title: Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice.
abstract: Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h, and proved significantly effective (p < 0.001) in reducing LC50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance.
authors: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Faculty of Health, C-MMR, Deakin University, Geelong, Victoria 3216, Australia.
authors: Jayanth Suryanarayanan
authors: JS
authors: Shankaranarayanan
authors: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Faculty of Health, C-MMR, Deakin University, Geelong, Victoria 3216, Australia.
authors: Jagat R
authors: JR
authors: Kanwar
authors: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Faculty of Health, C-MMR, Deakin University, Geelong, Victoria 3216, Australia.
authors: Afrah Jalil Abd
authors: AJ
authors: Al-Juhaishi
authors: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Faculty of Health, C-MMR, Deakin University, Geelong, Victoria 3216, Australia.
authors: Rupinder K
authors: RK
authors: Kanwar
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D054414:Chemokine CCL17 / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D007371:Interferon-gamma / Q000097:blood; D007501:Iron / Q000493:pharmacokinetics; D007781:Lactoferrin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018874:Spheroids, Cellular / Q000187:drug effects; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D054407:Chemokine CCL4; D004337:Drug Carriers; D009363:Neoplasm Proteins; D059005:Topoisomerase II Inhibitors; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D007371:Interferon-gamma; D007501:Iron; D007781:Lactoferrin