Systemic administration of therapeutic agents has been the preferred approach to treat most pathological conditions, in particular for cancer therapy. This treatment modality is associated with side effects, off-target accumulation, toxicity, and rapid renal and hepatic clearance. Multiple efforts have focused on incorporating targeting moieties into systemic therapeutic vehicles to enhance retention and minimize clearance and side effects. However, only a small percentage of the nanoparticles administered systemically accumulate at the tumor site, leading to poor therapeutic efficacy. This has prompted researchers to call the status quo treatment regimen into question and to leverage new delivery materials and alternative administration routes to improve therapeutic outcomes. Recent approaches rely on the use of local delivery platforms that circumvent the hurdles of systemic delivery. Local administration allows delivery of higher “effective” doses while enhancing therapeutic molecules’ stability, minimizing side effects, clearance, and accumulation in the liver and kidneys following systemic administration. Hydrogels have proven to be highly biocompatible materials that allow for versatile design to afford sensing and therapy at the same time. Hydrogels’ chemical and physical versatility can be exploited to attain disease-triggered in situ assembly and hydrogel programmed degradation and consequent drug release, and hydrogels can also serve as a biocompatible depot for local delivery of stimuli-responsive therapeutic cargo. We will focus this Account on the hydrogel platform that we have developed in our lab, based on dendrimer amine and dextran aldehyde. This hydrogel is disease-responsive and capable of sensing the microenvironment and reacting in a graded manner to diverse pathologies to render different properties, including tissue adhesion, biocompatibility, hydrogel degradation, and embedded drug release profile. We also studied the degradation kinetics of our stimuli-responsive materials in vivo and analyzed the in vitro conditions under which in vitro–in vivo correlation is attained. Identifying key parameters in the in vivo microenvironment under healthy and disease conditions was key to attaining that correlation. The adhesive capacity of our dendrimer–dextran hydrogel makes it optimal for localized and sustained release of embedded drugs. We demonstrated that it affords the delivery of a range of therapeutics to combat cancer, including nucleic acids, small molecules, and antibody drugs. As a depot for local delivery, it allows a high dose of active biomolecules to be delivered directly at the tumor site. Immunotherapy, a recently blooming area in cancer therapy, may exploit stimuli-responsive hydrogels to impart systemic effects following localized therapy. Local delivery would enable release of the proper drug dose and improve drug bioavailability where needed at the same time creating memory and exerting the therapeutic effect systemically. This Account highlights our perspective on how local and systemic therapies provided by stimuli-responsive hydrogels should be used to impart more precise, long-lasting, and potent therapeutic outcomes.

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设计按需治疗的水凝胶

系统性地施用治疗剂已经成为治疗大多数病理状况的首选方法，特别是对于癌症治疗。这种治疗方式与副作用，脱靶累积，毒性以及快速的肾和肝清除率相关。多种努力集中于将靶向部分掺入全身治疗载体中，以增强保留并最小化清除率和副作用。然而，全身施用的纳米颗粒的仅小部分积聚在肿瘤部位，导致不良的治疗功效。这促使研究人员对现状治疗方案提出质疑，并利用新的给药材料和替代的给药途径来改善治疗效果。最近的方法依赖于使用本地传递平台，该平台规避了系统传递的障碍。局部给药可提供更高的“有效”剂量，同时增强治疗性分子的稳定性，使全身性给药后肝脏和肾脏中的副作用，清除率和在肝脏和肾脏中的蓄积最小化。水凝胶已被证明是具有高度生物相容性的材料，可以进行多种设计以同时提供感测和治疗。可以利用水凝胶的化学和物理多功能性来实现疾病触发的原位组装和水凝胶程序化降解以及随之而来的药物释放，并且水凝胶还可以作为生物相容性储库，用于局部递送刺激反应性治疗药物。我们将把这个帐户的重点放在我们在实验室中开发的水凝胶平台上，基于树枝状大分子胺和葡聚糖醛。这种水凝胶对疾病敏感，能够感应微环境并以分级的方式对多种病理反应，以提供不同的特性，包括组织粘附，生物相容性，水凝胶降解和包埋的药物释放曲线。我们还研究了体内刺激反应材料的降解动力学，并分析了达到体外-体内相关性的体外条件。在健康和疾病条件下识别体内微环境中的关键参数是获得这种相关性的关键。我们的树状聚合物-葡聚糖水凝胶的粘合能力使其非常适合嵌入药物的局部和持续释放。我们证明了它提供了多种抗癌治疗方法，包括核酸，小分子和抗体药物。作为用于局部递送的贮库，其允许将高剂量的活性生物分子直接递送至肿瘤部位。免疫疗法是癌症疗法中的一个新兴领域，可以在局部疗法后利用刺激反应水凝胶赋予全身作用。局部递送将使得能够释放适当的药物剂量并在需要时改善药物的生物利用度，同时创建记忆并全身性地发挥治疗作用。该报告强调了我们关于应如何使用刺激性反应水凝胶提供的局部和全身疗法来赋予更精确，持久和有效的治疗效果的观点。它允许将高剂量的活性生物分子直接递送到肿瘤部位。免疫疗法是癌症疗法中的一个新兴领域，可以在局部疗法后利用刺激反应水凝胶赋予全身作用。局部递送将使得能够释放适当的药物剂量并在需要时改善药物的生物利用度，同时创建记忆并全身性地发挥治疗作用。该报告强调了我们关于应如何使用刺激性反应水凝胶提供的局部和全身疗法来赋予更精确，持久和有效的治疗效果的观点。它允许将高剂量的活性生物分子直接递送到肿瘤部位。免疫疗法是癌症疗法中的一个新兴领域，可以在局部疗法后利用刺激反应水凝胶赋予全身作用。局部递送将使得能够释放适当的药物剂量并在需要时改善药物的生物利用度，同时创建记忆并全身性地发挥治疗作用。该报告强调了我们关于应如何使用刺激性反应水凝胶提供的局部和全身疗法来赋予更精确，持久和有效的治疗效果的观点。局部递送将使得能够释放适当的药物剂量并在需要时改善药物的生物利用度，同时创建记忆并全身性地发挥治疗作用。该报告强调了我们关于应如何使用刺激性反应水凝胶提供的局部和全身疗法来赋予更精确，持久和有效的治疗效果的观点。局部递送将使得能够释放适当的药物剂量并在需要时改善药物的生物利用度，同时创建记忆并全身性地发挥治疗作用。该报告强调了我们关于应如何使用刺激性反应水凝胶提供的局部和全身疗法来赋予更精确，持久和有效的治疗效果的观点。