Pt(IV)/Re(I) Chitosan Conjugates as a Flexible Platform for the Transport of Therapeutic and/or Diagnostic Anticancer Agents

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 (IC 50 values in the range 13.5-33.7 µM) and was comparable to that found for the free Pt(IV) complex (IC 50 = 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.

Chemical Modification of Chitosan for Developing Cancer Nanotheranostics

“…After loading a model drug paclitaxel (PTX), the surface of PTX-TCS-GNSs was modified with the anti-EGFR (epidermal growth factor receptor) antibody by using EDC/NHS-catalyzed amidation reaction . Other amidation reagents such as O -1-benzotriazol-1-yl- N , N , N′ , N′ -tetramethyluronium hexafluorophosphate (HBTU)/ N , N -diisopropylethylamine (DIPEA) pairs and ethyl-3-(3-(dimethylamino)­propyl) carbodiimide (EDAC) were also used in the synthesis of acylated CS.…”

Polymer-Drug Conjugates as Nanotheranostic Agents

“…This pH-sensitive prodrug could have a certain potential for cancer therapy along with imaging [69]. Gabano et al suggest that the chitosan nanoparticle conjugated with the chemotherapeutic agent cisplatin and the photosensitizer Re(I) tricarbonyl complex could be used as a theranostic by replacing the fac-[Re(CO)3] + by the congener fac-[99mTc(CO)3] + core [93].…”

Multifunctional Iridium(III)–Platinum(IV) Conjugates as Potent Anticancer Theranostic Agents

“…In recent years, efforts have been made for the development of metallodrugs, a strategy to combine two or more active transition metals in a single platform in order to achieve a synergistic effect of two metals. − To date, pioneering studies have been reported to improve the cytotoxicity of Pt­(IV) prodrugs by combining with other metals which include Cu­(II), Fe­(II), , Ru­(II), ,, Re­(I), Gd­(III), , Au­(I), etc. For instance, Zhu and co-workers have reported heterodinuclear Pt­(IV)-Ru­(II) anticancer prodrugs to combat both drug resistance and cancer metastasis. , Gasser and co-workers have demonstrated a multi-targeted Ru­(II)-Pt­(IV) conjugate that combines cancer-activated chemotherapy with photodynamic therapy with multi-action mechanisms to overcome drug-resistant cancers .…”