| Differential delivery of therapeutic agents to lesion sites with nanoparticels, which eliminates premature drug release at undesired sites but selectively releases the drug in the lesion site, is a central goal and key challenge in nanomedicine development. However, the design and preparation of functionalized and responsive polymeric materials for the construction of differential drug delivery system has been a great challenge. Strategies utilizing the unique environment of the lesion site as the molecular cue to activate differential drug release have been employed in this dissertation. First, we synthesized a PEG-armed and polyphosphoester core-crosslinked nanogel via one-step ring-opening polymerization with an "arm-first" procedure. We then developed a multifunctional polyphosphoester core-crosslinked nanogel, surrounded by mannosyl poly(ethylene glycol), which provided macrophage targeting, drug accumulation at bacterial infection sites and bacteria-responsive drug release properties. We further developed a new strategy for differential delivery of antibiotics to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier, which selectively release drug with the presence of lipase-secreting bacteria. Last, we developed a new strategy for differential delivery of drug to tumor through the fabrication of a special bacteria-accumulated tumor environment that is responded by bacteria-sensitive TLN.The main content and conclusions of this dissertation are summarized below:1. PEG-armed and polyphosphoester core-crosslinked nanogel was synthesized by one-step ring-opening polymerization, using PEG as the initiator to polymerize a difunctional phosphate monomer, namely3,6-dioxaoctan-1,8-diyl bis(ethylene phosphate)(TEGDP). The nanogel with a core-shell structure is biocompatible to cells and exhibits efficient and convenient doxorubicin hydrochloride loading. The drug release was accelerated in the presence of phosphodiesterase I, due to the catalyzed degradation of polyphosphoester, while the release is retarded relatively in the absence of the enzyme, rendering the nanogel potential as the drug carrier for systemic administration.2. We developed a bacterial-responsive multifunctional nanogel for delivery of antibiotic to bacterial infection sites. This nanogel is polyphosphoester core-crosslinked. surrounded by mannosyl poly(ethylene glycol), which provides macrophage targeting, drug accumulation at bacterial infection sites and bacteria-responsive drug release properties. Using vancomycin as the model antibiotic, it was demonstrated that the nanogel released almost all the encapsulated antibiotic within24h in the presence of the methicillin-resistant Staphylococcus aureus MW2strain, significantly inhibiting bacterial growth. The vancomycin-loaded nanogel preferentially delivered the antibiotic to Raw264.7macrophages and was transported to the bacterial infection site in a zebrafish embryo model, which further released the encapsulated drug triggered by bacteria ingested by macrophages. This efficient vancomycin delivery system using a bacteria-responsive nanogel led to significantly improved therapeutic efficacy in infection in the zebrafish embryo model. This technique can be generalized to perform targeted delivery of a variety of antibiotics for the treatment of various infections caused by bacteria, and thus provides an effective and universal approach for the treatment of bacterial infectious disease.3. We developed a new strategy for differential delivery of antimicrobials to bacterial infection sites with a lipase-sensitive polymeric triple-layered nanogel (TLN) as the drug carrier. The TLN was synthesized by a convenient arm-first procedure using an amphiphilic diblock copolymer, namely monomethoxy poly(ethylene glycol)-b-poly(ε-caprolactone), to initiate the ring-opening polymerization of the difunctional monomer3-oxapentane-1,5-diyl bis(ethylene phosphate). The hydrophobic poly(s-caprolactone)(PCL) segments collapsed and surrounded the polyphosphoester core, forming a hydrophobic and compact molecular fence in aqueous solution which prevented antibiotic release from the polyphosphoester core prior to reaching bacterial infection sites. However, once the TLN sensed the lipase-secreting bacteria, the PCL fence of the TLN degraded to release the antibiotic. Using Staphylococcus aureus (S. aureus) as the model bacterium and vancomycin as the model antimicrobial, we demonstrated that the TLN released almost all the encapsulated vancomycin within24h only in the presence of S. aureus, significantly inhibiting S. aureus growth. The TLN further delivered the drug into bacteria-infected cells and efficiently released the drug to kill intracellular bacteria. This technique can be generalized to selectively deliver a variety of antibiotics for the treatment of various infections caused by lipase-secreting bacteria and thus provides a new, safe, effective, and universal approach for the treatment of extracellular and intracellular bacterial infections.4. We report a new strategy for differential delivery of anti-cancer drug to tumor through the fabrication of a special bacteria-accumulated tumor environment that is responded by bacteria-sensitive TLN. We demonstrate that the attenuated lipase-secreting bacteria SBY1selectively accumulated in tumors and were rapidly cleared from normal tissues after intravenous administration, leading to a unique bacteria-accumulated tumor environment. Subsequent administration of doxorubicin-loaded TLN (TLND) was thus selectively degraded in the bacteria-accumulated tumor environment after its accumulation in tumors mediated by the abnormal tumor vasculature, triggering differential doxorubicin release and selectively killing tumor cells. This concept can be extended and improved by using other factors secreted by bacteria or materials to fabricate a unique tumor environment for differential drug delivery, showing potential applications in drug delivery. |
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