A facile way to build up branched high functional polyaminoacids with tunable physicochemical and biological properties

Mauro, Nicolò; Fiorica, Calogero; Varvarà, Paola; Prima, Giulia Di; Giammona, Gaetano

doi:10.1016/j.eurpolymj.2016.02.006

Cited by 13 publications

(23 citation statements)

References 25 publications

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“…However, the way in which such polypeptides are obtained is not trivial, because α-amino acids are not soluble in aprotic polar solvents and have lower p K a values and higher steric hindrance than common primary amines (p K a = 9.4 vs p K a = 10.5), entailing a weak nucleophilicity. , For these reasons, the synthetic pathway that leads to such polypeptides (PAA) consisting in statistically arranged α and β aspartic units copolymerized with α and β argilyl-aspartamide repeating units involve the heterophase reaction between l -arginine and polysuccinimide (PSI) in H 2 O/DMF 72:28 (Scheme ), since this particular solvent mixture allows complete dissolution of the amino acid still maintaining a good solubility of PSI during the reaction. This reaction can be also kinetically controlled by tuning the pH of the reaction, yielding to PAAs with M W ranging from 10 to 67 kDa for pH 8.5 and 10.5, respectively …”

Section: Resultsmentioning

confidence: 99%

“…PAA was synthesized as previously reported . Briefly, polysuccinimide (PSI) was obtained by polycondensation of d , l -aspartic acid in phosphoric acid .…”

Section: Materials and Methodsmentioning

confidence: 99%

“…Someone might argue that the conjugation of arginine with biocompatible high molecular weight polymers is probably useful to impart ARPs properties while circumventing hydrolytic inactivation in vivo, as well as toxicity phenomena. We have previously developed a cost-effective synthetic branched copolymers with polypeptidic structure, named poly(argilylaspartamide)aspartic acid (PAA), consisting of a polyaspartic acid backbone statistically derivatized with arginine via amidic bond as side chain mimic of ARPs . Arginine residues endow PAA with cationic charges and hydrogen bonding properties necessary for interaction with the abundant anionic components of the bacterial membrane .…”

Section: Introductionmentioning

confidence: 99%

“…Arginine residues endow PAA with cationic charges and hydrogen bonding properties necessary for interaction with the abundant anionic components of the bacterial membrane . However, this copolymer is intrinsically amphoteric and prevailingly anionic under physiological conditions, as it exhibits one carboxylic function (p K a = 6.1, 4.4, 3.3, arginine, β and α aspartic acid, respectively) per repeating unit and about 0.7 guanidine groups (p K a ≈ 11.7), and it is not able to interact with the negatively charged bacterial membrane implying a negligible antimicrobial effect. While, the amphoteric nature of PAA is concurrently responsible for the emphasized biocompatibility showed by these polypeptides (IC 50 > 10 mg mL –1 after 7 days incubation). ,, …”

Section: Introductionmentioning

confidence: 99%

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Branched High Molecular Weight Glycopolypeptide With Broad-Spectrum Antimicrobial Activity for the Treatment of Biofilm Related Infections

Mauro

Schillaci

Varvarà

et al. 2017

ACS Appl. Mater. Interfaces

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There are few therapeutic options to simultaneously tackle Staphylococcus aureus and Pseudomonas aeruginosa, two of the most relevant nosocomial and antibiotic-resistant pathogens responsible for implant, catheters and wound severe infections. The design and synthesis of polymers with inherent antimicrobial activity have gained increasing attention as a safe strategy to treat multi-drug-resistant microbes. Here, we tested the activity of a new polymeric derivative with glycopolypeptide architecture (PAA-VC) bearing l-arginine, vancomycin, and colistin as side chains acting against multiple targets, which give rise to a broad spectrum antimicrobial activity favorably combining specific and nonspecific perturbation of the bacterial membrane. PAA-VC has been tested against planktonic and established biofilms of reference strains S. aureus ATCC 25923 and P. aeruginosa ATCC 15442 and susceptible or antibiotic resistant clinical isolates of the above-mentioned microorganisms. MIC values observed for the conjugate (48-190 and 95-190 nM for P. aeruginosa and S. aureus strains, respectively) showed higher efficacy if compared with the free vancomycin (MICs within 1.07-4.28 μM) and colistin (MICs within 0.63-1.33 μM). Additionally, being highly biocompatible (IC > 1000, 430, and 250 μg mL for PAA-VC, vancomycin and colistin respectively) high-dosage can be adopted for the eradication of infections in patients. This positively influences the anti-biofilm activity of the conjugate leading to a quasi-total eradication of established clinically relevant biofilms (inhibition >90% at 500 μg mL). We believe that the in vitro presented data, especially the activity against established biofilms of two relevant pathogens, the high biocompatibility and the good mucoadhesion properties, would allow the use of PAA-VC as promising candidate to successfully address emerging infections.

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Section: Resultsmentioning

confidence: 99%

“…PAA was synthesized as previously reported . Briefly, polysuccinimide (PSI) was obtained by polycondensation of d , l -aspartic acid in phosphoric acid .…”

Section: Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Branched High Molecular Weight Glycopolypeptide With Broad-Spectrum Antimicrobial Activity for the Treatment of Biofilm Related Infections

Mauro

Schillaci

Varvarà

et al. 2017

ACS Appl. Mater. Interfaces

Self Cite

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show abstract

“…A further potentiometric titration was performed in order to determine the K a constants; titration plot of backward was elaborated using Origin software according to the De Levie method of acid-base equilibria for polyprotic acid and bases, taking into account the activity corrections through the Davies expression (1) [29][30][31][32].…”

Section: Polymer Synthesis and Characterizationmentioning

confidence: 99%

Design of New Polyaspartamide Copolymers for siRNA Delivery in Antiasthmatic Therapy

et al. 2020

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Here, a novel protonable copolymer was realized for the production of polyplexes with a siRNA (inhibitor of STAT6 expression in asthma), with the aim of a pulmonary administration. The polycation was synthesized by derivatization of α,β-poly(N-2-hydroxyethyl)d,l-aspartamide (PHEA) with 1,2-Bis(3-aminopropylamino)ethane (bAPAE) in proper conditions to obtain a PHEA-g-bAPAE graft copolymer with a derivatization degree in amine (DDbAPAE%) equal to 35 mol%. The copolymer showed a proper buffering behavior, i.e., ranging between pH 5 and 7.4, to potentially give the endosomal escape of the obtained polycations. In effect, an in vitro experiment demonstrated the effect on biological membranes of the copolymer on bronchial epithelial cells (16-HBE) strongly dependent on the pH of the medium, i.e., higher at pH 5. bAPAE-based copolymers were further obtained with an increasing pegylation degree, i.e., equal to 1.9, 2.7, and 4.4 mol%, respectively. All the obtained copolymers were able to complex siRNA at a N/P ratio that decreases as the pegylation degree increases. At the same time, the tendency of polyplexes to aggregate and the capability to interact with mucin also decreases as the pegylation in the copolymer increases. Gene silencing experiments on 16-HBE showed that these copolymers have a significant role in improving the intracellular transport of naked siRNA, where the presence of PEG does not seem to hinder the cellular uptake of polyplexes. The latter obtained at polymer/siRNA weight ratio (R) equal to 10 with PHEA-g-PEG(C)-g-bAPAE also seems to be not susceptible to the presence of mucin, avoiding the polyanionic exchange of complexed siRNA, thus showing adequate behavior to be used as an effective vector for siRNA.

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Production and physicochemical characterization of a new amine derivative of gellan gum and rheological study of derived hydrogels

Fiorica

Pitarresi

Palumbo

et al. 2020

Carbohydrate Polymers

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A facile way to build up branched high functional polyaminoacids with tunable physicochemical and biological properties

Cited by 13 publications

References 25 publications

Branched High Molecular Weight Glycopolypeptide With Broad-Spectrum Antimicrobial Activity for the Treatment of Biofilm Related Infections

Branched High Molecular Weight Glycopolypeptide With Broad-Spectrum Antimicrobial Activity for the Treatment of Biofilm Related Infections

Design of New Polyaspartamide Copolymers for siRNA Delivery in Antiasthmatic Therapy

Production and physicochemical characterization of a new amine derivative of gellan gum and rheological study of derived hydrogels

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