MicroRNA-Guided Selective Release of Loads from Micro-/Nanocarriers Using Auxiliary Constitutional Dynamic Networks.

Pu Zhang,Margarita Vázquez-González,Liang Yue,Yang Sung Sohn,Zhixin Zhou,Itamar Willner,Wei-Hai Chen,Rachel Nechushtai

doi:10.1021/acsnano.9b06047

Abstract

Two different drug micro-carriers consisting of doxorubicin-dextran (DOX-D)- and camptothecin-modified carboxymethyl cellulose (CPT-CMC)-loaded nucleic acid-stabilized microcapsules, MC-1 and MC-2, or two different nanocarriers consisting of nucleic-acid-locked doxorubicin (DOX)- and camptothecin (CPT)-loaded metal–organic framework nanoparticles, NMOF-1 and NMOF-2, are coupled to auxiliary constitutional dynamic networks, CDNs, for the triggered release of the drugs. CDN “S” composed of four constituents AA′’, AB′, BA′, and BB′, and two hairpin structures, H1 and H2, leads to the CDN “S”-guided unlocking of the MC-1/MC-2 carriers and the release of DOX-D and CPT-CMC or of the NMOF-1 and NMOF-2 carriers that release DOX and CPT, respectively. The unlocking processes are activated by the cleavage of H1 and H2 by BB′ and BA′, respectively, to yield fragmented strands that unlock the gating units of the microcapsules/NMOFs carriers. In the presence of miRNA-155 or miRNA-124, dictated orthogonal reconfiguration of CDN “S” into CDN “X” or “Y” proceeds. The miRNA-155 stimulates the reconfiguration of CDN “S” to CDN “X”, where AA′ and BB′ are upregulated, and AB′ and BA′ are downregulated, leading to the enhanced release of DOX-D or DOX from the microcapsule/NMOFs carriers, and to the concomitant inhibition of the release of CPT-CMC or CPT from the respective carriers. Similarly, the miRNA-124-triggered reconfiguration of CDN “S” to CDN “Y” results in the BA′-guided cleavage of H2 and the preferred release of CPT-CMC or CPT from the respective carriers. The miRNA-triggered CDN-driven unlocking of the carriers stimulates the amplified and selective release of the drugs from the microcapsules/NMOFs carriers.

Highlights

camptothecin-modified carboxymethyl cellulose (CPT-CMC) or of the NMOF-1 and NMOF-2 carriers that release DOX and CPT, respectively
Chemical processes in cells are often driven by complex constitutional dynamic networks (CDNs) that are triggered by environmental stimuli.[1−4] The dynamic networks represent equilibrated systems of constituents that can be upregulated or downregulated by external triggers and, the control over the contents of the constituents might lead to emerging functionalities
Consists of a dynamically equilibrated system composed of four constituents AA′, AB′, BA′, and BB′

Summary

Introduction

CPT-CMC or of the NMOF-1 and NMOF-2 carriers that release DOX and CPT, respectively. The unlocking processes are activated by the cleavage of H1 and H2 by BB′ and BA′, respectively, to yield fragmented strands that unlock the gating units of the microcapsules/NMOFs carriers. The cleavage of H2 by the constituent BA′ is enhanced in the presence of CDN “Y”, resulting in an improved release of CPT-CMC from the microcapsules MC-2 as compared to the release of the load stimulated by BA′, present in CDN “S”.

Results

Conclusion