Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model

Abstract

Colorectal cancer is the second leading cause of cancer-related mortality. Many current therapies rely on chemotherapeutic agents with poor specificity for tumor cells. The clinical success of cisplatin has prompted the research and design of a huge number of metal-based complexes as potential chemotherapeutic agents. In this study, two zinc(II) complexes, [ZnL2] and [ZnL(AcO)], where AcO is acetate and L is an organic compound combining 8-hydroxyquinoline and a benzothiazole moiety, were developed and characterized. Analytical and spectroscopic studies, namely, NMR, FTIR, and UV-Vis allowed us to establish the complexes’ structures, demonstrating the ligand-binding versatility: tetradentate in [ZnL(AcO)] and bidentate in [ZnL2]. Complexes were screened in vitro using murine and human colon cancer cells cultured in 2D and 3D settings. In 2D cells, the IC50 values were <22 µM, while in 3D settings, much higher concentrations were required. [ZnL(AcO)] displayed more suitable antiproliferative properties than [ZnL2] and was chosen for further studies. Moreover, based on the weak selectivity of the zinc-based complex towards cancer cell lines in comparison to the non-tumorigenic cell line, its incorporation in long-blood-circulating liposomes was performed, aiming to improve its targetability. The resultant optimized liposomal nanoformulation presented an I.E. of 76% with a mean size under 130 nm and a neutral surface charge and released the metal complex in a pH-dependent manner. The antiproliferative properties of [ZnL(AcO)] were maintained after liposomal incorporation. Preliminary safety assays were carried out through hemolytic activity that never surpassed 2% for the free and liposomal forms of [ZnL(AcO)]. Finally, in a syngeneic murine colon cancer mouse model, while free [ZnL(AcO)] was not able to impair tumor progression, the respective liposomal nanoformulation was able to reduce the relative tumor volume in the same manner as the positive control 5-fluorouracil but, most importantly, using a dosage that was 3-fold lower. Overall, our results show that liposomes were able to solve the solubility issues of the new metal-based complex and target it to tumor sites.

Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential

“…The work was initiated with the synthesis of the compounds L1 – L3 , which were obtained by a base-catalyzed condensation between equimolar amounts of 8-hydroxy-2-quinolinecarboxaldehyde (8HQ-2CHO) and three different piperidine/morpholine-type amines. The ligand precursors were reacted ( in situ ) with ZnCl 2 or CuCl 2 in ethanol or methanol, yielding Zn­(II) [ Zn­(L1) 2 – Zn­(L3) 2 ] or Cu­(II) [ Cu 2 (L1) 4 , Cu 2 (L2) 4 , and Cu­(L3) 2 ] complexes, in moderate to good yields (Scheme ), using methodologies similar to those described in the literature for related compounds. ,,, The complexes are stable under air and moisture in the solid state, in contrast to the free ligands, which are hygroscopic and therefore were stored in sealed ampules.…”

“…Our strategy explored the increase in the coordination ability of 8HQ by introducing substituents in the ortho position to the quinoline N atom while also containing donor groups in suitable positions to participate in the chelation of the metal ion. Condensation with different nitrogen-containing molecules yielded different types of ligands, and overall, the compounds showed cytotoxic activity in different cancer cell lines such as malignant melanoma, lung, and colon. ,, The presence of two bioactive moieties, 8HQ and benzothiazole (another N -heterocycle), yielded a Schiff base with interesting anticancer properties. , Its Zn­(II) complex showed the ability to reduce the tumor volume in an in vivo study with a syngeneic colon cancer mouse model upon incorporation in a liposomal formulation to increase drug aqueous solubility and targeting efficacy …”

“…10,12 Its Zn(II) complex showed the ability to reduce the tumor volume in an in vivo study with a syngeneic colon cancer mouse model upon incorporation in a liposomal formulation to increase drug aqueous solubility and targeting efficacy. 12 A family of benzohydrazones derived from 8HQ-2carbaldehyde and benzylhydrazides substituted in the para position was also recently developed by us and complexed to oxidovanadium(IV) 9 and copper(II). 13 Their solution behavior was evaluated, and they were screened in malignant melanoma (A375) and lung (A549) cancer cells, showing IC 50 values in the low micromolar concentration range.…”

“…In our ongoing search for new anticancer drugs, we have developed different derivatives of 8-hydroxyquinolines (8HQ) and complexed them to different metal ions to take advantage of the synergistic effect of combining a bioactive organic moiety and biologically significant metals, such as copper, zinc, vanadium, iron, nickel, and ruthenium. − Coordination compounds present several advantages when compared to organic molecules since they may influence the size, charge, lipophilicity, and interaction with biomolecules, showing different coordination numbers and geometries and may also present redox activity. Our strategy explored the increase in the coordination ability of 8HQ by introducing substituents in the ortho position to the quinoline N atom while also containing donor groups in suitable positions to participate in the chelation of the metal ion.…”

“…9,10,12 The presence of two bioactive moieties, 8HQ and benzothiazole (another N-heterocycle), yielded a Schiff base with interesting anticancer properties. 10,12 Its Zn(II) complex showed the ability to reduce the tumor volume in an in vivo study with a syngeneic colon cancer mouse model upon incorporation in a liposomal formulation to increase drug aqueous solubility and targeting efficacy. 12 A family of benzohydrazones derived from 8HQ-2carbaldehyde and benzylhydrazides substituted in the para position was also recently developed by us and complexed to oxidovanadium(IV) 9 and copper(II).…”