Antineovascular therapy with angiogenic vessel-targeted polyethyleneglycol-shielded liposomal DPP-CNDAC.
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-beta-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 zeta-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.
Asai
Tomohiro
T
Department of Medical Biochemistry and Global COE, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Miyazawa
Souichiro
S
Maeda
Noriyuki
N
Hatanaka
Kentaro
K
Katanasaka
Yasufumi
Y
Shimizu
Kosuke
K
Shuto
Satoshi
S
Oku
Naoto
N
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001088:Arabinonucleotides / Q000008:administration & dosage* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001088:Arabinonucleotides; D008081:Liposomes; C114869:dpp-cndac; D011092:Polyethylene Glycols