Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers

Abstract

The aim of this work was to rationally design and characterize nanocapsules (NCs) composed of an oily core and a polyarginine (PARG) shell, intended for oral peptide delivery. The cationic polyaminoacid, PARG, and the oily core components were selected based on their penetration enhancing properties. Insulin was adopted as a model peptide to assess the performance of the NCs. After screening numerous formulation variables, including different oils and surfactants, we defined a composition consisting of oleic acid, sodium deoxycholate (SDC) and Span 80. This selected NCs composition, produced by the solvent displacement technique, exhibited the following key features: (i) an average size of 180nm and a low polydispersity (0.1), (ii) a high insulin association efficacy (80-90% AE), (iii) a good colloidal stability upon incubation in simulated intestinal fluids (SIF, FaSSIF-V2, FeSSIF-V2), and (iv) the capacity to control the release of the associated insulin for >4h. Furthermore, using the Caco-2 model cell line, PARG nanocapsules were able to interact with the enterocytes, and reversibly modify the TEER of the monolayer. Both cell adhesion and membrane permeabilization could account for the pronounced transport of the NCs-associated insulin (3.54%). This improved interaction was also visualized by confocal fluorescent microscopy following oral administration of PARG nanocapsulesto mice. Finally, in vivo efficacy studies performed in normoglycemic rats showed a significant decrease in their plasma glucose levels after treatment. In conclusion, here we disclose key formulation elements for making possible the oral administration of peptides.

Praziquantel&ndash;lipid nanocapsules: an oral nanotherapeutic with potential <em>Schistosoma mansoni</em> tegumental targeting

“…42 Furthermore, OA was added to modify the fluidity of LNCs and permeabilize cell membrane for enhanced LNCcell interaction and intestinal transport. 43,44 The reduction in heating-cooling range during LNC formation could be explained by OA-induced fluidization of the surfactant monolayer 45 and partial incorporation of some OA molecules into the surfactant film of the microemulsion phase. 46 MFS was incorporated for enhancing LNC structural integrity and imparting membrane activity.…”

The effect of nanoencapsulation of ICG on two-photon bioimaging

“…Poly-L-arginine (PLA) is the homopeptide of L-arginine, which has been used in medical applications for many centuries due to its cellular penetrating properties. [33][34][35][36][37][38][39] Additionally, it is a semi-essential amino-acid with various roles such as in cell metabolism, wound healing, protein synthesis, and it also shows antimicrobial and antitumor activity. [40][41][42][43][44][45] In particular, owing to their favorable properties, NPs comprised of PLA have garnered considerable interest for delivery of small molecules.…”

Engineering, on‐demand manufacturing, and scaling‐up of polymeric nanocapsules

“…For example, our results have shown the possibility of increasing the corneal penetration of drugs associated to the NCs. 6,25 Similarly, we have found that polymeric NCs led to an enhancement of the systemic absorption of peptide and protein drugs administered by the oral 11,15,16 or nasal 14,26 routes.…”

“…Due to their lipidic core, NCs were, originally, conceived as suitable carriers for lipophilic drugs. However, our lab has expanded this technology to allow NCs to carry hydrosoluble macromolecules, such as proteins, peptides, and polynucleotides, using them in different therapeutic areas. For example, in the oncology field, we have developed different polymeric NCs containing the cytotoxic drugs plitidepsin and docetaxel, which were able to prolong the blood circulation time of these drugs and reduce their toxicity.…”