11
期刊：
影响因子：
14
通讯作者：
Kiser, Patrick F.
中科院分区：
文献类型：
--
作者：
Mahalingam, Alamelu;Jay, Julie I.;Langheinrich, Kristofer;Shukair, Shetha;McRaven, Mike D.;Rohan, Lisa C.;Herold, Betsy C.;Hope, Thomas J.;Kiser, Patrick F.
结合递送活性成分的常规作用，精心设计的药物递送载体还可以提供增强系统的总体功效的辅助功能。受宫颈阴道粘液在酸性pH下阻碍HIV病毒粒子移动的能力的启发，我们设计了一种pH响应性合成聚合物，其通过在酸性和中性pH下抑制病毒转运而显示出优于天然存在的宫颈阴道粘液的改善的屏障性质。pH响应性合成粘蛋白样聚合物用苯基硼酸（PBA）和水杨基异羟肟酸（SHA）构建，各自独立地与2-羟丙基甲基丙烯酰胺（pHPMA）聚合物主链共聚。在pH4.8时，交联聚合物形成一个瞬态网络，其特征弛豫时间为0.9s，弹性模量为11 Pa。在加入精液时，聚合物形成具有大于60 s的特征松弛时间和1800 Pa的弹性模量的致密交联弹性网络。PBA-SHA交联聚合物和粘蛋白在酸性pH下的相互作用显示弹性模量和交联寿命显著增加（p < 0.05）。一项转运试验表明，在pH ≥ 4.8时，HIV和细胞的迁移被聚合物网络显著阻碍，HIV的扩散系数为0.160 × 10−3 µm2 /s。此外，这些交联聚合物在人阴道外植体或小鼠模型中均未诱导毒性或刺激症状。总之，本文报道的pH响应性交联聚合物系统有望作为一类杀微生物剂递送载体，其可以抑制病毒体从精液运输到靶组织，从而有助于杀微生物剂制剂的总体活性。
In conjunction with the routine role of delivering the active ingredient, carefully designed drug delivery vehicles can also provide ancillary functions that augment the overall efficacy of the system. Inspired by the ability of the cervicovaginal mucus to impede the movement of HIV virions at acidic pH, we have engineered a pH-responsive synthetic polymer that shows improved barrier properties over the naturally occurring cervicovaginal mucus by inhibiting viral transport at both acidic and neutral pH. The pH-responsive synthetic mucin-like polymer is constructed with phenylboronic acid (PBA) and salicylhydroxamic acid (SHA), each individually copolymerized with a 2-hydroxypropyl methacrylamide (pHPMA) polymer backbone. At pH 4.8, the crosslinked polymers form a transient network with a characteristic relaxation time of 0.9 s and elastic modulus of 11 Pa. On addition of semen, the polymers form a densely crosslinked elastic network with a characteristic relaxation time greater than 60 s and elastic modulus of 1800 Pa. Interactions between the PBA-SHA crosslinked polymers and mucin at acidic pH showed a significant increase in elastic modulus and crosslink lifetime (p < 0.05). A transport assay revealed that migration of HIV and cells was significantly impeded by the polymer network at pH ≥ 4.8 with a diffusion coefficient of 0.160 × 10−3 µm2 /s for HIV. Additionally, these crosslinked polymers did not induce symptoms of toxicity or irritation in either human vaginal explants or a mouse model. In summary the, pH-responsive crosslinked polymer system reported here holds promise as a class of microbicide delivery vehicle that could inhibit the transport of virions from semen to the target tissue and, thereby, contribute to the overall activity of the microbicide formulation.
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影响因子：
32.4
作者：
Hladik, Florian;Sakchalathorn, Polachai;Ballweber, Lamar;Lentz, Gretchen;Fialkow, Michael;Eschenbach, David;McElrath, M. Juliana
通讯作者：
McElrath, M. Juliana
影响因子：
4.6
作者：
Hägerström, H;Edsman, K
通讯作者：
Edsman, K
影响因子：
7.6
作者：
Lai, Bonnie E.;Geonnotti, Anthony R.;Katz, David F.
通讯作者：
Katz, David F.
影响因子：
2.3
作者：
CHOPLIN, L;SABATIE, J
通讯作者：
SABATIE, J
影响因子：
4.1
作者：
CARLSTEDT, I;LINDGREN, H;WINGERUP, L
通讯作者：
WINGERUP, L