Complex Structures Made Simple – Continuous Flow Production of Core Cross‐Linked Polymeric Micelles for Paclitaxel Pro‐Drug‐Delivery

Abstract

Translating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large‐scale high‐throughput synthesis with high reproducibility. Drug carriers in medicine embrace a complex subset of tasks calling for multifunctionality. Here, the synthesisof pro‐drug‐loaded core cross‐linked polymeric micelles (CCPMs) in a continuous flow processis reported, which combines the commonly separated steps of micelle formation, core cross‐linking, functionalization, and purification into a single process. Redox‐responsive CCPMs are formed from thiol‐reactive polypept(o)ides of polysarcosine‐block‐poly(S‐ethylsulfonyl‐l‐cysteine) and functional cross‐linkers based on dihydrolipoic acid hydrazide for pH‐dependent release of paclitaxel. The precisely controlled microfluidic process allows the production of spherical micelles (Dh = 35 nm) with low polydispersity values (PDI < 0.1) while avoiding toxic organic solvents and additives with unfavorable safety profiles. Self‐assembly and cross‐linking via slit interdigital micromixers produces 350–700 mg of CCPMs/h per single system, while purification by online tangential flow filtration successfully removes impurities (unimer ≤ 0.5%). The formed paclitaxel‐loaded CCPMs possess the desired pH‐responsive release profile, display stable drug encapsulation, an improved toxicity profile compared to Abraxane (a trademark of Bristol‐Myers Squibb), and therapeutic efficiency in the B16F1‐xenotransplanted zebrafish model. The combination of reactive polymers, functional cross‐linkers, and microfluidics enables the continuous‐flow synthesis of therapeutically active CCPMs in a single process.

Specific FRET Probes Sensitive to Chitosan-Based Polymeric Micelles Formation, Drug-Loading, and Fine Structural Features

“…Nanoparticles, along with micelles, deserve special attention as promising drug carriers [33][34][35][36]. Polymeric micelles are promising carriers of a wide range of drugs, since they have a number of properties [37][38][39][40][41][42][43]: (1) the external hydrophilic shell ensures the colloidal stability of the system; (2) the internal hydrophobic core is necessary for the solubilization of drugs, which are often poorly soluble (which limits their use in medicine); (3) thermodynamic stability; (4) the possibility of obtaining biocompatible micellar structures; (5) increased permeability of the drug to target cells due to fatty acids; (6) wide possibilities for creating stimulus-sensitive delivery systems, for example, in tumors. For the latter, chitosan demonstrated pH sensitivity to a slightly acidic environment (tumors), and lipoic acid residues with S-S bonds between various polymer chains provided glutathione sensitivity [44].…”

Thermoresponsive Core-cross-linked Nanoparticles from HA-b-ELP Diblock Copolymers

“…The stability of self-assembled nanoparticles is indeed directly linked to concentration since formed above a critical micellar concentration (CMC) and spontaneously dissociating into soluble unimers below the CMC. − In other words, upon systemic administration, multivalency of the ligand will be lost by instantaneous dilution of self-assembled NPs below the CMC, and consequently, the payload will also be lost prematurely. Stabilization of self-assembled nanocarriers is therefore essential to ensure the conservation of the structural integrity and properties of nanocarriers, and different cross-linking strategies have been proposed, giving rise to different generations of shell-cross-linked and core-cross-linked micelles. − …”

Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment

“…In order to selectively load macrophages with iron we developed superparamagnetic iron oxide nanoparticles loaded core-cross-linked polymeric micelles (SPION-CCPMs) . To ensure the efficient intracellular release of SPIONs, we employed amphiphilic polysarcosine- block -poly­( S -ethylsulfonyl cysteine) copolymers − to stabilize oleic-acid-coated SPIONs in water by incorporation in the hydrophobic core of the corresponding polymeric micelles. Next, dihydrolipoic acid was used to induce core cross-linking by chemoselective disulfide formation with the S -ethylsulfonyl thiol groups of the polypept­(o)­ide and in addition oleic acid on the surface of SPIONs was replaced yielding stable SPION-CCPMs .…”