Lipid nanoparticles for delivering antitumor drugs

Abstract

Lipid nanoparticles (LNs) in oil-in-water formulations were investigated for selective targeting of anticancer agents to tumor tissues and prolonged accumulation in tumor area. Simple and inexpensive lipid derivatives of polyethylene glycol (PEG) in order to decrease uptake of particles into the mononuclear phagocyte system (MPS) and highly lipophilic prodrug 4′- O-tetrahydropyranyl adriamycin (THP-ADM) in order to be entrapped into the lipid nanoparticles were synthesized and tested for their ability in tumor bearing mice. A simple PEG (1900)-lipid derivative with two long alkyl chains as the lipophilic moiety demonstrated substantial ability to form lipid nanoparticles (30–50 nm) together with phosphatidylcholine (PC), to decrease MPS uptake and to prolong circulation half-life. Plasma levels and the tissue distribution of the prodrug and anticancer active metabolites (THP-ADM and adriamycin (ADM)) were investigated after intravenous administration of LN into BALB/c mice bearing the Meth A fibrosarcoma. The blood half-life of the prodrug in LNs with PEG (1900)-lipid derivatives with two long alkyl chains (LN-E) was approximately 4.3 h. In tumor tissues, the peak height of the sum of drug concentrations [lipophilic prodrugs + metabolites (THP-ADM + ADM)] after LN-E injection did not markedly differ from that of drug concentrations [THP-ADM + metabolite (ADM)] after injection of THP-ADM itself, but a pronounced prolongation of tumor cell exposure to the drugs could be achieved. From the data on the pharmacokinetic properties of the nanoparticles, we conclude that new synthetic PEG derivatives with two long simple alkyl chains as the lipophilic moiety are useful emulsifiers for development of nanoparticles as vehicles to deliver chemotherapeutic agents to tumor.