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Design of Folate-Linked Liposomal Doxorubicin to its Antitumor Effect in Mice

Authors' Affiliations: ¹ Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan and ² Fukushima Medical University School of Nursing, Fukushima-City, Japan

Requests for reprints: Yoshie Maitani, Institute of Medicinal Chemistry, Hoshi University, Shinagawa, Ebara 2-4-41, Tokyo, 142-8501 Japan. Phone: 81-3-5498-5048; Fax: 81-3-5498-5048. E-mail: yoshie{at}hoshi.ac.jp.

Purpose: Tumor cell targeting is a promising strategy for enhancing the therapeutic potential of chemotherapy agents. Polyethylene glycol (PEG)-coated (sterically stabilized) liposomes show enhanced accumulation on the surface of tumors, but steric hindrance by PEGylation reduces the association of the liposome-bound ligand with its receptor. To increase folate receptor (FR) targeting, we optimized the concentration and PEG spacer length of folate-PEG-lipid in liposomes.

Experimental Design: Three types of folate-linked liposomal doxorubicin were designed and prepared by optimizing the concentration and PEG spacer length of folate-PEG-lipid in PEGylated or non-PEGylated liposomes and by masking folate-linked liposomes where the folate ligand is "masked" by adjacent PEG spacers. The liposome targeting efficacy was evaluated in vitro and in vivo.

Results: In human oral carcinoma KB cells, which overexpress FR, modification with sufficiently long PEG spacer and a high concentration of folate ligand to non-PEGylated liposomes increased the FR-mediated association and cytotoxicity more than with PEGylated and masked folate-linked liposomes. On the contrary, in mice bearing murine lung carcinoma M109, modification with the folate ligand in PEGylated and masked folate-linked liposomes showed significantly higher antitumor effect than with non-PEGylated liposomes irrespective of the length of time in the circulation after intravenous injection.

Conclusions: The results of this study will be beneficial for the design and preparation of ligand-targeting carriers for cancer treatment.