Innovative Prolonged In Vivo Circulation Nanomicelles—Sharp-Contrast Amphiphilic Janus Star Polymers Derived from β-Cyclodextrin

<b>Introduction:</b> Amphiphilic block polymer micelles have been widely utilized as nanocarriers for drug delivery due to their potential to reduce systemic toxicity, extend circulation time, and improve the bioavailability and biodistribution of therapeutic agents. However, their clinical application is hindered by poor stability in the bloodstream, leading to short in vivo circulation times and premature payload leakage. A promising approach to enhance micelle stability is through the design of micelles with sharp contrast in polarity, featuring a superhydrophobic lipid domain and a superhydrophilic zwitterionic polymer domain, which exhibit very low critical micellization concentrations (CMC). Despite this, designing micelles with a sufficiently dense and controllable shell to protect them in the bloodstream remains a significant challenge.<br/><b>Objective:</b> This study aims to develop a sharp-contrast Janus star-polymer with improved stability and extended circulation time in vivo. The polymer comprises multiple arms of superhydrophobic lipid domains and superhydrophilic poly(2-methacryloyloxyethyl phosphorylcholine) (pMPC) chains attached to a β-cyclodextrin (β-CD) core, denoted as Pal-βCD-pMPC. The goal is to form nanomicelles with a dense and controllable shell that can resist adsorption and penetration of blood proteins, thereby maintaining integrity in the bloodstream.<br/><b>Methods:</b> The Pal-βCD-pMPC polymer was synthesized by coupling superhydrophobic palmitoyl (Pal) groups with superhydrophilic pMPC chains, all attached to a β-CD core. The β-CD, a cone-shaped cyclic oligosaccharide composed of seven glucose units, serves as a multifunctional core that enhances the stability of the micelles. The stability and integrity of these nanomicelles were evaluated in various physiological environments, including phosphate-buffered saline (PBS), bovine serum albumin (BSA), fetal bovine serum (FBS), and blood plasma. The Förster resonance energy transfer (FRET) technique was employed to monitor micelle integrity in real-time during in vivo blood circulation.<br/><b>Results:</b><b> </b>The sharp-contrast Janus star-polymer, Pal-βCD-pMPC, formed nanomicelles with an exceptionally dense and controllable shell, providing robust protection against blood protein adsorption and penetration. These micelles maintained their integrity for 12 hours when incubated in physiological mimicking environments, such as BSA and FBS aqueous solutions. Addiitionally, their chain exchange rate was extremely low, with negligible payload exchange among Pal-βCD-pMPC micelles over five days. Upon extremely dilution in aqueous solution, the system still assembled as micelles with negligible free polymer detected. When fluorophore-loaded Pal-βCD-pMPC micelles were administered into blood circulation, they successfully prolonged the circulation of fluorophore payloads and maintained micelle integrity for 12 hours, as detected by FRET imaging.<br/><b>Conclusion: </b>The sharp-contrast Janus star-polymers present a novel and effective strategy for creating ultrastable micellar nanocarriers with extended in vivo circulation times. The Pal-βCD-pMPC micelles offer significant potential for clinical therapeutic applications, overcoming the limitations of traditional linear polymer micelles. This study highlights the advantages of Janus star-polymer design in developing advanced nanocarrier systems for efficient drug delivery.