Rochani Ankit, Agrahari Vivek, Chandra Neelima, Singh Onkar N, McCormick Timothy J, Doncel Gustavo F, Clark Meredith R, Kaushal Gagan
Department of Pharmaceutical Science, Thomas Jefferson University, Philadelphia, PA 19107, USA.
CONRAD, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
Polymers (Basel). 2022 Apr 23;14(9):1728. doi: 10.3390/polym14091728.
This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (C) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (C-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked C-polyvinyl alcohol-boric acid (C-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to C gelling properties) on vaginal application (at acidic pH of ~3.5-4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7-8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the C-PBA gel was formed by ionic interactions whereas C-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the C-PBA and C-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the C-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40-60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.
本研究探索了交联凝胶的开发，旨在为阴道精子运输提供潜在的物理屏障以实现避孕。制备了两种类型的凝胶，一种是物理交联的ι-卡拉胶（C）-苯硼酸功能化的羟丙基甲基丙烯酸酯共聚物（PBA）基（C-PBA）凝胶，其设计目的是阻断阴道精子运输。第二种凝胶是pH转变交联的C-聚乙烯醇-硼酸（C-PVA-BA）凝胶，其设计目的是调节其性质，使其在阴道给药时（在约3.5-4.5的酸性pH值下）形成粘弹性、弱交联的瞬态网络（由于C的凝胶化性质），而在精液的7-8碱性pH值下转变为更具弹性、紧密交联的（由于硼酸酯-二醇交联）凝胶网络，从而对活动精子起到物理屏障作用。对这些凝胶进行了动态流变学、物理化学性质以及对精子功能（活力、生存能力、穿透能力）影响的表征。流变学数据证实，C-PBA凝胶是通过离子相互作用形成的，而C-PVA-BA凝胶是化学交联的，并且在碱性pH值下变得更具弹性。基于筛选数据，选择先导凝胶进行体外精子功能测试。体外结果证实，C-PBA和C-PVA-BA凝胶在精子-凝胶界面处形成了屏障，具有精子阻断特性。为了进行临床前概念验证，将C-PBA凝胶经阴道给药，并在兔子身上测试其避孕效果，结果显示只有部分效果（40%-60%）。总体而言，体外和体内结果支持使用市售材料开发交联凝胶作为阴道避孕药并进一步优化。
