Pinpoint modification of thermoresponsive nanogels: turning cross-linking points into aldehydes

WOLFEL, ALEXIS; CALDERÓN, MARCELO; OSORIO BLANCO, ERNESTO; ALVAREZ IGARZABAL, CECILIA I.

Simposio; Virtual International Symposium on Nano/Microgels; 2020

Organized by Prof. Marcelo Calderón from Basque Center for Macromolecular Design & Engineering ? POLYMAT (Spain) and Prof. Miriam Strumia from Institute of Research and Development in Process Engineering and Applied Chemistry (IPQA) of the UNC

The scientific advances towards thermoresponsive nanogels (NGs) applications revealed theneed for precise control over the sizes, polydispersity, architecture and functionalization. Themost used strategy for the synthesis of NGs is precipitation polymerization. However, severallimitations are imposed by the method, which difficult the obtainment of the required features.For example, the relative reactivity between monomers and crosslinkers, the initiation rate, andthe concentration of the different species in the reaction media, directly affect the size andpolydispersity of the particles, and determine the incorporation and spatial distribution of acomponent in the microgel structure. Therefore, it is often necessary to elaborate strategies forarchitectural control (i.e. seeded polymerization or semi-batch synthesis) and functionalizationby post-synthetic modifications.[1]In particular, the functionalization of synthetic polymers with aldehyde functional groups (FGs) isgenerally a difficult and tedious task. The lability of aldehydes under free radical polymerizationconditions generates the need to preserve the aldehyde moiety by using protecting groups. Thus,it is required to synthesize the protected monomer (for example, as an acetal), undergo thepolymerization, and then, deprotect the aldehyde groups by using strong acids such astrifluoroacetic acid.[2] However, aldehyde FGs are of great interest for their ability to yieldcovalent linkages with amino-derivatives (such as amines, hydrazines and hydroxilamines),through selective reactions and under mild conditions.[3]In this work, we propose a methodology that enable an easy post-synthesis modification of thestructure of thermosensitive nano- and microgels while introducing aldehyde functional groups.For this purpose, we studied the incorporation of a cleavable crosslinker in the synthesis ofpoly(N-isopropylacrylamide) (pNIPAm), poly(N-isopropylmethacrylamide) (pNIPMAm) andpNIPAm-co-NIPMAm based NGs obtained via precipitation polymerization. The cleavablecrosslinker (+)-N,N´-diallyltartardiamide (DAT) presents vicinal diols which can be easily cleavedby sodium periodate aqueous solutions in a post-synthesis step (Figure 1).[4] As a result, thecrosslinker breakdown generated noticeable changes in the NGs structure while yielded valuable α-oxoaldehydes functional groups (FGs). These particular variety of aldehyde are useful forfurther chemical derivatizations and are often used to undergo bio-orthogonal reactions inpeptide bioconjugation.[5]In our work, we studied which parameters such as monomers and crosslinkers reactivity, or theinitiation method applied (either by thermal decomposition of only ammonium persulfate (APS),or with N,N,N,N-tetramethylethylenediamine (TEMED) as accelerator), affected the incorporationof the cleavable crosslinker. This incorporation was reflected in the hydrodynamic diameters (DH)of the NGs according to DAT concentration, and resulted more evident by the observed changes,in DH and morphology, after the periodate-mediated cleavage of the crosslinks.Finally, some of the skills introduced by the synthesis and post-synthetic modification methodwere briefly studied for their application in drug delivery platforms design. Firstly, the obtainedα-oxoaldehydes were used for the covalent linkage of doxorubicin hydrochloride throughhydrazone bonds under physiological conditions. In addition, the effects of theperiodate-triggered structural changes on the loading of bovine serum albumin, as a modelbiomacromolecule, were evaluated. We believe that the proposed chemical strategy could be avaluable tool for improvement of nanodevices through structural modifications andfunctionalization.[1] M. Karg et al., Langmuir, vol. 35, no. 19, pp. 6231?6255, 2019.[2] C. Legros, M. C. De Pauw-Gillet, K. C. Tam, S. Lecommandoux, and D. Taton, Eur. Polym. J., vol.62, pp. 322?330, 2015.[3] D. K. Kölmel and E. T. Kool, Chem. Rev., vol. 117, no. 15, pp. 10358?10376, 2017.[4] A. Wolfel, M. R. Romero, and C. I. Alvarez Igarzabal, Polymer, vol. 116, pp. 251?260, 2017.[5] O. El-Mahdi and O. Melnyk, Bioconjug. Chem., vol. 24, no. 5, pp. 735?765, May 2013