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Antitumor Drug Development

#3577


Targeted Liposomal Forms of Antitumor Drug Melphalan: Design, Preparation and Studies on the Mechanism of Action

Tech Area / Field

  • ENV-MIN/Monitoring and Instrumentation/Environment

Status
3 Approved without Funding

Registration date
01.08.2006

Leading Institute
VNIIEF, Russia, N. Novgorod reg., Sarov

Supporting institutes

  • Institute of Bioorganic Chemistry, Russia, Moscow

Collaborators

  • State University of New York University at Buffalo / Department of Pharmaceutical Sciences / School of Pharmacy and Pharmaceutical Sciences, USA, NY, Buffalo\nUniversiteit Utrecht / Faculty of Veterinary Medicine, The Netherlands, Utrecht\nGlycoMedical Research Institute, USA, CA, La Jolla

Project summary

Antitumor drugs used now in clinics have high systemic toxicity that hampers their treatment efficacy. This Project aims at the creation, on the basis of well known anticancer melphalan, of new antitumor remedy possessing reduced toxicity for normal tissues and organs.

For several years, a research group of IBC RAS develops targeted drug liposomes equipped with different specific carbohydrate structures. Inpidual selection of the latters makes it possible to get liposomal preparations directed against tumors of different origins. The Project authors suggested including antitumor drugs, which are mainly hydrophilic, into liposome membrane as lipophilic (lipid) precursors. This makes possible: to minimize the drug losses at the liposome damage in circulation and during fusion with the target cell; to reduce probability of the drug resistance rise; to facilitate the liposome unloading in the cell. It is significant that the usage of lipophilic precursors lightens drastically procedure of the drug liposome preparation.

The goal of the Project – design and preparation of targeted liposomal formulations of melphalan lipophilic prodrug with following studies on the antitumor action mechanisms.

Main Project objectives:

  • elaboration of the tritium-labeled melphalan synthesis;
  • elaboration of synthesis of the lipid derivative of tritium-labeled melphalan;
  • chemical synthesis of the main components of non-radioactive drug liposomes: lipid derivatives of unlabeled melphalan, and carbohydrate lipophilic conjugates (molecular addresses);
  • design of non-radioactive drug liposomes on the basis of natural lipids, their application for the treatment of mice with grafted mammary cancer (MC), and studies of approaches to analysis of the cells in microenvironment of tumors with rapid and slow growth;
  • design of liposomes with tritium-labeled melphalan lipid derivative, and studies of the drug pharmacokinetics and biodistribution on the mouse model with MC.

Expected results of the Project:
  • data on pharmacokinetics and biodistribution in the tumor-bearing animals of melphalan applied as lipid derivative in the different liposomal forms;
  • data on the action of the different liposomal melphalan forms on the tumor microenvironment cells, which are needed to reveal the targeted liposome action mechanisms and elaborate the most effective liposome preparations.

The data obtained will let to clear the way for performance of preclinical trials of new effective chemotherapeutic medicines for treatment oncology diseases.


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