Photochemically crosslinked, functionalized polypeptides represent a modern approach for the preparation of micelles and gels used in drug delivery systems as well as in the fabrication of biocompatible scaffolds for tissue engineering. The process of photochemical crosslinking enables precise spatial and temporal control over the linking of polypeptide chains, leading to the formation of stable and functional structures with desirable physicochemical properties. Within these systems, lysine has proven to be a particularly suitable amino acid due to its natural occurrence in the human body, high biocompatibility, and significant potential for functionalization, making it highly appropriate for the development of advanced biomaterials. Thanks to the tunable size, shape, and solubility of micelles, as well as their responsiveness to external stimuli such as pH, temperature, or light, these materials show great promise for targeted and controlled drug release.
Ring-opening polymerization (ROP) enables the synthesis of functional, biocompatible, and often biodegradable polymers. One of the main advantages of ROP is the precise control over polymer chain length and the narrow distribution of molecular weights. Since the reaction typically proceeds under mild conditions and at moderate temperatures, it is particularly well-suited for producing materials intended for use in biological environments. Additionally, ROP allows for straightforward end-group functionalization, which significantly facilitates further attachment of active substances, labels, or other bioactive molecules. Poly(Z-L-lysine) (PZLL) was further functionalized at the terminal chains with NHS-maleimide and a tetrazole derivative, a photoactive molecule, and their photochemical crosslinkability was investigated. PZLL was only partially deprotected, as certain physicochemical properties were crucial for the success of subsequent reactions in polar solvents. The reaction conditions for the conjugation of NHS-maleimide and the tetrazole derivative to the side, partially deprotected lysine chains were optimized. Both functionalized polymers were then exposed to light, successfully initiating photochemical crosslinking.
In addition to the experimental work, we performed quantum chemical calculations using the Spartan program, which provided insight into the reaction mechanisms between the model polymers (PZLL and PLL) and maleimide. By applying different methods (PM3, HF 3-21G, and HF 6-31G*), we evaluated the reaction and activation energies for two possible reaction pathways: classical nucleophilic acyl substitution and Michael addition. The results indicated that the Michael reaction with PZLL is both thermodynamically and kinetically more favorable, whereas the maleimide reaction with PLL is energetically less accessible. This computational approach offered an additional perspective on the reactivity of the systems and contributed to the optimization of the reaction conditions.
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