Bioresponsive micro-to-nano albumin-based systems for targeted drug delivery against complex fungal infections |
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Authors: | Liting Cheng Miao-Miao Niu Tong Yan Zhongyi Ma Kexin Huang Ling Yang Xin Zhong Chong Li |
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Affiliation: | 1. Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China;2. Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China |
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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. |
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Keywords: | Albumin SPARC MMP-3 Size-tunable strategy Microenvironment responsive Complex fungal infection AmB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0045" }," $$" :[{" #name" :" text" ," _" :" amphotericin B BBB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" blood‒brain barrier BSA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" bovine serum albumin DDS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" drug delivery system IME" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" infectious microenvironment MMP-3" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" matrix metalloproteinase 3 MTN" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" micro-to-nano NP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" nanoparticle PEG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0125" }," $$" :[{" #name" :" text" ," _" :" polyethylene glycol PMVECs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" pulmonary microvascular endothelial cells RFP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0145" }," $$" :[{" #name" :" text" ," _" :" red fluorescent protein SPARC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0155" }," $$" :[{" #name" :" text" ," _" :" secreted protein acidic and rich in cysteine |
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