Peptide nanosponges designed for rapid uptake by leukocytes and neural stem cells.

Asanka S Yapa,Hongwang Wang,Matthew T Basel,Jing Yu,Marla Pyle,Harshi Manawadu,Prem S Thapa,Nilusha L Kariyawasam,Raquel Ortega,Paul E Smith,Stefan H Bossmann,Tej B Shrestha,Ayomi S Perera,Yubisela Toledo,Sebastian O Wendel,Madumali Kalubowilage,Aruni P Malalasekera,Deryl L Troyer

doi:10.1039/c8ra00717a

Asanka S Yapa, Hongwang Wang + Show 16 more

Open Access

https://doi.org/10.1039/c8ra00717a

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Abstract

The structure of novel binary nanosponges consisting of (cholesterol-(K/D)nDEVDGC)3-trimaleimide units possessing a trigonal maleimide linker, to which either lysine (K)20 or aspartic acid (D)20 are tethered, has been elucidated by means of TEM. A high degree of agreement between these findings and structure predictions through explicit solvent and then coarse-grained molecular dynamics (MD) simulations has been found. Based on the nanosponges' structure and dynamics, caspase-6 mediated release of the model drug 5(6)-carboxyfluorescein has been demonstrated. Furthermore, the binary (DK20) nanosponges have been found to be virtually non-toxic in cultures of neural progenitor cells. It is of a special importance for the future development of cell-based therapies that DK20 nanosponges were taken up efficiently by leucocytes (WBC) in peripheral blood within 3 h of exposure. The percentage of live cells among the WBC was not significantly decreased by the DK20 nanosponges. In contrast to stem cell or leucocyte cell cultures, which have to be matched to the patient, autologous cells are optimal for cell-mediated therapy. Therefore, the nanosponges hold great promise for effective cell-based tumor targeting.

Highlights

One of the grand challenges in nanomedicine is the effective targeting of tumors and metastases.[1]
The nanosponges that are discussed here will be able to efficiently target neural progenitor cells[38,53] and leucocytes, either ex vivo or, preferentially, in peripheral blood to utilize the advantages of autologous cells for patient-speci c cell therapies
The structural and dynamic understanding of the nanosponges has enabled several applications of these novel materials, which, principally, prove them as advanced biomaterials in cell-mediated drug transport to solid tumors/metastases and infectious diseases: caspase-activated drug release was demonstrated with 5(6)carboxy uorescein-loaded nanosponges

Summary

Introduction

One of the grand challenges in nanomedicine is the effective targeting of tumors and metastases.[1] For almost a generation, Enhanced Permeation and Retention (EPR),[2,3] the passive diffusion of nanosize delivery vehicles Exosomes,[6] nanoparticles,[7] polymer-based nanostructures8–10) through gaps in the vasculature that have been built rapidly around tumor tissue, has been hailed as an important breakthrough in the ght against cancer. Emerging evidence clearly suggests that the EPR effect works well in rodent models (especially in nude mice), but not in humans, who feature distinctly different vasculature and, compared to rodents, signi cantly slower tumor growth.[2,3,11] alternative targeting approaches are urgently needed. Among them are stem cells,[29] monocytes/macrophages[30,31] and neutrophils.[32,33] Neural stem cells, which can be, principally, cultured and matched to patient-types, have been successfully utilized for cell-mediated therapies in rodent models,[22,27,34] as well as neutrophils[35,36] and monocytes.[10,23,24,27]

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