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Peptide-Based Hydrogels and Nanogels for Delivery of Doxorubicin

Authors Gallo E, Diaferia C, Rosa E, Smaldone G, Morelli G, Accardo A

Received 8 December 2020

Accepted for publication 23 January 2021

Published 1 March 2021 Volume 2021:16 Pages 1617—1630


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster

Enrico Gallo,1 Carlo Diaferia,2 Elisabetta Rosa,2 Giovanni Smaldone,1 Giancarlo Morelli,2 Antonella Accardo2

1IRCCS SDN, Naples, 80143, Italy; 2Department of Pharmacy and Research Centre on Bioactive Peptides (CIRPeB), University of Naples “Federico II”, Naples, 80134, Italy

Correspondence: Antonella Accardo
Department of Pharmacy and Research Centre on Bioactive Peptides (CIRPeB), University of Naples “Federico II”, Via Mezzocannone 16, Naples, 80134, Italy
Tel +39 0812532045
Fax +39 0812536642
Email [email protected]

Introduction: The clinical use of the antitumoral drug doxorubicin (Dox) is reduced by its dose-limiting toxicity, related to cardiotoxic side effects and myelosuppression. In order to overcome these drawbacks, here we describe the synthesis, the structural characterization and the in vitro cytotoxicity assays of hydrogels (HGs) and nanogels (NGs) based on short peptide sequences loaded with Dox or with its liposomal formulation, Doxil.
Methods: Fmoc-FF alone or in combination with (FY)3 or PEG8-(FY)3 peptides, at two different ratios (1/1 and 2/1 v/v), were used for HGs and NGs formulations. HGs were prepared according to the “solvent-switch” method, whereas NGs were obtained through HG submicronition by the top-down methodology in presence of TWEEN® 60 and SPAN® 60 as stabilizing agents. HGs gelation kinetics were assessed by Circular Dichroism (CD). Stability and size of NGs were studied using Dynamic Light Scattering (DLS) measurements. Cell viability of empty and filled Dox HGs and NGs was evaluated on MDA-MB-231 breast cancer cells. Moreover, cell internalization of the drug was evaluated using immunofluorescence assays.
Results: Dox filled hydrogels exhibit a high drug loading content (DLC=0.440), without syneresis after 10 days. Gelation kinetics (20– 40 min) and the drug release (16– 28%) over time of HGs were found dependent on relative peptide composition. Dox filled NGs exhibit a DLC of 0.137 and a low drug release (20– 40%) after 72 h. Empty HGs and NGs show a high cell viability (> 95%), whereas Dox loaded ones significantly reduce cell viability after 24 h (49– 57%) and 72 h (7– 25%) of incubation, respectively. Immunofluorescence assays evidenced a different cell localization for Dox delivered through HGs and NGs with respect to the free drug.
Discussion: A modulation of the Dox release can be obtained by changing the ratios of the peptide components. The different cellular localization of the drug loaded into HGs and NGs suggests an alternative internalization mechanism. The high DLC, the low drug release and preliminary in vitro results suggest a potential employment of peptide-based HGs and NGs as drug delivery tools.

Keywords: hydrogels, nanogels, drug delivery, peptide materials, doxorubicin, in vitro assays

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