Hydroxyapatite nanocrystals as local anticancer platinum complexes delivery system

Control at a nanosize level is a fundamental rule in the production of biomimetic materials particularly in the case of bone substitutes where the chemical and biological properties are very much size dependent. Synthetic hydroxyapatite (HA) nanocrystals represent an elective material for bone substitutes, moreover their surface functionalization with bioactive molecules makes them able to transfer information to and to act selectively on the biological environment. In this paper we have investigated the adsorption and desorption of cis-diamminedichloroplatinum(II) (CDDP or cisplatin), alendronate, and the new platinum(II) complex di(ethylendiamineplatinum)medronate (DPM) towards two bio-mimetic synthetic hydroxyapatite nanocrystal materials having different crystal shape and chemico-physical properties. The adsorption and desorption kinetics are dependent upon the specific properties of the drugs and of the HA’s (needle-shaped HAns and plate-shaped HAps). It is found that in the adsorption process the two platinum compounds keep the nitrogen ligands while CDDP looses its chlorides. Despite their opposite charges, the negatively charged alendronate and the positively charged acquated CDDP are the most adsorbed, while the neutral DPM shows the lowest affinity towards the apatitic surface. Considering that HA surface is in all negatively charged, data suggest that in the case of the two platinum complexes adsorption kinetics are driven by electrostatic attractions. On the other hand, the HA-alendronate interaction appears to consist of a “ligand exchange” process between the phosphonate functions of the drug molecule and two phosphates groups located on the surface of the HA nanocrystals. There is also a modulating effect of the specific HA used: adsorption of positively charged aquated CDDP is favored on phosphate reacher HAns surface while adsorption of negatively charged alendronate is favored on calcium reacher HAps surface. The latter type of short-range electrostatic interactions (positively charged aquated CDDP anchored by phosphate anions and negatively charged alendronate anchored by calcium cations) appear to dominate the desorption kinetics. Therefore the drug release is greater for neutral DPM than for charged alendronate and aquated CDDP. Moreover, while the release per unit area of charged species (aquated CDDP and alendronate) is the same for the two types of HA’s, the release of DPM is faster for HAns, which is poorer in surface calcium, than for HAps. This work demonstrates that the properties of HA nanocrystals can be modulated in such a way to produce HA/biomolecule conjugates tailored for specific therapeutical applications.