Abstract
In this work, we present biocompatible nanocarriers based on modified polysaccharides capable of transporting insulin macromolecules through human skin without any auxiliary techniques. N-Alkylamidated carboxymethyl cellulose (CMC) derivatives CMC-6 and CMC-12 were synthesized and characterized using attenuated total reflectance Fourier transform infrared (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, gel permeation chromatography and thermogravimetric, calorimetric and microscopic techniques. The prepared modified polysaccharides spontaneously assemble into soft nanoaggregates capable of adjusting to both aqueous and lipid environments. Due to this remarkable self-adjustment ability, CMC-6 and CMC-12 were examined for transdermal delivery of insulin. First, a significant increase in the amount of insulin present in lipid media upon encapsulation in CMC-12 was observed in vitro. Then, ex vivo studies on human skin were conducted. Those studies revealed that the CMC-12 carrier led to an enhancement of transdermal insulin delivery, showing a remarkable 85% insulin permeation. Finally, toxicity studies revealed no alteration in epidermal viability upon treatment and the absence of any skin irritation or amplified cytokine release, verifying the safety of the prepared carriers. Three-dimensional (3D) molecular modeling and conformational dynamics of CMC-6 and CMC-12 polymer chains explained their binding capacities and the ability to transport insulin macromolecules. The presented carriers have the potential to become a biocompatible, safe and feasible platform for the design of effective systems for transdermal delivery of bioactive macromolecules in medicine and cosmetics. In addition, transdermal insulin delivery reduces the pain and infection risk in comparison to injections, which may increase the compliance and glycemic control of diabetic patients.