Cheng Liting, Niu Miao-Miao, Yan Tong, Ma Zhongyi, Huang Kexin, Yang Ling, Zhong Xin, Li Chong
Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China.
Acta Pharm Sin B. 2021 Oct;11(10):3220-3230. doi: 10.1016/j.apsb.2021.04.020. Epub 2021 May 8.
As a typical human pathogenic fungus, is a life-threatening invasive fungal pathogen with a worldwide distribution causing ∼700,000 deaths annually. Cryptococcosis is not just an infection with multi-organ involvement, intracellular survival and extracellular multiplication of the fungus also play important roles in the pathogenesis of infections. Because adequate accumulation of drugs at target organs and cells is still difficult to achieve, an effective delivery strategy is desperately required to treat these infections. Here, we report a bioresponsive micro-to-nano (MTN) system that effectively clears the . This strategy is based on our in-depth study of the overexpression of matrix metalloproteinase 3 (MMP-3) in infectious microenvironments (IMEs) and secreted protein acidic and rich in cysteine (SPARC) in several associated target cells. In this MTN system, bovine serum albumin (BSA, a natural ligand of SPARC) was used for the preparation of nanoparticles (NPs), and then microspheres were constructed by conjugation with a special linker, which mainly consisted of a BSA-binding peptide and an MMP-3-responsive peptide. This MTN system was mechanically captured by the smallest capillaries of the lungs after intravenous injection, and then hydrolyzed into BSA NPs by MMP-3 in the IMEs. The NPs further targeted the lung tissue, brain and infected macrophages based on the overexpression of SPARC, reaching multiple targets and achieving efficient treatment. We have developed a size-tunable strategy where microspheres "shrink" to NPs in IMEs, which effectively combines active and passive targeting and may be especially powerful in the fight against complex fungal infections.
作为一种典型的人类致病真菌，是一种危及生命的侵袭性真菌病原体，在全球范围内分布，每年导致约70万人死亡。隐球菌病不仅仅是一种多器官受累的感染，真菌的细胞内存活和细胞外增殖在感染的发病机制中也起着重要作用。由于仍难以在靶器官和细胞中实现药物的充分蓄积，迫切需要一种有效的给药策略来治疗这些感染。在此，我们报告了一种能有效清除该真菌的生物响应性微纳（MTN）系统。该策略基于我们对感染微环境（IME）中基质金属蛋白酶3（MMP-3）的过表达以及几种相关靶细胞中富含半胱氨酸的酸性分泌蛋白（SPARC）的深入研究。在这个MTN系统中，牛血清白蛋白（BSA，SPARC的天然配体）用于制备纳米颗粒（NP），然后通过与一种特殊的连接子偶联构建微球，该连接子主要由一个BSA结合肽和一个MMP-3响应肽组成。静脉注射后，这个MTN系统被肺中最小的毛细血管机械捕获，然后在IME中被MMP-3水解成BSA NPs。基于SPARC的过表达，这些NPs进一步靶向肺组织、脑和受感染的巨噬细胞，实现多靶点并达到高效治疗。我们开发了一种尺寸可调策略，即微球在IME中“收缩”为NPs，这有效地结合了主动和被动靶向，在对抗复杂真菌感染方面可能特别有效。
