1. Journal of Inorganic Biochemistry 100 (2006) 1819–1826
Preclinical characterization of anticancer gallium(III) complexes: Solubility, stability, lipophilicity and binding to serum proteins
Journal of Inorganic Biochemistry 100 (2006) 1819–1826

2. Revise:
Complexation for Solubility modification
Metal – complex formation
Chelation concept

3. Introduction: Read From The Article
Materials: Gallium complexes,
Human serum albumin, solvents,….. Methods & Results 1. Solubility determination: Read From The Article 2. logP determination: Read From The Article -shake flask method ??

4. Results Solubility AND Kd : Read From The Article ++
Compared with literature;
the only value
Available for gallium complexes of interest,
is water solubility of KP46, i.e., 22 mg/l or 4.4 E-5M,
Kd, KP46= 7.5

6. Effect of the metal- ligand ratio
1:1 stoichiometry (KP1492 and KP1497) are less hydrophobic molecules than the corresponding chelates with a metal-to-ligand ratio of 1:2, KP1500 (hydrophobic counter ion)
Kd, KP1492 = 0.037
Kd, KP1500= 0.89

7. b. Effect of the nature of the counter ion
KP1089 improved solubility is due to less hydrophobic counterion and 4N-substituents (two methyl groups)
Kd, KP1089 = 0.071

8. 3. Hydrolysis rate Determination The hydrolytic stability of gallium complexes in water and physiological buffer (10 mM NaH2PO4/Na2HPO4, 100 mM NaCl, pH 7.4) was evaluated by incubating a given solution at 37 C, taking aliquots continuously for analysis, and monitoring a decrease of the concentration. The kinetic series was repeated four times for each gallium complex hydrolysis medium combination to calculate the average rate constant (khyd) and the standard deviation. The halflife was also calculated.

9. Results Hydrolytic stability: Read from the article ++
Complexation with strong, chelating ligands renders gallium(III) high stability against hydrolysis. Furthermore, one can anticipate that other possible metabolic processes do not also affect much the integrity of oral gallium drugs on the way to cancer cells.

10. 4. Protein-binding kinetics Determination All binding experiments were performed in buffer solution at pH 7.4 as incubation solution, at 37 C and with 1.0E-5 M KP46 or KP1089. The protein concentration in the reaction mixture was kept constant at 5.0E-5 M. The apparent rate constant (k) was calculated assuming that the binding reaction obeys the first-order kinetics and the following equation is valid: lnA = kt.

11. Results Protein-binding kinetics

12. The higher rate of protein adducts formation observed for KP1089 is probably associated with the cationic nature of the interacting gallium functionality [both proteins of interest bear a negative net charge at the extracellular pH]. Gallium-protein binding is expected to proceed in a high-speed way for other cationic chelates as well. According to the values of apparent binding rate constants determined for both KP46 and KP1089 bind to transferrin faster than to albumin. This implies that transferrin would rather mediate the accumulation of gallium antineoplastic agents in solid tumors. End