Enzyme-directed assembly of a nanoparticle probe in tumor tissue.
Enzyme-directed assembly of a nanoparticle probe in tumor tissue.
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DOI：
10.1002/adma.201300823
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发表时间：
2013-07-12
影响因子：
29.4
通讯作者：
Gianneschi, Nathan C.
中科院分区：
文献类型：
--
作者：
Chien, Miao-Ping;Thompson, Matthew P.;Barback, Christopher V.;Ku, Ti-Hsuan;Hall, David J.;Gianneschi, Nathan C.
靶向治疗学和分子诊断学的目标是在疾病部位积累比身体其他部位更多的药物或探针。为了实现这一点，人们对能够作为体内治疗和诊断的载体或储存库的纳米材料的开发产生了极大的兴趣。[1]一般来说，纳米颗粒在这项任务中受到青睐[2]，因为它们可以大到足以作为给定小分子的多个副本的载体，可以表现出多种靶向功能，并且可以小到足以安全地注射到血液中。[3]总体目标是，颗粒要么通过增强的通透性和保留力(EPR)效应被动地靶向，要么通过加入靶向基团来主动地进行靶向，或者两者兼而有之。4]纳米颗粒靶向策略在很大程度上依赖于表面共轭配体的使用，该配体旨在结合与给定细胞类型相关的过度表达的细胞膜受体。[5]我们设想了另一种靶向策略，该策略将通过肿瘤组织特异性的超分子组装事件导致纳米颗粒的主动积聚，该事件发生在特定信号的响应下(图1)。刺激诱导靶向最理想的方法是利用内源性信号，该信号特定于病变组织本身，能够主动靶向通过静脉注射(IV)引入的材料。这种方法与开发能够通过局部施加外部刺激(如光或磁场)来靶向和释放系统的努力形成对比。[7]对于可行的内源信号，人们可以合理地考虑响应刺激而积累的材料，包括pH变化、温度变化、[9]或氧化还原反应。[10]然而，我们的目标是开发能够在体内组装的纳米颗粒，以响应选择性的、内源性的、生物分子信号。为此，我们的目标是利用酶作为刺激，而不是其他识别事件，因为它们独特地能够通过催化放大在体内传播信号，就像在酶前药物治疗策略中一样。[12]我们假设，如果特定的酶信号可以用来化学改变纳米颗粒，并诱导它们在肿瘤内形成新的、缓慢清除的形态，那么酶引导的纳米颗粒积累和保留过程是可能的。[13]我们推断，探索这一概念的最佳信号将来自基质金属蛋白酶的催化活性，已知的是在某些肿瘤类型中过表达，并被证明是能够激活体内基于多肽的荧光探针的可行生物标志物。我们设计了一套对基质金属蛋白酶有反应的球形纳米颗粒，用于静脉注射到HT-1080异种移植鼠体内，已知在肿瘤组织中有高水平的基质金属蛋白酶-2和基质金属蛋白酶-9水平。[15]我们假设纳米颗粒将在整个生物体中循环，然后通过在肿瘤组织内发生的基质金属蛋白酶驱动的蓄积事件而聚集(图1)。此外，这些颗粒被标记以产生与酶诱导的结构相关联的特定荧光信号，这些结构与组织特异性积累事件相结合。为了在肿瘤组织中产生能够产生FRET(Förster Response Energy Transfer)探针的酶反应颗粒，我们设计了一套由肿瘤相关酶MMP2和…的多肽底物组成的新型多肽-聚合物两亲物
The goal of targeted therapeutics and molecular diagnostics is to accumulate drugs or probes at the site of disease in higher quantities relative to other locations in the body. To achieve this, there is tremendous interest in the development of nanomaterials capable of acting as carriers or reservoirs of therapeutics and diagnostics in vivo.[1] Generally, nanoscale particles are favored for this task [2] as they can be large enough to function as carriers of multiple copies of a given small mole cule, can display multiple targeting functionalities, and can be small enough to be safely injected into the blood stream.[3] The general goal is that particles will either target passively via the enhanced permeability and retention (EPR) effect, actively by incorporation of targeting groups, or by a combination of both.[3b, 4] Nanoparticle targeting strategies have largely relied on the use of surface conjugated ligands designed to bind overexpressed cellmembrane receptors associated with a given cell-type.[5] We envisioned an alternative targeting strategy that would lead to an active accumulation of nanoparticles by virtue of a supramolecular assembly event specific to tumor tissue, occurring in response to a specific signal (Figure 1). The most desirable approach to stimuli-induced targeting would be to utilize an endogenous signal, specific to the diseased tissue itself, capable of actively targeting materials introduced via intravenous (IV) injection. Such an approach is in contrast to efforts to develop systems capable of targeting and release via the local application of external stimuli such as light [6] or magnetic fields.[7] With respect to viable endogenous signals, one could reasonably consider materials that accumulate in response to stimuli including pH changes,[8] temperature variation,[9] or redox reactions.[10] However, we aim to develop nanoparticles capable of assembling in vivo in response to selective, endogenous, biomolecular signals.[11] For this purpose, we aim to utilize enzymes as stimuli, rather than other recognition events, because they are uniquely capable of propagating a signal via catalytic amplification in vivo as in enzyme-prodrug therapy strategies.[12] We hypothesized that an enzyme-directed, nanoparticle accumulation and retention process would be possible if a specific enzymatic signal could be used to chemically alter nanoparticles and induce them to form a new, slowly clearing morphology within tumors.[13] We reasoned that the best signal for exploring this concept would come from the catalytic activity specific to matrix metalloproteinases, MMP-2 and MMP-9, known to be overexpressed in certain tumor types and proven as viable biomarkers capable of activating peptide-based fluorogenic probes in vivo.[13c, 14] To achieve this, we designed a set of MMP-responsive spherical nanoparticles for IV injection into HT-1080 xenograft mice, known to have elevated levels of MMP-2 and MMP-9 within the tumor tissue.[15] We hypothesized that nanoparticles would circulate throughout the organism then collect by virtue of a MMP-driven accumulation event occurring within the tumor tissue (Figure 1). Furthermore, the particles were labeled to generate specific fluorescent signals associated with the enzymeinduced structures that arise in conjunction with the tissuespecific accumulation events. Therefore, enzyme-driven accumulation and retention would give rise to a probe for tumor tissue.To generate enzyme-responsive particles capable of generating a FRET (Förster resonance energy transfer) probe in tumor tissue, we designed a set of novel peptide-polymer amphiphiles (PPA) that consist of a peptide substrate for cancer-associated enzymes MMP-2 …
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影响因子：
7.3
作者：
Galande, Amit K.;Hilderbrand, Scott A.;Tung, Ching-Hsuan
通讯作者：
Tung, Ching-Hsuan
紫外线和近红外线触发聚合物纳米颗粒的释放。
影响因子：
15
作者：
Fomina, Nadezda;McFearin, Cathryn;Sermsakdi, Marleen;Edigin, Osayimwense;Almutairi, Adah
通讯作者：
Almutairi, Adah
DOI：
10.1073/pnas.0601755103
发表时间：
2006-04-18
影响因子：
11.1
作者：
Farokhzad, OC;Cheng, JJ;Langer, R
通讯作者：
Langer, R
影响因子：
15
作者：
Amir, Roey J.;Zhong, Sheng;Hawker, Craig J.
通讯作者：
Hawker, Craig J.
影响因子：
38.3
作者：
Geng, Yan;Dalhaimer, Paul;Discher, Dennis E.
通讯作者：
Discher, Dennis E.