Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery,Chemical Science

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Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery
Chemical Science ( IF 7.6 ) Pub Date : 2020/03/06 , DOI: 10.1039/d0sc00078g
Gayathri R. Ediriweera _{1,

2,

3,

4,

5} , Joshua D. Simpson _{1,

2,

3,

4,

5} , Adrian V. Fuchs _{1,

2,

3,

4,

5} , Taracad K. Venkatachalam _{1,

2,

3,

4,

5} , Matthias Van De Walle _{3,

4,

6,

7} , Christopher B. Howard _{2,

3,

4,

5,

8} , Stephen M. Mahler _{2,

3,

4,

5,

8} , James P. Blinco _{3,

4,

6,

7} , Nicholas L. Fletcher _{1,

2,

3,

4,

5} , Zachary H. Houston _{1,

2,

3,

4,

5} , Craig A. Bell _{1,

2,

3,

4,

5} , Kristofer J. Thurecht _{1,

2,

3,

4,

5}

Affiliation

There remain several key challenges to existing therapeutic systems for cancer therapy, such as quantitatively determining the true, tissue-specific drug release profile in vivo, as well as reducing side-effects for an increased standard of care. Hence, it is crucial to engineer new materials that allow for a better understanding of the in vivo pharmacokinetic/pharmacodynamic behaviours of therapeutics. We have expanded on recent “click-to-release” bioorthogonal pro-drug activation of antibody-drug conjugates (ADCs) to develop a modular and controlled theranostic system for quantitatively assessing site-specific drug activation and deposition from a nanocarrier molecule, by employing defined chemistries. The exploitation of quantitative imaging using positron emission tomography (PET) together with pre-targeted bioorthogonal chemistries in our system provided an effective means to assess in real-time the exact amount of active drug administered at precise sites in the animal; our methodology introduces flexibility in both the targeting and therapeutic components that is specific to nanomedicines and offers unique advantages over other technologies. In this approach, the in vivo click reaction facilitates pro-drug activation as well as provides a quantitative means to investigate the dynamic behaviour of the therapeutic agent.

中文翻译：

采用生物正交化学的靶向和模块化建筑聚合物，用于定量治疗

现有的用于癌症治疗的治疗系统仍然存在一些关键挑战，例如定量确定体内真实的，组织特异性的药物释放曲线，以及减少副作用以提高护理标准。因此，设计新材料以更好地了解体内至关重要。治疗剂的药代动力学/药效动力学行为。我们已经扩展了抗体-药物偶联物（ADC）的最新“点击释放”生物正交药物前激活作用，以开发模块化和可控制的治疗药物学系统，通过采用以下方法定量评估位点特异性药物的活化和从纳米载体分子中的沉积确定的化学物质。在我们的系统中，利用正电子发射断层扫描（PET）结合预先定标的生物正交化学方法对定量成像的开发，提供了一种有效的手段，可以实时评估在动物的精确部位施用的活性药物的确切数量；我们的方法论为纳米药物特有的靶向和治疗成分引入了灵活性，并提供了优于其他技术的独特优势。通过这种方法，体内点击反应促进前药活化，并提供定量方法来研究治疗剂的动态行为。

更新日期：2020-03-26

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