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Abstract Polymeric micro‐ and nanoparticles are useful vehicles for delivering cytokines to diseased tissues such as solid tumors. Double emulsion solvent evaporation is one of the most common techniques to formulate cytokines into vehicles made from hydrophobic polymers; however, the liquid–liquid interfaces formed during emulsification can greatly affect the stability and therapeutic performance of encapsulated cytokines. To develop more effective cytokine‐delivery systems, a clear molecular understanding of the interactions between relevant proteins and solvents used in the preparation of such particles is needed. We utilized an integrated computational and experimental approach for studying the governing mechanisms by which interleukin‐12 (IL‐12), a clinically relevant cytokine, is protected from denaturation by albumin, a common stabilizing protein, at an organic‐aqueous solvent interface formed during double emulsification. We investigated protein–protein interactions between human (h)IL‐12 and albumin and simulated these components in pure water, dichloromethane (DCM), and along a water/DCM interface to replicate the solvent regimes formed during double emulsification. We observed that (i) hIL‐12 experiences increased structural deviations near the water/DCM interface, and (ii) hIL‐12 structural deviations are reduced in the presence of albumin. Experimentally, we found that hIL‐12 bioactivity is retained when released from particles in which albumin is added to the aqueous phase in molar excess to hIL‐12 and sufficient time is allowed for albumin‐hIL‐12 binding. Findings from this work have implications in establishing design principles to enhance the stability of cytokines and other unstable proteins in particles formed by double emulsification for improved stability and therapeutic efficacy. 

Microrobots are being explored for biomedical applications, such as drug delivery, biological cargo transport, and minimally invasive surgery. However, current efforts largely focus on proof-of-concept studies with nontranslatable materials through a "design-and-apply" approach, limiting the potential for clinical adaptation. While these proof-of-concept studies have been key to advancing microrobot technologies, we believe that the distinguishing capabilities of microrobots will be most readily brought to patient bedsides through a "design-by-problem" approach, which involves focusing on unsolved problems to inform the design of microrobots with practical capabilities. As outlined below, we propose that the clinical translation of microrobots will be accelerated by a judicious choice of target applications, improved delivery considerations, and the rational selection of translation-ready biomaterials, ultimately reducing patient burden and enhancing the efficacy of therapeutic drugs for difficult-to-treat diseases.