Immunology Section, Head Inmuno-Biology Molecular Laboratory, Gregorio Marañón University General Hospital, Gregorio Marañón Health Research Institute (IiSGM), Spanish HIV HGM BioBank, Madrid, Spain,
Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain,
Int J Nanomedicine. 2019 Apr 2;14:2371-2381. doi: 10.2147/IJN.S188495. eCollection 2019.
HIV-1 and herpes simplex virus type-2 (HSV-2) represent two of the most relevant sexually transmitted diseases (STDs) worldwide. Moreover, each year there are >200 million pregnancies worldwide, and more than half are unintended. Continued high rates of unintended pregnancies and spread of HIV-1 and HSV-2 require new approaches to address these problems. G1-S4 and G2-S16 dendrimers emerge as potential candidates for the development of a topical microbicide due to their safety and effectivity against HIV-1 and HSV-2 infection, both in vitro and in vivo. Our goal is to develop a dual topical microbicide to prevent the transmission of STDs and unintended pregnancies. Platycodin D (PD) was selected for its great spermicidal activity, topical application, and biocompatibility.
Toxicology and inhibitory profile of G1-S4/PD and G2-S16/PD were evaluated in vitro and in vivo. Spermicidal activity was assessed by a computer-assisted sperm analysis system (CASA).
G1-S4/PD and G2-S16/PD presented >95% of HIV-1 inhibition in TZM-bl cells and peripheral blood mononuclear cells. CASA assessment determined that 0.25 mM of PD with therapeutic concentrations of G1-S4 or G2-S16 was able to induce 100% immobilization of the sperm in 30 seconds. To evaluate the toxicity in vivo, a vaginal toxicity assay was performed in BALB/c mice. No significant changes or damage to the vaginal epithelium after 7 consecutive days of application were observed.
Our data indicate that G1-S4/PD and G2-S16/PD combinations are promising candidates to be developed for vaginal microbicides with contraceptive activity.
艾滋病毒 1 型（HIV-1）和单纯疱疹病毒 2 型（HSV-2）是全球两种最重要的性传播疾病（STD）。此外，全球每年有超过 2 亿例妊娠，其中一半以上是意外妊娠。意外妊娠率居高不下以及 HIV-1 和 HSV-2 的传播，需要采取新的方法来解决这些问题。G1-S4 和 G2-S16 树枝状聚合物由于其在体外和体内对 HIV-1 和 HSV-2 感染的安全性和有效性，成为开发局部杀微生物剂的潜在候选物。我们的目标是开发一种双重局部杀微生物剂，以预防 STD 和意外妊娠的传播。桔梗皂苷 D（PD）因其强大的杀精活性、局部应用和生物相容性而被选中。
在体外和体内评估了 G1-S4/PD 和 G2-S16/PD 的毒理学和抑制谱。通过计算机辅助精子分析系统（CASA）评估杀精活性。
G1-S4/PD 和 G2-S16/PD 在 TZM-bl 细胞和外周血单核细胞中对 HIV-1 的抑制率均超过 95%。CASA 评估确定，在 30 秒内，PD 的 0.25mM 与治疗浓度的 G1-S4 或 G2-S16 可使精子 100%固定。为了评估体内毒性，在 BALB/c 小鼠中进行了阴道毒性试验。在连续 7 天应用后，未观察到阴道上皮有明显变化或损伤。
我们的数据表明，G1-S4/PD 和 G2-S16/PD 联合使用是开发具有避孕活性的阴道杀微生物剂的有前途的候选物。
