A L-PROLINE BASED THERMORESPONIVE AND pH-SWITCHABLE NANOGEL AS DRUG DELIVERY VEHICLE

The advantageous properties of polymeric nanogels, combining the characteristics of hydrogels and nanoparticles, make them one of the most promising types of nanomaterials for applications in drug delivery. In particular, stimuli-responsive nanogels are extremely appealing as they offer the possibility of tailoring targeted release. Thermo-responsive polymers have already found applications in areas such as drug and gene delivery, tissue engineering, detection and sensing. More recently research interest is shifting towards materials with dual stimuli-responsive properties.¹ Materials showing dual temperature and pH response characteristics have been developed demonstrating efficient triggered release.² In recent years, temperature responsive nanogels have been extensively studied, and the introduction of a pH switch also explored by using monomers such as acrylic acid (AAc), methacrylic acid or 4-vinylpyridine.^3,4 Despite the significant advances, there is still a lack of understanding of how the chemical composition of the polymerisation mixtures can contribute to the tailoring of material properties, to better address the needs of the different applications.

Herein, we report a novel dual stimuli-responsive nanogel based on N-n-propylacrylamide (NPAM) and a L-proline-based monomer (A-Pro-OH, Figure 1). Combinations of three thermo-responsive monomers (NIPAM, NPAM and NAPr), crosslinked with different percentages of MBA, were used in the preparation of 25 nanogels to explore the impact of chemical composition on morphology, and to tailor thermo-responsive properties. The incorporation of a proline-based monomer into the matrix of the nanogel based on NPAM and polymerized with the lowest cross-linker amount (10 % mol), resulted in a nanogel responsive to temperature and pH. Nile Blue A (NBA) was used as model drug to demonstrate drug upload and tailored released at 43 °C and low pH. Thus, this new dual responsive nanogel represents a promising system for future applications in targeted drug release at cancer tissues or for the treatment of inflammatory condition.

Figure 1. Left: monomers used in the preparation of the thermo- and pH-responsive nanogel reported; Right: schematic representation of the mechanism of drug release in acid conditions and above VPTT.

References

[1] Zhuang, J. Gordon, M. R., Ventura, J., Li, L., Thayumanavan, S. (2013) Multi-stimuli responsive macromolecules and their assemblies. Chem. Soc. Rev. 42: 7421–7435.

[2] Cheng, R., Meng, F., Deng, C., Klok, H. A., Zhong, Z. (2013) Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34: 3647–3657.

[3] Liu, K., Guo H., Zha, L. (2012) Study of pH/temperature dual stimuli-responsive nanogels with interpenetrating polymer network structure. Polym. Int. 61: 1144-1150

[4] Xiong, W., Wang, W., Wang, Y., Zhao, Y., Chen, H., Xu, H., Yang, X. (2011) Dual temperature/pH-sensitive drug delivery of poly(N-isopropylacrylamide-co-acrylic acid) nanogels conjugated with doxorubicin for potential application in tumor hyperthermia therapy. Colloids and Surfaces B: Biointerfaces 84: 447-453