ABSTRACT
Tumor-targeting of anticancer drugs is an interesting approach for the treatment of cancer since chemotherapies possess several adverse effects. In the present study, we propose a novel strategy to deliver anticancer drugs to the tumor cells through the mannose-6-phosphate/insulin-like growth factor receptor (M6P/IGF-IIR) which are abundantly expressed in several human tumors. We developed a drug carrier against M6P/IGF-II receptor by modifying human serum albumin (HSA) with M6P moieties. M6P-HSA specifically bound and internalized into M6P/IGF-IIR-expressing B16 melanoma cells as demonstrated with radioactive studies and anti-HSA immunostaining. In vivo, M6P-HSA rapidly accumulated in subcutaneous tumors in tumor and stromal components after an intravenous injection. To demonstrate the application of M6P-HSA as a drug carrier, we coupled doxorubicin to it. Dox-HSA-M6P conjugate could release doxorubicin at lysosomal pH and showed M6P-specific binding and uptake in tumor cells. In vitro, a short exposure with Dox-HSA-M6P induced killing of tumor cells, which could be blocked by excess M6P-HSA. In vivo, Dox-HSA-M6P distributed to tumors and some other organs while free doxorubicin distributed to all organs but slightly to tumors. In B16 tumor-bearing mice, Dox-HSA-M6P significantly inhibited the tumor growth whereas an equimolar dose of free doxorubicin did not show any anti-tumor effect. In addition, targeted doxorubicin did not show any side-effects on liver and kidney function tests, body weight and blood cell counts. In conclusion, M6P-HSA is a suitable carrier for delivery of anticancer drugs to tumors through M6P/IGF-IIR. Improved antitumor effects of the targeted doxorubicin by M6P-HSA suggest that this novel approach may be applied to improve the therapeutic efficacy of anticancer drugs.
Subject(s)
Antineoplastic Agents/administration & dosage , Doxorubicin/administration & dosage , Mannosephosphates/administration & dosage , Neoplasms, Experimental/drug therapy , Receptor, IGF Type 2/metabolism , Serum Albumin/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Blotting, Western , Cell Line, Tumor , Doxorubicin/pharmacokinetics , Drug Carriers/pharmacology , Drug Delivery Systems , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Mannosephosphates/pharmacokinetics , Mice , Serum Albumin/pharmacokineticsABSTRACT
BACKGROUND: Reticular basement membrane (RBM) thickening has been variably associated with asthma and chronic obstructive pulmonary disease (COPD). Even if RBM thickness is similar in both diseases, its composition might still differ. OBJECTIVE: To assess whether RBM thickness and composition differ between asthma and COPD. METHODS: We investigated 24 allergic asthmatics (forced expiratory volume in one second [FEV(1)] 92% predicted), and 17 nonallergic COPD patients (FEV(1) 60% predicted), and for each group a control group of similar age and smoking habits (12 and 10 persons, respectively). Snap-frozen sections of bronchial biopsies were stained with hematoxylin/eosin and for collagen I, III, IV, V, laminin and tenascin. RBM thickening was assessed by digital image analysis. Relative staining intensity of each matrix component was determined. RESULTS: Mean (SD) RBM thickness was not significantly different between asthma and COPD 5.5 (1.3) vs 6.0 (1.8) microm, but significantly larger than in their healthy counterparts, ie, 4.7 (0.9) and 4.8 (1.2) microm, respectively. Collagen I and laminin stained significantly stronger in asthma than in COPD. Tenascin stained stronger in asthma than in healthy controls of similar age, and stronger in COPD controls than in asthma controls (p < 0.05). CONCLUSION: RBM thickening occurs both in asthma and COPD. We provide supportive evidence that its composition differs in asthma and COPD.
