Engineering enzymatically induced sequential mesophase transitions within polymeric formulations Parul Rathee ‡a,b,c , Nicole Edelstein-Pardo ‡a,b,c , Francesca Netti b,c,d , Lihi Adler-Abramovich b,c,d , Amit Sitt a,b,c,e ,Roey J. Amir ,a,b,c,e a School of Chemistry, Tel-Aviv University, Israel, b The Center for Physics and Chemistry of Living Systems, Tel-Aviv University, Israel, c Center for Nanoscience and Nanotechnology, Tel-Aviv University, Israel, d Department of Oral Biology, Tel Aviv University, Israel, e ADAMA Center for Novel Delivery Systems in Crop Protection, Tel-Aviv University, Israel Stimuli-responsive polymeric micelles have been extensively studied as potential delivery carriers, owing to their capability to encapsulate or covalently bind hydrophobic drugs and subsequently release them in response to specific cues. Among the various types of stimuli, the overexpression of disease-associated enzymes such as matrix metalloproteinases or cathepsin B, especially prevalent in cancer, holds significant promise for biomedical applications. However, despite their great potential, enzymes are also the most challenging type of stimuli for triggering drug release due to their substrate selectivity and larger size in comparison with other dimensionless stimuli. Over the past decade, our research group has studied the potential for fine-tuning both the stability and reactivity of enzyme-responsive micelles. This has been achieved by adjusting the molecular weight and hydrophilic-to- lipophilic balance (HLB) of PEG-dendron di-block amphiphiles (DBA). In more recent times, we have extended the scope of our studies to encompass an architecture involving dendron-PEG-dendron tri-block amphiphiles (TBA). These TBA structures are composed of dendrons as hydrophobic side blocks and polyethylene glycol (PEG) as the hydrophilic middle chain. Herein, we utilized the different reactivities of di- and tri-block amphiphiles, which have the same HLB, toward enzymatic degradation as a tool for programming formulations to undergo three sequential enzymatically induced transitions from (i) micelles to (ii) hydrogel and finally to (iii) dissolved polymers. We demonstrate that the rate of transition between the mesophases can be programmed by changing the ratio of the amphiphiles in the formulation, as well as the ability of the formed hydrogel to maintain encapsulated cargo that was loaded into the micelles 1 . The design of materials that can undergo multiple sequential mesophase transitions often requires incorporating different types of responsive units. However, we show this can also be achieved by incorporating a single responsive unit, demonstrating the versatility of molecular architecture as a tool for programming smart formulations, thus presenting a novel approach. This system can allow for rapid circulation, as micelles in the body and selective accumulation as a hydrogel at the disease site, enabling the controlled release of cargo molecules. Furthermore, the final disassembly of hydrogels into soluble polymers offers a higher degree of clearance for the delivery system from the body after completing its task. References 1. P. Rathee, N. E. Pardo, F. Netti, L. A. Abramovich, A. Sitt, and R. J. Amir. Architecture-based programming of polymeric micelles to undergo sequential mesophase transitions. ACS Macro Lett. 2023, 12 , 814-820.
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