Abstract

Two generations of positively charged poly(amidoamine) dendrimers (PAMAMs) were selected for study as potential carriers for the anticancer drug 5-fluorouracil (5FU), a drug primarily used in the treatment of colorectal cancer. Analytical techniques, such as UV-Vis spectrophotometry, NMR Spectroscopy and Laser Doppler Velocimetry (LDV), have shown that the most critical factor determining the formation of a PAMAM–5FU complex is the starting components’ protonation degree. The tests confirmed the system’s ability to attach about 20 5FU molecules per one dendrimer molecule for the G4PAMAM dendrimer and about 25 molecules for the G6PAMAM dendrimer, which gives a system yield of 16% for the fourth generation and 5% for sixth generation dendrimers. Additionally, using the QCM-D method, the adsorption efficiency and the number of drug molecules immobilized in the dendrimer structure were determined. A new aspect in our study was the determination of the change in zeta potential (ζ) induced by the immobilization of 5FU molecules on the dendrimer’s outer shell and the importance of this effect in the direct contact of the carrier with cells. Cytotoxicity tests (resazurin reduction and MTS tests) showed no toxicity of dendrimers against mouse fibroblast cells (L929) and a significant decrease in cell viability in the case of four human malignant cell lines: malignant melanoma (A375), glioblastoma (SNB-19), prostate cancer (Du-145) and colon adenocarcinoma (HT-29) during incubation with PAMAM–5FU complexes. The purpose of our work was to investigate the correlation between the physicochemical properties of the carrier and active substance and the system efficiency and optimizing conditions for the formation of an efficient system based on PAMAM dendrimers as nanocarriers for 5-fluorouracil. An additional aspect was to identify potential application properties of the complexes, as demonstrated by cytotoxicity tests.

Highlights

  • We indicated the surface charge of the fourth and generation poly(amidoamine) dendrimers (PAMAMs) dendrimers and determined the values of the effective charge (Nc ) and the degree of ionization of the dendrimers as a function of generation and pH, which corresponded to the conditions of complex formation

  • Experimental studies show that analysis of physicochemical properties of both PAMAM dendrimers and 5-fluorouracil play a significant role in the formation of highefficiency PAMAM–5FU complex

  • The fact that drug molecules bind most effectively under alkaline conditions when the dendrimer is close to the isoelectric point indicates a greater influence of the ligand charge which occurs in a deprotonated form

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Summary

Introduction

Chemotherapy, which uses chemicals to block the growth or kill rapidly growing cancer cells, thereby killing healthy cells, plays a major role in cancer treatment. A promising form of therapy may be the implementation of a Controlled Drug Delivery System (CDDS) [2]. The development of a CDDS requires interdisciplinary knowledge, including chemistry, pharmaceutical sciences, medical sciences, or materials engineering [3]. CDDS’ task is to eliminate the problems that arise during conventional drug administration by extending the active ingredient’s release time, increasing the solubility, or stopping the process of accumulation of the active substance in healthy body tissues by releasing it directly to target cells [2,3]. Nanotechnology has played an essential role in medicine for several decades, including cancer diagnostics and treatment [4]

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