Designing Hydrogels for On-Demand Therapy.
Designing Hydrogels for On-Demand Therapy.
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DOI：
10.1021/acs.accounts.6b00536
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发表时间：
2017-04-18
影响因子：
18.3
通讯作者：
Artzi N
中科院分区：
文献类型：
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作者：
Oliva N;Conde J;Wang K;Artzi N
全身给药一直是治疗大多数病理疾病，特别是癌症治疗的首选方法。这种治疗方式与副作用、靶外蓄积、毒性以及快速的肾和肝清除有关。多项努力的重点是将靶向部分纳入全身治疗载体，以增强保留并最大限度地减少清除和副作用。然而，只有一小部分给药的纳米颗粒系统地积累在肿瘤部位，导致治疗效果很差。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给药途径来改善治疗结果。最近的方法依赖于使用当地的交付平台，以绕过系统性交付的障碍。局部给药可以提供更高的“有效”剂量，同时增强治疗分子的稳定性，最大限度地减少副作用，清除和全身给药后在肝脏和肾脏的蓄积。水凝胶已被证明是高度生物相容性的材料，允许多样化的设计，同时提供传感和治疗。水凝胶的化学和物理多样性可以被用来实现疾病触发的原位组装和水凝胶的程序化降解以及随后的药物释放，水凝胶也可以作为生物相容性仓库，用于局部输送刺激响应性治疗货物。我们将把重点放在我们实验室开发的基于树枝状大分子胺和葡聚糖醛的水凝胶平台上。这种水凝胶对疾病敏感，能够感知微环境，并以分级的方式对不同的病理做出反应，以呈现不同的特性，包括组织粘附性、生物相容性、水凝胶降解性和嵌入的药物释放轮廓。我们还研究了我们的刺激响应材料在体内的降解动力学，并分析了获得体外−体内相关性的体外条件。确定健康和疾病条件下体内微环境中的关键参数是实现这种相关性的关键。我们的树枝状大分子−葡聚糖水凝胶的粘附性使其成为包埋药物局部和持续释放的最佳选择。我们证明，它提供了一系列抗癌治疗药物，包括核酸、小分子和抗体药物。作为局部输送的仓库，它允许高剂量的活性生物分子直接输送到肿瘤部位。免疫治疗是最近兴起的癌症治疗领域，在局部治疗后，可以利用刺激响应性水凝胶来传递全身效应。局部给药可以在需要的地方释放适当的药物剂量，提高药物的生物利用度，同时创造记忆，系统地发挥治疗效果。这篇文章突出了我们对如何使用刺激响应性水凝胶提供的局部和系统治疗来提供更精确、持久和有效的治疗结果的看法。
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 effcacy. 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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影响因子：
41.2
作者：
Conde J;Oliva N;Atilano M;Song HS;Artzi N
通讯作者：
Artzi N
影响因子：
5.4
作者：
Lu, Qiang;Bai, Shumeng;Kaplan, David L.
通讯作者：
Kaplan, David L.
影响因子：
14
作者：
Hori, Yuki;Winans, Amy M.;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
DOI：
10.1016/j.ejpb.2006.11.022
发表时间：
2007-06-01
影响因子：
4.9
作者：
Kakinoki, Sachiro;Taguchi, Tetsushi;Tateishi, Tetsuya
通讯作者：
Tateishi, Tetsuya
影响因子：
41.2
作者：
通讯作者：
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