Antineovascular therapy with angiogenic vessel‐targeted polyethyleneglycol‐shielded liposomal DPP–CNDAC

• Published in: Cancer science Vol. 99; no. 5; pp. 1029 - 1033
• Main Authors: Asai, Tomohiro, Miyazawa, Souichiro, Maeda, Noriyuki, Hatanaka, Kentaro, Katanasaka, Yasufumi, Shimizu, Kosuke, Shuto, Satoshi, Oku, Naoto
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01-05-2008; Blackwell
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Arabinonucleotides - administration & dosage; Arabinonucleotides - therapeutic use; Biological and medical sciences; Drug Delivery Systems; Liposomes - chemistry; Male; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - drug therapy; Neovascularization, Pathologic - drug therapy; Original /Report; Polyethylene Glycols - chemistry; Tissue Distribution; Tumor Cells, Cultured; Tumors; Angiogenesis; Cancerology; Treatment; Targeted therapy; Blood vessel; Liposome; Circulatory system; Neovascularization
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2008.00758.x

Causing damage to angiogenic vessels is a promising approach for cancer chemotherapy. The present study is a codification of a designed liposomal drug delivery system (DDS) for antineovascular therapy (ANET) with 2′‐C‐cyano‐2′‐deoxy‐1‐β‐D‐arabino‐pentofuranosylcytosine (CNDAC). The authors have previously reported that liposomalized 5′‐O‐dipalmitoylphosphatidyl CNDAC (DPP–CNDAC), a phospholipid derivative of the novel antitumor nucleoside CNDAC, is quite useful for ANET. DPP–CNDAC liposomes modified with APRPG, a peptide having affinity toward angiogenic vessels, efficiently suppressed tumor growth by damaging angiogenic endothelial cells. In the present study, the authors masked the hydrophilic moiety of DPP–CNDAC, namely, CNDAC, on the liposomal surface with APRPG–polyethyleneglycol (PEG) conjugate to improve the availability of DPP–CNDAC liposomes. The use of the APRPG–PEG conjugate attenuated the negative ζ‐potential of the DPP–CNDAC liposomes and reduced the agglutinability of them in the presence of serum. These effects improved the blood level of DPP–CNDAC liposomes in colon 26 NL‐17 tumor‐bearing BALB/c male mice, resulting in enhanced accumulation of them in the tumor. Laser scanning microscopic observations indicated that APRPG–PEG‐modified DPP–CNDAC liposomes (LipCNDAC/APRPG–PEG) colocalized with angiogenic vessels and strongly induced apoptosis of tumor cells, whereas PEG‐modified DPP–CNDAC liposomes (LipCNDAC/PEG) did not. In fact, LipCNDAC/APRPG–PEG suppressed the tumor growth more strongly compared to LipCNDAC/PEG and increased significantly the life span of the mice. The present study is a good example of an effective liposomal DDS for ANET that is characterized by: (i) phospholipid derivatization of a certain anticancer drug to suit the liposomal formulation; (ii) PEG‐shielding for masking undesirable properties of the drug on the liposomal surface; and (iii) active targeting to angiogenic endothelial cells using a specific probe. (Cancer Sci 2008; 99: 1029–1033)