Brudno Yevgeny, Silva Eduardo A, Kearney Cathal J, Lewin Sarah A, Miller Alex, Martinick Kathleen D, Aizenberg Michael, Mooney David J
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138;
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; Department of Biomedical Engineering, University of California, Davis, CA 95616; and.
Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12722-7. doi: 10.1073/pnas.1413027111. Epub 2014 Aug 19.
Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN-carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.
局部给药储库具有显著的临床应用价值，但目前一旦其药物载荷耗尽，尚无无创技术来重新填充这些系统。受纳米治疗剂靶向特定组织能力的启发，我们推测血源药物载荷可经修饰后归巢至水凝胶药物递送系统并对其进行重新填充。为探讨这种可能性，用寡脱氧核苷酸（ODN）对水凝胶进行修饰，这些寡脱氧核苷酸为携带互补ODN的游离藻酸盐链形式的药物载荷提供靶点。将ODN与藻酸盐链偶联导致在体外与携带互补ODN的藻酸盐凝胶以及在体内与注射的凝胶发生特异性结合。当与药物载荷偶联时，由肿瘤内水凝胶组成的递送储库的序列靶向重新填充完全消除了肿瘤生长。这些结果提示了纳米治疗药物递送的一种新范式，并且这一概念有望应用于癌症治疗、伤口愈合以及药物洗脱血管移植物和支架中的药物储库重新填充。
