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by Keyword: Micelles

Duro-Castano, Aroa, Rodríguez-Arco, Laura, Ruiz-Pérez, Lorena, De Pace, Cesare, Marchello, Gabriele, Noble-Jesus, Carlos, Battaglia, Giuseppe, (2021). One-Pot Synthesis of Oxidation-Sensitive Supramolecular Gels and Vesicles Biomacromolecules 22, 5052-5064

Polypeptide-based nanoparticles offer unique advantages from a nanomedicine perspective such as biocompatibility, biodegradability, and stimuli-responsive properties to (patho)physiological conditions. Conventionally, self-assembled polypeptide nanostructures are prepared by first synthesizing their constituent amphiphilic polypeptides followed by postpolymerization self-assembly. Herein, we describe the one-pot synthesis of oxidation-sensitive supramolecular micelles and vesicles. This was achieved by polymerization-induced self-assembly (PISA) of the N-carboxyanhydride (NCA) precursor of methionine using poly(ethylene oxide) as a stabilizing and hydrophilic block in dimethyl sulfoxide (DMSO). By adjusting the hydrophobic block length and concentration, we obtained a range of morphologies from spherical to wormlike micelles, to vesicles. Remarkably, the secondary structure of polypeptides greatly influenced the final morphology of the assemblies. Surprisingly, wormlike micellar morphologies were obtained for a wide range of methionine block lengths and solid contents, with spherical micelles restricted to very short hydrophobic lengths. Wormlike micelles further assembled into oxidation-sensitive, self-standing gels in the reaction pot. Both vesicles and wormlike micelles obtained using this method demonstrated to degrade under controlled oxidant conditions, which would expand their biomedical applications such as in sustained drug release or as cellular scaffolds in tissue engineering.

JTD Keywords: alpha-amino-acid, hydrogels, leuchs anhydrides, platform, polypeptides, transformation, triggered cargo release, Amino acids, Amphiphilics, Biocompatibility, Biodegradability, Block lengths, Controlled drug delivery, Dimethyl sulfoxide, Ethylene, Gels, Hydrophobicity, Medical nanotechnology, Methionine, Micelles, Morphology, One-pot synthesis, Organic solvents, Oxidation, Physiological condition, Polyethylene oxides, Post-polymerization, Ring-opening polymerization, Scaffolds (biology), Self assembly, Stimuli-responsive properties, Supramolecular chemistry, Supramolecular gels, Supramolecular micelles, Wormlike micelle


Fernanda, Andrade, Pedro, Fonte, Ana, Costa, Cassilda Cunha, Reis, Rute, Nunes, Andreia, Almeida, Domingos, Ferreira, Mireia, Oliva, Bruno, Sarmento, (2016). Pharmacological and toxicological assessment of innovative self-assembled polymeric micelles as powders for insulin pulmonary delivery Nanomedicine 11, (17), 2305-2317

Aim: Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. Materials & methods: Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. Results: Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 μm. Endotracheally instilled powders have shown a faster onset of action than subcutaneous administration of insulin at a dose of 10 IU/kg, with pharmacological availabilities up to 32.5% of those achieved by subcutaneous route. Additionally, micelles improved the hypoglycemic effect of insulin. Bronchoalveolar lavage screening for toxicity markers (e.g., lactate dehydrogenase, cytokines) revealed no signs of lung inflammation and cytotoxicity 14 days postadministration. Conclusion: Developed powders showed promising safety and efficacy characteristics for the systemic delivery of insulin by pulmonary administration.

JTD Keywords: Fine particle fraction, Inhalation, Insulin, In vivo, Pharmacological availability, Polymeric micelles, Pulmonary toxicity


Andrade, F., Neves, J. D., Gener, P., Schwartz, S., Ferreira, D., Oliva, M., Sarmento, B., (2015). Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin Nanomedicine: Nanotechnology, Biology, and Medicine 11, (7), 1621-1631

Pulmonary delivery of drugs for both local and systemic action has gained new attention over the last decades. In this work, different amphiphilic polymers (Soluplus®, Pluronic® F68, Pluronic® F108 and Pluronic® F127) were used to produce lyophilized formulations for inhalation of insulin. Development of stimuli-responsive, namely glucose-sensitive, formulations was also attempted with the addition of phenylboronic acid (PBA). Despite influencing the in vitro release of insulin from micelles, PBA did not confer glucose-sensitive properties to formulations. Lyophilized powders with aerodynamic diameter (<. 6. μm) compatible with good deposition in the lungs did not present significant in vitro toxicity for respiratory cell lines. Additionally, some formulations, in particular Pluronic® F127-based formulations, enhanced the permeation of insulin through pulmonary epithelial models and underwent minimal internalization by macrophages in vitro. Overall, formulations based on polymeric micelles presenting promising characteristics were developed for the delivery of insulin by inhalation. From the Clinical Editor: The ability to deliver other systemic drugs via inhalation has received renewed interests in the clinical setting. This is especially true for drugs which usually require injections for delivery, like insulin. In this article, the authors investigated their previously developed amphiphilic polymers for inhalation of insulin in an in vitro model. The results should provide basis for future in vivo studies.

JTD Keywords: Cytotoxicity, Inhalation, Permeability, Phagocytosis, Polymeric micelles, Protein delivery


Andrade, F., Fonte, P., Oliva, M., Videira, M., Ferreira, D., Sarmento, B., (2015). Solid state formulations composed by amphiphilic polymers for delivery of proteins: Characterization and stability International Journal of Pharmaceutics 486, (1-2), 195-206

Abstract Nanocomposite powders composed by polymeric micelles as vehicles for delivery proteins were developed in this work, using insulin as model protein. Results showed that size and polydispersity of micelles were dependent on the amphiphilic polymer used, being all lower than 300 nm, while all the formulations displayed spherical shape and surface charge close to neutrality. Percentages of association efficiency and loading capacity up to 94.15 ± 3.92 and 8.56 ± 0.36, respectively, were obtained. X-ray photoelectron spectroscopy (XPS) measurements confirmed that insulin was partially present at the hydrophilic shell of the micelles. Lyophilization did not significantly change the physical characteristics of micelles, further providing easily dispersion when in contact to aqueous medium. The native-like conformation of insulin was maintained at high percentages (around 80%) after lyophilization as indicated by Fourier transform infrared spectroscopy (FTIR) and far-UV circular dichroism (CD). Moreover, Raman spectroscopy did not evidenced significant interactions among the formulation components. The formulations shown to be physically stable upon storage up to 6 months both at room-temperature (20 C) and fridge (4 C), with only a slight loss (maximum of 15%) of the secondary structure of the protein. Among the polymers tested, Pluronic® F127 produced the carrier formulations more promising for delivery of proteins.

JTD Keywords: Amphiphilic polymers, Insulin, Lyophilization, Polymeric micelles, Stability