Abstract
An efficient doxorubicin (DOX) drug delivery system with specificity against tumor cells was developed, based on multi-walled carbon nanotubes (MWCNTs) functionalized with guanidinylated dendritic molecular transporters. Acid-treated MWCNTs (oxCNTs) interacted both electrostatically and through hydrogen bonding and van der Waals attraction forces with guanidinylated derivatives of 5000 and 25,000 Da molecular weight hyperbranched polyethyleneimine (GPEI5K and GPEI25K). Chemical characterization of these GPEI-functionalized oxCNTs revealed successful decoration with GPEIs all over the oxCNTs sidewalls, which, due to the presence of guanidinium groups, gave them aqueous compatibility and, thus, exceptional colloidal stability. These GPEI-functionalized CNTs were subsequently loaded with DOX for selective anticancer activity, yielding systems of high DOX loading, up to 99.5% encapsulation efficiency, while the DOX-loaded systems exhibited pH-triggered release and higher therapeutic efficacy compared to that of free DOX. Most importantly, the oxCNTs@GPEI5K-DOX system caused high and selective toxicity against cancer cells in a non-apoptotic, fast and catastrophic manner that cancer cells cannot recover from. Therefore, the oxCNTs@GPEI5K nanocarrier was found to be a potent and efficient nanoscale DOX delivery system, exhibiting high selectivity against cancerous cells, thus constituting a promising candidate for cancer therapy.
Highlights
Introduction published maps and institutional affilIn recent years, chemotherapy has been the most common strategy for cancer treatment
For the preparation of the nanohybrids oxidized multi-walled carbon nanotubes (oxCNTs)@GPEI5K and oxCNTs@GPEI25K, 50 mg oxCNTs was dispersed in 50 mL dd H2 O by ultrasonication for 30 min using a Hielscher UP200S high-intensity ultrasonic processor coupled with a sonotrode with a tip of 3 mm diameter (50% amplitude, 0.5 cycles/s)
One drop of oxCNTs@GPEIs solution in methanol was placed on the diamond element, and the solvent was removed under a steam of nitrogen to produce a thin film
Summary
Multi-walled carbon nanotubes containing carboxyl groups > 8% w/w (CNTs), hyperbranched polyethyleneimine (PEI) of 5000 Da (Lupasol® G100, water-free, 99%) and. 25,000 Da molecular weight (Lupasol® WF, water-free, 99%) and doxorubicin hydrochloride were kindly donated by Glonatech S.A (Athens, Greece), BASF (Ludwigshafen, Germany) and Regulon S.A. 1H-Pyrazole-1-carboxamidine hydrochloride, N,N-diisopropylethylamine (DIPEA), thiazolyl blue tetrazolium bromide (MTT), rhodamine B isothiocyanate and dialysis tubes (M.W. cut-off: 1200) were purchased from Sigma-Aldrich Ltd. D-MEM low glucose with phenol red, fetal bovine serum (FBS), penicillin/streptomycin, L-glutamine, phosphate buffer saline (PBS) and trypsin/EDTA were purchased from Biochrom (Berlin, Germany). FITC Annexin V Apoptosis Detection Kit with 7-AAD was purchased from BioLegend Way (San Diego, CA, USA). High-purity solvents such as N,N-dimethylformamide (DMF), diethyl ether, methanol and isopropanol were obtained from Merck KGaA (Calbiochem® , Darmstadt, Germany)
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