Bio-Orthogonal Nanogels for Multiresponsive Release.

Mohammad Shafee Alkanawati,Héloïse Thérien-Aubin,Katharina Landfester,Marina Machtakova

doi:10.1021/acs.biomac.1c00378

Mohammad Shafee Alkanawati, Héloïse Thérien-Aubin + Show 2 more

Open Access

https://doi.org/10.1021/acs.biomac.1c00378

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Abstract

Responsive nanogel systems are interesting for the drug delivery of bioactive molecules due to their high stability in aqueous media. The development of nanogels that are able to respond to biochemical cues and compatible with the encapsulation and the release of large and sensitive payloads remains challenging. Here, multistimuli-responsive nanogels were synthesized using a bio-orthogonal and reversible reaction and were designed for the selective release of encapsulated cargos in a spatiotemporally controlled manner. The nanogels were composed of a functionalized polysaccharide cross-linked with pH-responsive hydrazone linkages. The effect of the pH value of the environment on the nanogels was fully reversible, leading to a reversible control of the release of the payloads and a “stop-and-go” release profile. In addition to the pH-sensitive nature of the hydrazone network, the dextran backbone can be degraded through enzymatic cleavage. Furthermore, the cross-linkers were designed to be responsive to oxidoreductive cues. Disulfide groups, responsive to reducing environments, and thioketal groups, responsive to oxidative environments, were integrated into the nanogel network. The release of model payloads was investigated in response to changes in the pH value of the environment or to the presence of reducing or oxidizing agents.

Highlights

In recent years, stimuli-responsive nanogels (NGs) have emerged as a class of efficient nanocarriers for drug and gene therapy.[1,2] Stimuli-responsive NGs combine the properties of other nanocarriers, such as high drug loading, extended biodistribution, and large surface area, allowing for their efficient surface functionalization
The results show that after two to three cycles in the microfluidizer, the two initially distinct aqueous phases were thoroughly mixed
The results show that a rapid release of the payload was observed at a pH value of 5.2, but slowed down and almost stop at a pH value of 7.4, and the variation of the pH value of the environment could be used to modulate the release profile of the payload from the DNGs

Summary

■ INTRODUCTION

Stimuli-responsive nanogels (NGs) have emerged as a class of efficient nanocarriers for drug and gene therapy.[1,2] Stimuli-responsive NGs combine the properties of other nanocarriers, such as high drug loading, extended biodistribution, and large surface area, allowing for their efficient surface functionalization. A bio-orthogonal reaction is a reaction that preferably proceeds under normal physiological conditions, does not require the use of toxic catalysts or radiation, has a fast kinetics, does not yield side products, and cannot undergo side reactions with molecules and functional groups present in biological environments.[30] Such bio-orthogonal chemistries have been used as the cross-linking strategies in the design of new hydrogels.[31,32] For example, gelatin polymers with pendant tetrazine or norbornene are a pair of reagents that spontaneously undergo bio-orthogonal cross-linking to form hydrogels when they are mixed Such a system produced injectable gels and maintained the cell-responsive properties of native gelatin.[33]. The release of the payload was measured by fluorescence spectroscopy after the centrifugal ultrafiltration of the NG suspensions incubated for different periods of time in a buffer solution at controlled pH values and concentration of either reducing or oxidizing agents. Details of the in vitro experiments are described in the Supporting Information

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES