Abstract
Cancer chemotherapeutic systems with high antitumor effects and less adverse effects are eagerly desired. Here, a pH-sensitive delivery system for bleomycin (BLM) was developed using egg yolk phosphatidylcholine liposomes modified with poly(ethylene glycol)-lipid (PEG-PE) for long circulation in the bloodstream and 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidylethanolamine (CHexPG-PE) for pH sensitization. The PEG-PE/CHexPG-PE-introduced liposomes showed content release responding to pH decrease and were taken up by tumor cells at a rate 2.5 times higher than that of liposomes without CHexPG-PE. BLM-loaded PEG-PE/CHexPG-PE-introduced liposomes exhibited comparable cytotoxicity with that of the free drug. Intravenous administration of these liposomes suppressed tumor growth more effectively in tumor-bearing mice than did the free drug and liposomes without CHexPG-PE. However, at a high dosage of BLM, these liposomes showed severe toxicity to the spleen, liver, and lungs, indicating the trapping of liposomes by mononuclear phagocyte systems, probably because of recognition of the carboxylates on the liposomes. An increase in PEG molecular weight on the liposome surface significantly decreased toxicity to the liver and spleen, although toxicity to the lungs remained. Further improvements such as the optimization of PEG density and lipid composition and the introduction of targeting ligands to the liposomes are required to increase therapeutic effects and to reduce adverse effects.
Highlights
Cancer chemotherapy is a standard therapy to treat malignant tumors
These results indicate that organs, high doses of BLMliposomes might release at tumor tissues and at other normal thereby causing loaded pH-sensitive liposomes might release BLM at tumor tissues and at other normal severe adverse effects to mice, as described in the histological analysis
These results suggest that, at the high dosage, BLM-loaded pH-sensitive liposomes were trapped in moderately thickened after treatment with free BLM and BLM-loaded pH-sensitive liposomes (5 and mononuclear phagocyte systems (MPS) in the spleen, liver, and lungs and released BLM at these tissues, 10 mg/kg)
Summary
Cancer chemotherapy is a standard therapy to treat malignant tumors. Anticancer drugs can kill cancer cells and suppress tumor growth, systemic distribution of these drugs exerts adverse effects on normal cells and normal tissues. The selective delivery of anticancer drugs to tumors and avoidance of drug distribution to normal cells would improve cancer therapeutic effects and improve patients’ quality of life during cancer treatments. For this purpose, drug delivery systems (DDSs), which control drug release from carriers, drug absorption to target tissues, and selective. Drug carriers of around 100 nm in size are known to accumulate efficiently in tumor tissues because of the leaky blood vessel structure in tumor tissues and the lack of lymphatic systems compared with normal tissues. Some PEG-modified liposomes encapsulating anticancer drugs such as doxorubicin (DOX) are clinically available for cancer treatments
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