Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Granada, Granada, Spain.
Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain; Instituto de Parasitología y Biomedicina "López-Neyra" (IPBLN-CSIC), PTS Granada, Armilla, Spain; GENYO, Centro de Genómica e Investigación Oncológica: Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, Granada, Spain.
J Control Release. 2015 Jan 10;197:190-8. doi: 10.1016/j.jconrel.2014.11.002. Epub 2014 Nov 10.
Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.
靶向递药是一种用于治疗传染病的选择性方法。引起非洲锥虫病的非洲锥虫的表面覆盖着一层表面被膜，该被膜由单个变异表面糖蛋白（称为 VSG）组成。该被膜通过内吞作用以非常高的速度被回收，使得锥虫表面成为递送杀锥虫药物的极好靶标。在这里，我们报告了一种基于聚乙二醇（PEG）的药物纳米载体的设计，该载体通过共价连接（PEG 化）到聚（D，L-乳酸-共-乙醇酸）（PLGA）上而生成 PEG 化 PLGA 纳米颗粒。该纳米载体与单域重链抗体片段（纳米抗体）偶联，该纳米抗体特异性识别原生动物病原体布氏锥虫的表面。纳米颗粒负载戊二脒，戊二脒是 T. b. gambiense 急性感染的一线药物。体外效力测定表明，与游离药物相比，该制剂的半抑制浓度（IC50）降低了 7 倍。此外，使用非洲锥虫病的小鼠模型进行的体内治疗表明，该制剂以比游离戊二脒的最小完全治愈剂量低 10 倍的剂量治愈了所有感染的小鼠，而以比游离戊二脒低 100 倍的剂量治愈了 60％的小鼠。该纳米载体是使用已批准用于人类的成分设计的，并负载目前用于治疗该疾病的药物。此外，这种基于灵活纳米抗体的系统可以适应负载任何化合物，为其他疾病的应用开辟了一系列新的潜在治疗方法。
