Abstract
Ibuprofen has been reported to possess anticancer activity. In the present work, four ibuprofen conjugates of resorcinarene-Polyamidoamine PAMAM-dendrimers were synthesized with eight or 16 ibuprofen moieties. The ibuprofen was released from the dendrimers in a dependent manner. The drug-conjugated nanoresorcinarene-dendrimers showed higher cellular uptake than free ibuprofen. In vitro cytotoxicity studies were performed with free ibuprofen and with the synthesized conjugates in U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and MDA-MB-231 (human mammary adenocarcinoma) cancer cell lines by different cytotoxicity assays. Ibuprofen conjugates of the first and second generations showed significant cytotoxic effects towards the human glioblastoma (U251) and human mammary adenocarcinoma (MCF-7, MDA) cell lines. Moreover, the ibuprofen conjugates improved cytotoxicity compared to free ibuprofen. Increased therapeutic efficacy was observed with specific ibuprofen conjugates of the second generation using low doses.
Highlights
2-(4-isobutylphenyl) propionic acid, well known as ibuprofen, is a non-steroidal anti-inflammatory drug (NSAID) used to treat inflammatory rheumatoid diseases and relieve acute pain
Studies on the mechanism of interaction between polyamidoamine PAMAM-dendrimers and cells show that the main internalization mechanism is the clathrin-mediated endocytosis pathway, where vesicles fuse with early endosomes following an acidification route that finishes in lysosomes [17]
U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA-MB-231 cell lines were supplied by the National Cancer Institute (Bethesda, MD, USA)
Summary
2-(4-isobutylphenyl) propionic acid, well known as ibuprofen, is a non-steroidal anti-inflammatory drug (NSAID) used to treat inflammatory rheumatoid diseases and relieve acute pain. The use of this therapeutic agent is restricted due to its side effects such as stomach ulceration, bleeding, and perforation [1,2]. Ibuprofen has been used as an anticancer drug by itself or in conjunction with drug carriers such as hydrogels [10], liposomes [11,12], dendrimers [13], and micelles [14] Of these drug carriers, dendrimers are a promising delivery system for several drugs due to their low solubility, size, high biocompatibility, good efficiency in drug delivery, and therapeutic activity [15]. We report our new in vitro anticancer activity results using resorcinarene-dendrimers as carriers of ibuprofen
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