Dual-peptide functionalized acetalated dextran-based nanoparticles for sequential targeting of macrophages during myocardial infarction

Abstract

The advent of nanomedicine has recently started to innovate the treatment of cardiovascular diseases, in particular myocardial infarction. Although current approaches are very promising, there is still an urgent need for advanced targeting strategies. In this work, the exploitation of macrophage recruitment is proposed as a novel and synergistic approach to improve the addressability of the infarcted myocardium achieved by current peptide-based heart targeting strategies. For this purpose, an acetalated dextran-based nanosystem is designed and successfully functionalized with two different peptides, atrial natriuretic peptide (ANP) and linTT1, which target, respectively, cardiac cells and macrophages associated with atherosclerotic plaques. The biocompatibility of the nanocarrier is screened on both macrophage cell lines and primary macrophages, showing high safety, in particular after functionalization of the nanoparticles' surface. Furthermore, the system shows higher association versus uptake ratio towards M2-like macrophages (approximately 2-fold and 6-fold increase in murine and human primary M2-like macrophages, respectively, compared to M1-like). Overall, the results demonstrate that the nanosystem has potential to exploit the "hitchhike" effect on M2-like macrophages and potentially improve, in a dual targeting strategy, the ability of the ANP peptide to target infarcted heart. † Electronic supplementary information (ESI) available. See

Acetalated dextran based nano- and microparticles: synthesis, fabrication, and therapeutic applications

“…18 (c) Amine-modified dextran synthesis, by partially oxidation of dextran, acetalation, imine bond formation and reduction. 19,20,23 (d) Grafted Ac-DEX polymers by conjugation of a chain transfer agent (CTA), followed by reversible addition-fragmentation chain-transfer (RAFT) polymerization. 26,28,29 (e) Amphiphilic Ac-DEX block copolymers, synthesized by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction.…”

“…31,32 further conjugation of targeting moieties or polyethylene glycol (PEG) to enhance the stability. [21][22][23][24] Ac-DEX-based copolymers represent another category of functionalized Ac-DEX family. According to the synthetic strategy, copolymers are synthesized by either ''grafting from'' or ''grafting to'' approaches.…”

“…Conventional single emulsion techniques are often chosen in the production of Ac-DEX and derivatives micro-and nano-particles, particularly for Ac-DEX with positively charged modifications (SpAcDEX and Putresceinconjugated Ac-DEX). 22,23,41 The polymer is dissolved in the organic phase (e.g., dichloromethane) before adding the aqueous phase containing the surfactant (e.g., PVA) and formation of the emulsion by homogenizer or high intensity sonication. 41,64 The careful optimization of the volumes of dispersed and continuous phase, intensity and duration of the sonication and the temperature of the emulsion allow to achieve particles with size ca.…”

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…In a following study, the same group demonstrated that acid-sensitive polyketal nanoparticles (~500 nm) loaded with NOX2-NADPH oxidase siRNA can significantly attenuate NOX2 expression and recover cardiac function by inhibiting oxidative stress, after intramyocardial injection in mice with MI [ 162 ]. In other studies, pH-responsive microparticles based on acetalated dextran were examined for tunable release of a cardioprotective growth factor to the heart by local delivery [ 284 ], and peptide-functionalized acetalated dextran-derived nanoparticles (100-200 nm) were used for M2-like macrophage-mediated targeted delivery of small hydrophobic compounds to the infarcted heart for MI therapy [ 285 ]. Murry and coworkers designed a pH-responsive, injectable hydrogel [ 286 ], based on a pH- and temperature-responsive copolymer, i.e., poly(N-isopropylacrylamide-co-propylacrylic acid-co-butyl acrylate).…”

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…The vascular stabilization of angiogenic neovessels could be also a viable option for regenerative medicine to improve blood perfusion and nutrient delivery, not only for acute injuries with high metabolic demand, but also chronic injuries where hypoxia and angiogenic, nonfunctional blood vessels persist [89]. Furthermore, biphasic homing peptides that target two different ECM molecules, tenascin-C and fibronectin, in tumor ECM [90,91], could also be used for regenerative medicine, as the granulation tissue in acute tissue injuries is rich in these two ECM molecules [92].…”