Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117, United States.
Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, United States.
Bioconjug Chem. 2020 Nov 18;31(11):2541-2552. doi: 10.1021/acs.bioconjchem.0c00483. Epub 2020 Oct 28.
Exosomes have been widely demonstrated as an effective anticancer therapeutic moiety. However, their clinical translation has been limited by the requirement of prohibitively high therapeutic doses due to their lack of specificity in delivery and, consequently, short systemic half-life. To overcome these challenges, we engineered a platform for modifying exosomes with an active targeting modality composed of membrane Anchor (BODIPY)-Spacer (PEG)-targeting Ligands (cyclic RGD peptide) (ASL). Herein, we show that the intramembrane incorporation of a trackable, targeting system renders ASL exosomes (AExs) a modular platform. AExs significantly overcome challenges associated with exosome modification, including potential damage for functionalization, or destabilizing interactions between dyes and drugs. ASL-modification not only enhanced stability in imparting active targeting but also introduced a built-in bioimaging modality. Our studies show that AExs target B16F10 melanoma tumor sites by the specific interaction of cyclic RGD and integrin. Doxorubicin encapsulated AExs (dAExs) significantly inhibited the growth of melanoma and . Thus, we conclude that ASL-modification allows exosomes to be transformed into a novel therapeutic vehicle uniquely integrating tracking and robust targeting with drug delivery. We anticipate that the therapeutic, targeting, and diagnostic modularity provided by ASL will potentiate translational applications of exosome-based vehicles beyond anticancer therapy.
外泌体已被广泛证明是一种有效的抗癌治疗药物。然而，由于其在传递方面缺乏特异性，并且因此系统半衰期短，因此需要极高的治疗剂量，从而限制了其临床转化。为了克服这些挑战，我们设计了一个平台，通过由膜锚（BODIPY）-间隔物（PEG）-靶向配体（环状 RGD 肽）（ASL）组成的主动靶向模式来修饰外泌体。在此，我们表明，可追踪的靶向系统的跨膜掺入使 ASL 外泌体（AExs）成为模块化平台。AExs 显著克服了与外泌体修饰相关的挑战，包括功能化的潜在损伤或染料和药物之间的不稳定相互作用。ASL 修饰不仅通过赋予主动靶向增强了稳定性，而且还引入了内置的生物成像模式。我们的研究表明，AExs 通过环状 RGD 和整合素的特异性相互作用靶向 B16F10 黑色素瘤肿瘤部位。阿霉素包封的 AExs（dAExs）显著抑制了黑色素瘤的生长和。因此，我们得出结论，ASL 修饰允许外泌体转化为一种新型治疗载体，将跟踪和强大的靶向与药物输送独特地结合在一起。我们预计，ASL 提供的治疗、靶向和诊断的多功能性将增强基于外泌体的载体在癌症治疗以外的转化应用。
