Novel nanoplatforms for targeting melanoma with 8-hydroxyquinoline metal complexes
Medicinal and Biological Chemistry for Health
Main area: Bioinorganic Chemistry
Partners: FFUL 244000
Cancer is one of the most challenging diseases and cancer-related deaths are estimated to rise as life expectancy increases.1 Melanoma is the sixth most frequently diagnosed cancer and the most common malignant skin neoplasm. Once metastasized, it usually becomes fatal due to the scarce therapeutic options available. Although relevant progress has been obtained in the treatment of several cancer diseases over the past few decades, the incidence and mortality associated with malignant melanoma continues to increase. Delivery of a drug to the target tumor site is a critical challenge as therapeutic drugs typically lack target specificity, have poor bioavailability and are easily excreted before exerting their therapeutic effect. Other drawbacks, including undesirable side effects, acquired resistance, or even disease relapse, are common and therefore, there is the need to develop new, efficient and more selective drugs.
In this project, we propose to develop new metallodrugs based on a bioactive scaffold, 8-hydroxyquinoline (8HQ), aiming at stable, efficient and selective compounds. A family of such type of compounds was preliminary tested by us in in vitro cytotoxicity assays, showing high potential for melanoma therapy. These findings inspired us to develop new compounds based on this initial family, and to formulate the most active in lipid or polymeric-based systems, aiming to provide safe and selective drug delivery and ultimately to improve the efficacy of the treatment for malignant melanoma.
We will take advantage of 8HQ, a scaffold that has shown broad biological activity, and attach additional donor functionalities through condensation with selected amines. These will allow to modulate electronic, stereochemical and metal binding properties of 8HQ, and to increase the stability of the metal complexes. The metal ions selected are Cu(II), V(IV) and Zn(II), as these also have documented therapeutic potential.
Since the pharmacokinetic properties of a drug are strongly dependent on its solubility, lipophilicity and stability, these properties will be studied by determining partition coefficients (log P), protonation constants of the ligands and formation constants of the complexes. Evaluation of metal speciation is also fundamental to predict the active species of a metallodrug, this enabling the design of drugs with improved performance. The stability and speciation of the new compounds will be evaluated in aqueous media of different complexities: aqueous solutions at physiological pH, cell culture media and human plasma.
Following the initial characterization, the compounds will be screened in vitro in different human and murine melanoma cells, and the most active will be selected for encapsulation in liposomes and polymeric nanoparticles, since their association to drug delivery systems is a valuable strategy that may provide improved efficacy and selective drug targeting.2-4 The evaluation of the cellular uptake of the compounds as well as the study of the mechanisms of cell death will be carried out with the most promising compounds identified in the cellular screening. The establishment of structure-activity relationships will allow identification of lead compounds. Identification of cellular targets will also be performed with docking studies, taking advantage of the current knowledge in the field.
The most promising compounds will then be nanoformulated using two different approaches, and studied in cellular models of melanoma using the above-mentioned methodologies. The first approach will include the preparation of liposomes as carriers for the best compound, for intravenous administration. The main goal of this approach is to treat the advanced-stage of metastatic melanoma. The second approach will include the preparation of polymeric nanoparticles that will release the compound in situ (in the tumor area) after intratumoral injection. Compounds selected in in vitro screenings will be tested in vivo in immunocompetent murine melanoma models. Efficacy and safety studies will be performed to achieve adequate and high-value formulations for melanoma therapy, with potential interest to pharma industry.
The strategy encompasses aggregating distinct approaches so that the combined results will guide the design towards compounds with optimal performance. This ambitious project faces numerous challenges, however the team is multidisciplinary and highly skilled with the required expertizes. The researchers have already successfully collaborated and preliminary data supports the proposed strategy to obtain active drugs for melanoma therapy. We, thus, predict that the use of structure-activity relationships will enable the selection of lead compounds for pre-clinical trials.