Fibrin‐targeting delivery: a novel platform for cardiac regenerative medicine

Huang, Zheyong; Song, Yanan; Pang, Zhiqing; Li, Minghui; Guliya, Yerkintay; Shen, Yunli; Qian, Juying

doi:10.1111/jcmm.12912

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…The fibrin-based provisional matrix is the "first order" and most important provisional matrix after MI. 25,33 In agreement with previous studies, 26 our results revealed that fibrin was expressed in the acute phase and lasted during the proliferative phase, which lasted from 48 h to 5 days 25 after MI in rodents. Abundant fibrin was visualized in the infarcted area Abbreviations: cTnT, cardiac troponin T; DaPI, 4′,6-diamidino-2-phenylindole; gaPDh, glyceraldehyde-3-phosphate dehydrogenase; cNP-Tβ4, cysteine-arginineglutamic acid-lysine-alanine and thymosin beta 4 conjugated to nanoparticles; MI, myocardial infarction; sMαa, smooth muscle α-actin; cD31, cluster of differentiation 31; PBs, phosphate-buffered saline; Tβ4, thymosin beta 4; NP-Tβ4, thymosin beta 4 conjugated to nanoparticles; DaPI, 4′,6-diamidino-2-phenylindole.…”

Section: Discussionsupporting

confidence: 92%

“…26 The high abundance might accordingly favor excellent targeting efficiency when fibrin functions as the therapeutic target. 33 Clot-binding peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA) is a tumor-homing peptide obtained by in vivo phage display. Both our and other studies had recently found that CREKA could specifically bind to fibrin in microthrombus and stroma of tumors.…”

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confidence: 99%

“…Provided therapeutic agents (eg, exogenously administered cells, growth factors, peptides, or small molecule compounds) could be connected with CREKA effectively and efficiently, the fibrin-targeting system could be capable of localizing systemically delivered cells/drugs to the injured heart, enhancing their efficacy and reducing their dosing. 33,48 In addition, fibrin is the common provisionally pathological matrix after …”

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confidence: 99%

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Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

Huang

Song

Pang

et al. 2017

IJN

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Purpose Thymosin beta 4 (Tβ4) has multiple beneficial facets for myocardial injury, but its efficiency is limited by the low local concentration within the infarct. Here, we established a Tβ4 delivery system for cardiac repair based on the interaction between the abundant fibrin in the infarct zone and the fibrin-targeting moiety clot-binding peptide cysteine–arginine–glutamic acid–lysine–alanine (CREKA). Methods and results CREKA and Tβ4 were conjugated to nanoparticles (CNP–Tβ4). In vitro binding test revealed that CNP–Tβ4 had a significant binding ability to the surface of fibrin clots when compared to the control clots (NP–Tβ4). Based on the validation of fibrin expression in the early stage of ischemia injury, CNP–Tβ4 was intravenously administered to mice with acute myocardial ischemia–reperfusion injury. CNP–Tβ4 revealed a stronger fibrin-targeting ability than the NP–Tβ4 group and accumulated mainly in the infarcted area and colocalized with fibrin. Subsequently, treatment with CNP–Tβ4 resulted in a better therapeutic effect. Conclusion CRKEA modification favored Tβ4 accumulation and retention in the infarcted region, leading to augmented functional benefits. Fibrin-targeting delivery system represents a generalizable platform technology for regenerative medicine.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

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confidence: 99%

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Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

Huang

Song

Pang

et al. 2017

IJN

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“…The fibrin‐targeting platform described here would not be limited to MSCs and might be extended to other types of cells or even drugs. Provided that therapeutic agents (cells or small molecules) could be effectively and safely combined with CREKA, the fibrin‐homing system might localize systemically delivered cells/drugs to the injured heart, enhance their efficacy and reduce their dosing . Meanwhile, fibrin provides a universal provisional matrix during repair of almost all tissue injury , offering the possibility that a fibrin targeting strategy might be applicable beyond MI to tissue injury with rich fibrin deposition at an early time period.…”

Section: Discussionmentioning

confidence: 99%

“…Fibrin almost exclusively deposits in the injured myocardium , which is congruent with the target region of regenerative therapy. The spatiotemporal characteristics of fibrin expression after MI render fibrin an ideal target for the delivery of stem cells .…”

Section: Introductionmentioning

confidence: 99%

Modification with CREKA Improves Cell Retention in a Rat Model of Myocardial Ischemia Reperfusion

et al. 2019

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Poor cell homing limits the efficacy of cardiac cellular therapy. The homing peptide, cysteinearginine-glutamic acid-lysine-alanine (CREKA), targets fibrin effectively which is involved in the repair process of tissue injury. Here, we assessed if CREKA-modified stem cells had enhanced fibrin-mediated homing ability resulting in better functional recovery and structural preservation in a rat myocardial injury model. CREKA-modified mesenchymal stem cells (CREKA-MSCs) were obtained via membrane fusion with CREKA-modified liposomes. The fibrin targeting ability of CREKA-MSCs was examined both in vitro and in vivo. Under both static and flow conditions in vitro, CREKA significantly enhanced MSCs binding ability to fibrin clots (2.6-and 2.3-fold, respectively). CREKA-MSCs showed 6.5-fold higher accumulation than unmodified MSCs in injured rat myocardium one day after administration, resulting in better structural preservation and functional recovery. Fibrin is, therefore, a novel target for enhancing homing of transplanted cells to injured myocardium, and the delivery system of fibrin-targeting is on behalf of a universalizable platform technology for regenerative medicine. STEM CELLS 2019;37:663-676 SIGNIFICANCE STATEMENTPoor cell homing limits the efficacy of cardiac cellular therapy. Fibrin expression after myocardial injury renders fibrin, an ideal target for the delivery of stem cells. In this study, the authors developed fibrin-targeting stem cells for the repair of myocardial injury using cysteine-arginineglutamic acid-lysine-alanine (CREKA) as the targeting moiety. CREKA-modified mesenchymal stem cells (MSCs) exhibited potent fibrin-targeting ability both in vitro and in vivo, highlighting the utility of active fibrin targeting in cardiac cellular therapy.

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Milestones and current achievements in development of multifunctional bioscaffolds for medical application

Litowczenko

Woźniak-Budych

Staszak

et al. 2021

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Fibrin‐targeting delivery: a novel platform for cardiac regenerative medicine

Cited by 9 publications

References 34 publications

Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

Modification with CREKA Improves Cell Retention in a Rat Model of Myocardial Ischemia Reperfusion

Milestones and current achievements in development of multifunctional bioscaffolds for medical application

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