Medicine formulations at the nanoscale, referred to as nanomedicines, have managed to overcome key challenges encountered during the development of new medical treatments and entered clinical practice, but considerable improvement in terms of local efficacy and reduced toxicity still need to be achieved. Currently, the fourth-generation of nanomedicines is being developed, employing biocompatible nanocarriers that are targeted, multifunctional, and stimuli-responsive. Proteins and polypeptides can fit the standards of an efficient nanovector because of their biodegradability, intrinsic bioactivity, chemical reactivity, stimuliresponsiveness, and ability to participate in complex supramolecular assemblies. These biomacromolecules can be obtained from natural resources, produced in heterologous hosts, or chemically synthesized, allowing for different designs to access suitable carriers for a variety of drugs. To enhance targeting or therapeutic functionality, additional chemical modifications can be applied. This review demonstrates the potential of polypeptide and protein materials for the design of drug delivery nanocarriers with a special focus on their preclinical evaluation in vitro and in vivo.
Two pairs of oppositely charged PEO-b-poly(amino acid) copolymers with neutral poly(ethylene oxide) block and polypeptide block composed of the hydrophobic L-phenylalanine (Phe) amino acid mixed with either negative L-glutamic acid (Glu) or positive L-lysine (Lys) units were synthesized. N-carboxyanhydride (NCA) ring opening polymerization (ROP) was performed with either PEO46-NH2 or PEO114-NH2 macroinitiators, leading respectively to PEO46b-P(Glu100-co-Phe65) and PEO46-b-P(Lys100-co-Phe65), and PEO114-b-P(Glu60-co-Phe40) and PEO114-b-P(Lys60-co-Phe40). Polyion complexes (PIC) formed at near charge equilibrium led to vesicle formation (PICsomes), as shown by DLS, zetametry and TEM. The good stability of PICsomes, even in high salinity media, was interpreted by π-π stacking hydrophobic interactions between the Phe residues, playing the role of "physical cross-linking". These PICsomes were successfully loaded with siRNA directed against firefly luciferase enzyme expression. They also exhibit minimal cell cytotoxicity while superior silencing efficacy was shown by cell bioluminescence assay as compared to free siRNA and a standard lipofectamine-siRNA complex. As such, self-assembly of oppositely charged PEO-b-poly(amino acids) block copolymers enabled forming PICsomes of high stability thanks to π-π interactions of the Phe comonomer in the polypeptide block, with high potential as biocompatible nanocarriers for RNA interference.
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