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Utilizing Inverse Emulsion Polymerization To Generate Responsive Nanogels for Cytosolic Protein Delivery
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-11-02 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00643
Kishore Raghupathi 1 , Scott J. Eron 1 , Francesca Anson 1 , Jeanne A. Hardy 1 , S. Thayumanavan 1
Affiliation  

Therapeutic biologics have various advantages over synthetic drugs in terms of selectivity, their catalytic nature, and, thus, therapeutic efficacy. These properties offer the potential for more effective treatments that may also overcome the undesirable side effects observed due to off-target toxicities of small molecule drugs. Unfortunately, systemic administration of biologics is challenging due to cellular penetration, renal clearance, and enzymatic degradation difficulties. A delivery vehicle that can overcome these challenges and deliver biologics to specific cellular populations has the potential for significant therapeutic impact. In this work, we describe a redox-responsive nanoparticle platform, which can encapsulate hydrophilic proteins and release them only in the presence of a reducing stimulus. We have formulated these nanoparticles using an inverse emulsion polymerization (IEP) methodology, yielding inverse nanoemulsions, or nanogels. We have demonstrated our ability to overcome the liabilities that contribute to activity loss by delivering a highly challenging cargo, functionally active caspase-3, a cysteine protease susceptible to oxidative and self-proteolytic insults, to the cytosol of HeLa cells by encapsulation inside a redox-responsive nanogel.

中文翻译:

利用反相乳液聚合产生响应性的纳米凝胶,用于胞质蛋白的输送。

就选择性,催化性质以及因此的治疗功效而言,治疗生物制剂比合成药物具有多种优势。这些特性为更有效的治疗提供了可能,该治疗还可克服由于小分子药物的脱靶毒性而观察到的不良副作用。不幸的是,由于细胞渗透,肾脏清除和酶促降解的困难,生物制剂的全身给药具有挑战性。可以克服这些挑战并将生物制剂递送至特定细胞群的递送载体具有产生重大治疗效果的潜力。在这项工作中,我们描述了一个氧化还原响应的纳米粒子平台,它可以封装亲水性蛋白质并仅在存在还原刺激的情况下释放它们。我们使用反相乳液聚合(IEP)方法配制了这些纳米颗粒,从而产生了反相纳米乳液或纳米凝胶。我们已经证明了我们有能力克服挑战,通过将高挑战性货物,功能活跃的caspase-3(一种易受氧化和自蛋白水解损伤的半胱氨酸蛋白酶)递送到HeLa细胞的胞质溶胶中,将其封装在氧化还原液中反应灵敏的纳米凝胶。
更新日期:2017-11-03
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