Synthesis and in Vivo Biodisposition of [¹⁴C]-Quaternary Ammonium−Melphalan Conjugate, a Potential Cartilage-Targeted Alkylating Drug

Abstract

For the purpose of developing more selective anticancer drugs that would concentrate in the malignant cartilaginous tumors (chondrosarcomas), and so improve therapeutic index through a reduction of side effects, a quaternary ammonium (QA) conjugate of melphalan was synthesized and labeled with (14)C by linking the QA moiety to nitrogen mustard via an amide bond. Comparative pharmacokinetic study of [(14)C]-melphalan and its [(14)C]-QA conjugate conducted on rats showed that the two compounds were principally excreted by the urinary way. The blood elimination of the QA conjugate was faster than that of the melphalan. In the other hand a higher rate of radioactivity derived of [(14)C]-MQA was found in feces. In the biodisposition for most organs, no striking differences were found between melphalan and its QA conjugate except for cartilages which exhibited more higher radioactivity level. Amounts of radioactivity derived from [(14)C]-QA conjugates measured in cartilaginous tissues until 1 h after injection demonstrate that the introduction of a QA moiety on melphalan allows the molecule to be carried selectively to cartilaginous tissues. As the [(14)C]-QA conjugate is radiolabeled on the chloroethyl alkylating moiety, levels of radioactivity measured in the cartilaginous tissues results from unchanged compound or metabolite having kept the active group.

Drug delivery strategies for cathepsin inhibitors in joint diseases

“…Based on this principle, Madelmont and colleagues have done some preliminary work in cartilage-targeted delivery [113,114]. Basically, they synthesised a series of positively charged compounds with quaternary ammonium in the structure and hypothesised that the positive charge would recognise the negatively charged cartilage and direct the payload to the tissue.…”

Preclinical investigation of tolerance and antitumour activity of new fluorodeoxyglucose-coupled chlorambucil alkylating agents

“…For many years, our group has been recognized for its expertise in vectorization strategies, through its work on identifying chemical carriers able to deliver radiopharmaceuticals and drugs selectively to tissues for targeted imaging and therapy respectively [4][5][6]. Our previous work has shown in particular that imaging agents and drugs can be targeted towards certain biochemical and phenotypical tumour features, e.g.…”

Quaternary ammonium-melphalan conjugate for anticancer therapy of chondrosarcoma: in vitro and in vivo preclinical studies

“…Each of these approaches led to high in-joint compound concentrations after in vivo administration [6,[11][12][13].…”

“…Among the numerous strategies aimed at increasing intarget drug accumulation, "vectors" with high specific affinities for one or more targets offer one of the most promising therapeutic opportunities [4]. Our team has built up recognized expertise in vectorization strategies through work identifying chemical carriers able to selectively deliver radionuclides and drugs to tissues for targeted imaging and therapy [5,6]. Our chondrosarcoma management-oriented strategy is to exploit the chondrogenic nature of the tumour in order to selectively deliver drugs or radioisotopes to tumoural tissue.…”

“…Here, we focused on the quaternary ammonium derivative of melphalan (Mel-AQ), which previously been demonstrated to exhibit high accumulation in cartilage in vivo [6].…”