Abstract
New chitosan derivatives modified with (3-carboxypropyl)trimethylammonium chloride (1) and coupled with (OC-6-44)-diammine(4-carboxypropanoato)dichloridoethanolatoplatinum(IV) (2), were synthesized and their preliminary biological evaluation carried out in human tumor cells. Some of these derivatives were also loaded with a chelating ligand (3) that was derived from bis(quinolin-2-ylmethyl)amine to obtain chitosan-based nanoparticles for an EPR-mediated delivery of Pt(IV) prodrugs and Re(I) tricarbonyl complexes (4), to explore a multimodal theranostic approach to cancer. The cytotoxicity of the different chitosan conjugates (C12, C123, and C1234), carrying different combinations of the Pt(IV) complex, the chelator and the Re(I) complex, was evaluated in the A2780 human ovarian cancer cell line using the MTT assay. The Pt(IV)-containing nanosystems showed low to moderate cytotoxic activity (IC50 values in the range 13.5–33.7 µM) and was comparable to that found for the free Pt(IV) complex (IC50 = 13.7 µM). Therefore, the Pt(IV)-chitosan conjugation did not enhance the cytotoxic activity of the Pt(IV) prodrug, which certainly reflects the inefficient cellular uptake of the nanoconjugates. Nevertheless, a clearer view of their potential for the delivery of anticancer agents requires further in vivo tests because the EPR effect increases extravasation and retention within the tumor tissue, not necessarily within the tumor cells.
Highlights
In 1978, cisplatin (i.e., (SP-4-2)-diamminedichloridoplatinum(II)) was approved by the Food andDrug Administration as an anticancer drug
The number of N-acetyl groups is expressed as molar percentage and is defined as acetylation degree (AD)
Another characteristic that allows the evaluation the nature of the polysaccharide is the solubility in aqueous solution of organic acids, which is verified for AD
Summary
Since this simple Pt(II) compound has become one of the most widely used chemotherapeutic agents. One of the major problems of Pt chemotherapeutic agents is their non-specific toxicity. Such toxic action to normal cells limits the dose of the anticancer drugs to be administered to patients, which results in unsatisfactory efficacy. To overcome this obstacle, conjugation of the drugs to suitable carriers has been studied to provide site-specificity and to increase the drug concentration at the tumor site (drug targeting and delivery, DTD)
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