Polyzwitterion-Based pH-Responsive Shell of Polymeric Micelle: Evaluation of Physicochemical Properties and <i>In Vivo</i> Functionalities

As well-known nanocarriers for systemically injectable drug delivery systems, lipid-based polymeric micelles show potency for improving cancer treatment. Polyethylene glycol (PEG) is commonly used as a component of polymeric micelles owing to its biocompatibility but can cause immunogenic side reactions, which highlights the need for non-PEG-based systems for the delivery of therapeutic agents. To address this need, we herein synthesized a poly(<i>N</i>-{<i>N</i>'-[<i>N</i>″-(2-carboxyethyl)-2-aminoethyl]-2-aminoethyl}glutamide) [PGlu(DET-Car)]-lipid conjugate, prepared polymeric micelles with PGlu(DET-Car) surfaces, and investigated their physicochemical characteristics and <i>in vivo</i> performance. The micelles showed acidic pH-induced cellular uptake and endosomal escape behaviors superior to those of their PEG-based counterparts and elicited negligible immune responses, as revealed by antibody and cytokine production measurements. Thus, PGlu(DET-Car) presents itself as a viable alternative to PEG-based micelles a as smart drug carrier with specific sensitivity toward a narrow tumorous pH window and minimized immune reactions.