New Concepts of Anti-Cancer Therapy:

Synthesis and assessment of biovectors

 Hafid Belhadj-Tahar^1,2, Yvon Coulais² , Marie–Hélène Darbieu³, Jean-Louis Lacout⁴ , Michel Vidal⁵, Azzedine Bousseksou⁶ and Uldericco Mazzi⁷

1- Groupe Santé Recherche, 35 rue Bernard de VENTADOUR, 31300 Toulouse.

(Collaborations : 2- EA3033-UPS, Toulouse ; 3- Laboratoire de Chimie Pharmaceutique-UPS, Toulouse ; 4- INP-Toulouse, 5- ERAS Labo, Genoble ; 6- LCC-CNRS UP8241, Toulouse ; 7- Radiopharmacy Dpt , Padova university -Italy) 

Cancer is one of the first causes of mortality in the world. Therapeutic successes in the treatment of cancer depend on early diagnosis, extension assessment and initial treatment of primitive tumors and its metastases. Until now, treatments are rarely selective and based on probabilistic strategies combining the staging and grading of malignant tumors (namely Pretreatment clinical and post surgical histopathological classifications). In this context, tumoral targeting using biomolecule vectors as radiometallic probes (beta- and gamma-emitters) seem to be an/the ideal strategy for anticancer therapy. Thus, biovectorization allows to draw up the exact intrinsic profile of the tumor: its metastatic potentiality, its predictive radioresistance or its multichimio-resistance. We expose two applications of radiometallic vectorisation: ^99mTechnetium (gamma emitter) for diagnosis, ^186/188Rhenium (beta emitter) for radiotherapy and cold 185/187Rhenium for chemotherapy.  

1st Biovector agents derived from CCK₄.  The Tetragastrin (CCK₄: Trp-Met-Asp-Phe-NH2), a vector related to gastrine, exhibits specific affinity for CCKB receptors which are preferentially expressed by some tumoral cells of the digestive tract. The S-EOE-MAG3-beta-alanine-CCK4 vector was synthesised with high chemical purity and was efficiently labelled (yield > 95 %) in one step under pH 7-8 and 40°C conditions. Rhenium complexes were obtained with high yield and exhibit the same physiochemical properties as ^99mTc-CCK₄. These studies carried out with the 99m/99Tc- CCK₄, revealed good affinity for the CCK_B receptors (IC^₅₀ pentagastin : 10^-9 M vs IC^{₅₀ 99}Tc-CCK₄ = 8.10^-8 M). These biovectors exhibit remarkable pharmacokinetic properties related to low background noise resulting from lack of hepatic uptake and may be proposed as pharmaceutic kit in cancer treatment as well as in vitro pharmacological probe.  

2nd Cement of hydroxyapatite used in metastatic bone therapy.  Hydroxyapatite cement is used as a bone substitute in orthopaedics. This biocompatible matrix has been suggested as therapeutic delivery system used in osseous excavation (antibiotics, antimitotic drugs). Recently, we have focused our interest on kinetics of ^185/187Rhenium released by these cements in aqueous media in order to use them as appropriate matrices for local diffusion of antimitotic agents. Hydroxyapatite was synthesized by mixing of 1.45Ca₄P₂O₉ +1.325 Ca₃(PO4)₂ +0.225Ca(H₂PO₄)2,H₂O à Ca₁₀(PO₄)₆(OH)₂ in aqueous media. We determined the equation of rhenium kinetics release from the osseous matrix: Dt= D₀ .(1-exp[-0.03. t ] ).

Finally, this study shows that hydroxyapatite cements may be used as appropriate matrices for bone delivery system of radio and chemotherapeutic agents (with ^186/188 Re & ^185/187Re). Moreover, such loaded matrix can be proposed in intracavity therapy for tumoral stroma sterilisation.