Synthesis and pharmacokinetic profile of a quaternary ammonium derivative of chlorambucil, a potential anticancer drug for the chemotherapy of chondrosarcoma

Rapp, Maryse; Giraud, Isabelle; Maurizis, Jean‐Claude; Madelmont, J. C.

doi:10.1016/j.bmc.2003.09.006

Cited by 11 publications

(3 citation statements)

References 15 publications

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“…Based on these early observations efforts have been devoted to exploit the ion exchange properties of the ECM to enhance drug accumulation in the cartilage tissue. Various positively charged organic molecules have been observed to distribute into cartilage 138–147. This includes (i) radiodiagnostic agents for joint imaging containing a N‐quaternary functional group,142, 143 (ii) N‐quaternary analogues of anti‐inflammatory oxicams,140, 144 and (iii) a derivative of the potential DMOAD doxycycline 147…”

Section: Drug Transport and Distribution Processes In A Synovial Envimentioning

confidence: 99%

Intra‐articular depot formulation principles: Role in the management of postoperative pain and arthritic disorders

Larsen

Østergaard

Larsen

et al. 2008

Journal of Pharmaceutical Sciences

250

212

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Section: Drug Transport and Distribution Processes In A Synovial Envimentioning

confidence: 99%

Intra‐articular depot formulation principles: Role in the management of postoperative pain and arthritic disorders

Larsen

Østergaard

Larsen

et al. 2008

Journal of Pharmaceutical Sciences

250

212

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“…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.…”

Section: Cartilage-targeting Drug Deliverymentioning

confidence: 98%

Drug delivery strategies for cathepsin inhibitors in joint diseases

Wang

Brὂmme

2005

Expert Opinion on Drug Delivery

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Cathepsins play important roles in the development of joint and bone diseases such as osteoporosis, rheumatoid arthritis (RA) and osteoarthritis (OA). Cathepsin inhibitors are presently in development and clinical testing for use as novel disease-modifying drugs for the improved treatment of osteoporosis. They may also be applicable for the treatment of joint diseases. However, some barriers still hamper their clinical applications in these indications. Based on pathophysiological features of RA and OA, the authors discuss six potential drug delivery strategies for the effective delivery of cathepsin inhibitors or other antiarthritic drugs to the arthritic joint tissue. Successful application of these strategies may significantly contribute to a more effective and safe treatment of RA and OA.

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“…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.…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2009

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Our strategy is to increase drug accumulation in target tumour cells using specific "vectors" tailored to neoplastic tissue characteristics, which ideally are not found in healthy tissues. The aim of this work was to use 2-fluoro-2-deoxyglucose (FDG) as a drug carrier, in view of its well-known accumulation by most primary and disseminated human tumours. We had previously selected two FDG-cytotoxic conjugates of chlorambucil (CLB), i.e. compounds 21a and 40a, on the basis of their in vitro profiles. Here we investigated the antitumour profile and tolerance of these compounds in vitro and in vivo in two murine cell lines of solid tumours. In vitro, we found that micromolar concentrations of compounds 21a and 40a inhibited proliferation of B16F0 and CT-26 cell lines. Interestingly, compounds 21a and 40a were found to act at different levels in the cell cycle: S and subG1 accumulation for 21a and G2 accumulation for 40a. In vivo, a single-dose-finding study to select the Maximum Tolerated Dose (MTD) by the intraperitoneal route (IP) showed that the two peracetylated glucoconjugates of CLB were less toxic than CLB itself. When given to tumour-bearing mice (melanoma and colon carcinoma models), according to a "q4d × 3" schedule (i.e., three doses at 4-day intervals) both compounds demonstrated a promising antitumour activity, with Log Cell Kill (LCK) values higher than 1.3 in both B16F0 and CT-26 models. Hence compounds 21a and 40a are good candidates for further works to develop new highly active antineoplastic compounds.

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Synthesis and pharmacokinetic profile of a quaternary ammonium derivative of chlorambucil, a potential anticancer drug for the chemotherapy of chondrosarcoma

Cited by 11 publications

References 15 publications

Intra‐articular depot formulation principles: Role in the management of postoperative pain and arthritic disorders

Intra‐articular depot formulation principles: Role in the management of postoperative pain and arthritic disorders

Drug delivery strategies for cathepsin inhibitors in joint diseases

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

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