Oral insulin delivery by spatiotemporal polymeric Micelles: Existing Barriers, Status Quo and opportunities

Since the discovery of insulin, its parenteral use has been discouraged by the inadequacy of the treatment protocol such as action on non-target sites and liver-compromised effects. Eventually, this results in peripheral insulin resistance and immunogenicity. In contrast, oral insulin delivery has become a popular and well-accepted approach that enables hepatic insulin action via portal circulation to regulate glucose output. Indeed, such action is crucial for preserving glucose homeostasis. However, the primary challenge is associated with the gastrointestinal barrier. Polymeric micelles (PMs) formed from amphiphilic block copolymers (ABCs) specially designed for oral insulin using stimuli-responsive moieties, polysaccharide-based blocks, charge reversible blocks, etc. in the form of zwitterionic PMs, complex PMs, and dual/multi-responsive PMs can overcome the limitations. Their self-assembly at lower critical micelle concentration (0.1–1 µM) offers higher thermodynamic stability. Eventually, this makes them unique over other nanoparticles. Thus, PMs harness the potential to improve the efficacy of insulin by providing ease of administration, controlled systemic exposure, prolonged residence time, and broad flexibility and tunability. However, toxicity and inadequate release are claimed to be major concerns for PMs. In this work, we have scrutinised the critical molecular features of ABCs influencing the physicochemical characteristics of PMs for spatiotemporal insulin release. Herein, we discuss key issues that restrict their translation to the clinical practice followed by opportunities that can be used to overcome the same for the success of oral insulin PMs.