Bioresponsive micro-to-nano albumin-based systems for targeted drug delivery against complex fungal infections

Abstract

As a typical human pathogenic fungus, Cryptococcus neoformans 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 C. neoformans 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 C. neoformans in vivo . 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.

Peptide‐conjugated Nanoparticle Platforms for Targeted Delivery, Imaging, and Biosensing Applications

“…A number of peptide‐conjugated NP systems were designed to treat different types of bacterial infections such as mesoporous Si nanoparticles for orthopedic implant‐related infection, [87] Ag NPs for MDR‐AB (Multidrug‐Resistant Acinetobacter baumannii complex) infections, calcium phosphate nanoparticles for pneumococcal infection, [88] bovine serum albumin (BSA)‐based NPs for fungal infections, [89] PLGA NPs for Klebsiella pneumoniae, [90] and others.…”

Advances in anti-invasive fungal drug delivery systems

“…研究表明，由于毛细血管的机械过滤作用，7~30 μm粒径的微球在静脉注射后可以迅速被机械截留在肺部，产生肺部被动靶向性 ［ 71 ］ 。Ramaiah等 ［ 72 ］ 以BSA为原料，采用乳液聚合法制备了载药微球，其平均粒径为10.02 μm，能最大程度地被机械截留沉积在肺部，实现药物肺部靶向。尽管微球递药系统具有良好的被动靶向性，但只有当药物载体通过肺泡-毛细血管屏障进入肺泡间隙才能有效到达疾病部位发挥治疗作用，因此药物载体穿透肺部血管的能力对药效具有重要影响。Cheng等 ［ 73 ］ 构建了一个纳米粒-微球相结合的微环境响应型微纳米白蛋白递药系统，首先制备包载AmB的BSA纳米粒，采用MMP-3敏感的双功能连接剂PN-PEG将纳米粒组装成微球，并以微球的粒径为指标，将连接剂与之孵育，通过优化配比成功制备出微环境响应型微纳米白蛋白递药系统。该响应性递送系统可以通过被动靶向快速富集到肺部，形成一个药物储库，随后由于感染微环境中MMP-3的上调而导致连接臂断裂，药物以纳米粒的形式释放，再利用BSA纳米粒本身的特异性靶向及特点，成功穿透肺部血管及血脑屏障，精准靶向到感染部位，从而实现增效减毒。…”

Advancements in Macrophage-Targeted Drug Delivery for Effective Disease Management

“…35 However, as the particle size of the carriers increases to the micrometer scale, they can significantly break through the limitations of the hepatic endothelial system to achieve aggregation in the lungs. 36 Lymph is a colorless, transparent fluid composed of plasma, lymphocytes, and other solutes. Its circulation rate is significantly lower than in the blood.…”