Abstract
Nanoparticles based on the biocompatible amphiphilic poly(N-vinylpyrrolidone) (Amph-PVP) derivatives are promising for drug delivery. Amph-PVPs self-aggregate in aqueous solutions with the formation of micellar nanoscaled structures. Amph-PVP nanoparticles are able to immobilize therapeutic molecules under mild conditions. As is well known, many efforts have been made to exploit the DR5-dependent apoptosis induction for cancer treatment. The aim of the study was to fabricate Amph-PVP-based nanoparticles covalently conjugated with antitumor DR5-specific TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) variant DR5-B and to evaluate their in vitro cytotoxicity in 3D tumor spheroids. The Amph-PVP nanoparticles were obtained from a 1:1 mixture of unmodified and maleimide-modified polymeric chains, while DR5-B protein was modified by cysteine residue at the N-end for covalent conjugation with Amph-PVP. The nanoparticles were found to enhance cytotoxicity effects compared to those of free DR5-B in both 2D (monolayer culture) and 3D (tumor spheroids) in vitro models. The cytotoxicity of the nanoparticles was investigated in human cell lines, namely breast adenocarcinoma MCF-7 and colorectal carcinomas HCT116 and HT29. Notably, DR5-B conjugation with Amph-PVP nanoparticles sensitized resistant multicellular tumor spheroids from MCF-7 and HT29 cells. Taking into account the nanoparticles loading ability with a wide range of low-molecular-weight antitumor chemotherapeutics into hydrophobic core and feasibility of conjugation with hydrophilic therapeutic molecules by click chemistry, we suggest further development to obtain a versatile system for targeted drug delivery into tumor cells.
Highlights
IntroductionNanocarriers are increasingly developed for the treatment of solid tumors [1]
Prothionamide, stearoyl chloride, maleimide, potassium tert-butylate, dimethylsulfoxide (DMSO), fetal bovine serum (FBS), phosphate buffer saline (PBS), and all other chemicals were obtained from Sigma-Aldrich (Saint Louis, MO, USA)
The core of the self-assemblies was loaded with hydrophobic model substance prothionamide, an anti-tuberculosis drug without antitumor activity
Summary
Nanocarriers are increasingly developed for the treatment of solid tumors [1]. Polymeric micellar nanoparticles are of great interest due to their high stability, tunable properties and the ability for multi-drug delivery [2,3,4]. A number or polymeric micelles with active tumor-targeting properties were proposed for drug delivery, for example, c(RGDyK)-linked poly(carboxybetaine methacrylate)-poly(crcaprolactone)based [5], cRGD-conjugated poly(ethylene glycol)-b-poly(L-glutamic acid)-based [6], citric acid-functionalized poly(ε-caprolactone)-based micelles [7].
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