CARMUSTINE LOADED LACTOFERRIN NANOPARTICLES DEMONSTRATES AN ENHANCED ANTIPROLIFERATIVE ACTIVITY AGAINST GLIOBLASTOMA IN VITRO
DOI:
https://doi.org/10.22159/ijap.2018v10i6.28004Keywords:
Lactoferrin nanoparticles, Carmustine, Glioblastoma, Drug delivery vehicleAbstract
Objective: Despite sophisticated treatment regimens, there is no significant improvement in the mortality rates of glioblastoma due to insufficient dosage delivery, reoccurrence of tumors, higher systemic toxicity, etc. Since brain endothelial cells and glioblastoma cells express lactoferrin receptors, a target-specific drug delivery vehicle was developed using lactoferrin itself as a matrix, into which carmustine was loaded. The objective was to use carmustine loaded lactoferrin nanoparticles (CLN) to achieve higher therapeutic efficacy and target specificity compared to free carmustine.
Methods: CLN were prepared using the Sol-oil method. The nanoparticles prepared were characterized for their size, shape, polydispersity, and stability using FESEM and DLS methods. Drug loading and drug releasing efficiencies were also estimated. Further, cellular uptake of nanoparticles and their antiproliferative efficacy against glioblastoma cells were evaluated.
Results: Characterization of CLN showed that they were spherical with ≤ 41 nm diameter and exhibited homogeneously dispersed stable distribution. Loading efficiency of carmustine in CLN was estimated to be 43±3.7 %. Drug release from the nanoparticles was pH dependent with the maximum observed at pH 5. At physiological and gastric pH, drug release was lower, whereas maximum release was observed at endocytotic vesicular and around tumor extracellular pH. Confocal microscopic studies showed an active cellular uptake of nanoparticles. Results of antiproliferative analysis substantiated a higher antiproliferative effect for CLN compared to free carmustine.
Conclusion: The results of the study demonstrated that CLN serves as a vital tool, in designing an effective treatment strategy for targeted drug delivery to glioblastoma.
Downloads
References
Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the united states in 2010-2014. Neurol Oncol 2017;19 Suppl 5:1-88.
Johnson KJC, Cullen J, Barnholtz Sloan JS, Ostrom QT, Langer CE, Turner MC, et al. Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomarkers Prev 2014;23:2716-36.
Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a state of the science review. Neurol Oncol 2014;16:896-913.
Wiemels J, Wrensch M, Claus EB. Epidemiology and etiology of meningioma. J Neurooncol 2010;99:307-14.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97–109.
Quirk BJ, Brandal G, Donlon S, Vera JC, Mang TS, Foy AB, et al. Photodynamic therapy (PDT) for malignant brain tumors–where do we stand? Photodiagnosis Photodyn Ther 2015;12:530-44.
Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA 2013;310:1842-50.
Demuth T, Berens ME. Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 2004;70:217-28.
Stupp R, Mason WP, Van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (gliadel wafers) in patients with primary malignant glioma. Neurol Oncol 2003;5:79-88.
Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995;345:1008-12.
Patel MA, Kim JE, Ruzevick J, Li G, Lim M. The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers 2014;6:1953-85.
Woodworth GF, Dunn GP, Nance EA, Hanes J, Brem H. Emerging insights into barriers to effective brain tumor therapeutics. Front Oncol 2014;4:1-14.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-60.
Beier D, Schulz JB, Beier CP. Chemoresistance of glioblastoma cancer stem cells-much more complex than expected. Mol Cancer 2011;10:1-11.
Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, et al. Mechanisms of chemoresistance in malignant glioma. Clin Cancer Res 2008;14:2900-8.
Zhang J, Stevens MF, Laughton CA, Madhusudan S, Bradshaw TD. Acquired resistance to temozolomide in glioma cell lines: molecular mechanisms and potential translational applications. Oncology 2010;78:103-14.
Blakeley J, Grossman SA. Chemotherapy with cytotoxic and cytostatic agents in brain cancer. In: Aminoff MJ, Boller F, Swaab DF. editors. Handbook of Clinical Neurology. Elsevier; 2012. p. 229-54.
Lin SH, Kleinberg LR. Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. Expert Rev Anticancer Ther 2008;8:343-59.
Chamberlain MC. Temozolomide: therapeutic limitations in the treatment of adult high-grade gliomas. Expert Rev Neurother 2010;10:1537-44.
Krupa P, Rehak S, Diaz Garcia D, Filip S. Nanotechnology-new trends in the treatment of brain tumors. Acta Med 2014;57:142-50.
Invernici G, Cristini S, Alessandri G, Navone SE, Canzi L, Tavian D, et al. Nanotechnology advances in brain tumors: the state of the art. Recent Pat Anticancer Drug Discovery 2011;6:58-69.
Rempe R, Cramer S, Qiao R, Galla HJ. Strategies to overcome the barrier: use of nanoparticles as carriers and modulators of barrier properties. Cell Tissue Res 2014;355:717-26.
Chang J, Paillard A, Passirani C, Morille M, Benoit JP, Betbeder D, et al. Transferrin adsorption onto PLGA nanoparticles governs their interaction with biological systems from blood circulation to brain cancer cells. Pharm Res 2012;29:1495-505.
Nuijens JH, Van Berkel PHC, Schanbacher FL. Structure and biological actions of lactoferrin. J Mammary Gland Biol Neoplasia 1996;1:285-95.
Ward PP, Paz E, Conneely OM. Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 2005;62:2540-8.
Moreno-Exposito L, Illescas-Montes R, Melguizo-Rodriguez L, Ruiz C, Ramos-Torrecillas J, de Luna-Bertos E. Multifunctional capacity and therapeutic potential of lactoferrin. Life Sci 2018;195:61-4.
Jayasinghe S, Siriwardhana A, Karunaratne V. Natural iron sequestering agents: their roles in nature and therapeutic potential. Int J Pharm Pharm Sci 2015;7:8-12.
Huang RQ, Ke WL, Qu YH, Zhu JH, Pei YY, Jiang C. Characterization of lactoferrin receptor in brain endothelial capillary cells and mouse brain. J Biomed Sci 2007;14:121-8.
Ji B, Maeda J, Higuchi M, Inoue K, Akita H, Harashima H, et al. Pharmacokinetics and brain uptake of lactoferrin in rats. Life Sci 2006;78:851-5.
Fillebeen C, Descamps L, Dehouck M, Fenart L, Benaıssa M, Spik G, et al. Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem 1999;274:7011–7.
Qiao R, Jia Q, Huwel S, Xia R, Liu T, Gao F, et al. Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier. ACS Nanol 2012;6:3304-10.
Fang JH, Lai YH, Chiu TL, Chen YY, Hu SH, Chen SY. Magnetic core-shell nanocapsules with dual-targeting capabilities and co-delivery of multiple drugs to treat brain gliomas. Adv Healthc Mater 2014;3:1250-60.
Talukder MJ, Takeuchi T, Harada E. Characteristics of lactoferrin receptor in bovine intestine: higher binding activity to the epithelium overlying Peyer's patches. J Vet Med A Physiol Pathol Clin Med 2003;50:123-31.
Sanchez L, Calvo M, Brock JH. Biological role of lactoferrin. Arch Dis Child 1992;67:657-61.
Krishna AD, Mandraju RK, Kishore G, Kondapi AK. An efficient targeted drug delivery through apotransferrin loaded nanoparticles. PLoS One 2009;4:e7240.
Lakshmi YS, Kumar P, Kishore G, Bhaskar C, Kondapi AK. Triple combination MPT vaginal microbicide using curcumin and efavirenz loaded lactoferrin nanoparticles. Sci Rep 2016;6:25479.
Kumari S, Kondapi AK. Lactoferrin nanoparticle mediated targeted delivery of 5-fluorouracil for enhanced therapeutic efficacy. Int J Biol Macromol 2017;95:232-7.
Ahmed F, Ali MJ, Kondapi AK. Carboplatin loaded protein nanoparticles exhibit improve anti-proliferative activity in retinoblastoma cells. Int J Biol Macromol 2014;70:572-82.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55-63.
Wike Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984;2:343-66.
Weiss RB, Issell BF. The nitrosoureas: carmustine (BCNU) and lomustine (CCNU). Cancer Treat Rev 1982;9:313-30.
Chang CH, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, et al. Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. Cancer 1983;52:997-1007.
Selker RG, Shapiro WR, Burger P, Blackwood MS, Arena VC, Gilder JC, et al. The brain tumor cooperative group NIH trial 87-01:a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery 2002;51:343-57.
De Vita VT, Carbone PP, Owens AH, Gold GL, Krant MJ, Edmonson J. Clinical trials with 1, 3-bis(2-chloroethyl)-1-nitrosourea, NSC-409962. Cancer Res 1965;25:1876-81.
O'Driscoll BR, Kalra S, Gattamaneni HR, Woodcock AA. Late carmustine lung fibrosis. Age at treatment may influence severity and survival. Chest 1995;107:1355-7.
Bota DA, Desjardins A, Quinn JA, Affronti ML, Friedman HS. Interstitial chemotherapy with biodegradable BCNU (gliadel) wafers in the treatment of malignant gliomas. Ther Clin Risk Manag 2007;3:707-15.
Subach BR, Witham TF, Kondziolka D, Lunsford LD, Bozik M, Schiff D. Morbidity and survival after 1,3-bis(2-chloroethyl)-1-nitrosourea wafer implantation for recurrent glioblastoma: a retrospective case-matched cohort series. Neurosurgery 1999;45:17-22.
McGovern PC, Lautenbach E, Brennan PJ, Lustig RA, Fishman NO. Risk factors for postcraniotomy surgical site infection after 1,3-bis (2-chloroethyl)-1-nitrosourea (gliadel) wafer placement. Clin Infect Dis 2003;36:759-65.
Weber EL, Goebel EA. Cerebral edema associated with gliadel wafers: two case studies. Neurol Oncol 2005;7:84-9.
Engelhard HH. Tumor bed cyst formation after BCNU wafer implantation: report of two cases. Surg Neurol 2000;53:220-4.
Kleinberg LR, Weingart J, Burger P, Carson K, Grossman SA, Li K, et al. Clinical course and pathologic findings after gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management. Cancer Invest 2004;22:1-9.
Shome D, Poddar N, Sharma V, Sheorey U, Maru GB, Ingle A, et al. Does a nanomolecule of carboplatin injected periocularly help in attaining higher intravitreal concentrations? Invest Ophthalmol Vis Sci 2009;50:5896-900.
Olivi A, Grossman SA, Tatter S, Barker F, Judy K, Olsen J, et al. Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a new approaches to brain tumor therapy CNS consortium trial. J Clin Oncol 2003;21:1845-9.
Sharma A, Sharma US. Liposomes in drug delivery: progress and limitations. Int J Pharm 1997;154:123-40.
Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 2008;5:505-15.
Masserini M. Nanoparticles for brain drug delivery. ISRN Biochem 2013;2013:1-18.
Ferroni L, Gardin C, Puppa DA, Sivolella S, Brunello G, Scienza R, et al. Novel nanotechnologies for brain cancer therapeutics and imaging. J Biomed Nanotechnol 2015;11:1899-912.
Hemant K, Raizaday A, Sivadasu P, Uniyal S, Kumar SH. Cancer nanotechnology: nanoparticulate drug delivery for the treatment of cancer. Int J Pharm Pharm Sci 2015;7:40-6.
Sonavane G, Tomoda K, Makino K. Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. Colloids Surf B 2008;66:274-80.
Etame AB, Smith CA, Chan WC, Rutka JT. Design and potential application of PEGylated gold nanoparticles with size-dependent permeation through brain microvasculature. Nanomedicine 2011;7:992-1000.
Hanada S, Fujioka K, Inoue Y, Kanaya F, Manome Y, Yamamoto K. Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles brain permeability in association with particle size and surface modification. Int J Mol Sci 2014;15:1812-25.
Williams PM, Oatley-Radcliffe DL, Hilal N. Feed solution characterization. In: Hilal N, Ismail AF, Matsuura T, Oatley-Radcliffe D. editors. Membrane characterization. Elsevier; 2017. p. 379-404.
Uskokovic V. Dynamic light scattering based microelectrophoresis: main prospects and limitations. J Dispers Sci Technol 2012;33:1762-86.
Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004;4:891-9.
Webb BA, Chimenti M, Jacobson MP, Barber DL. Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer 2011;11:671-7.
Kitamura I, Kochi M, Matsumoto Y, Ueoka R, Kuratsu J, Ushio Y. Intrathecal chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea encapsulated into hybrid liposomes for meningeal gliomatosis: an experimental study. Cancer Res 1996;56:3986-92.
Chen PY, Liu HL, Hua MY, Yang HW, Huang CY, Chu PC, et al. Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment. Neurol Oncol 2010;12:1050-60.
Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J Controlled Release 2017;264:306-32.
Zhang F, Xu CL, Liu CM. Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma. Drug Des Dev Ther 2015;9:2089-100.
Bhujbal SV, de Vos P, Niclo SP. Drug and cell encapsulation: alternative delivery options for the treatment of malignant brain tumors. Adv Drug Delivery Rev 2014;67-68:142-53.
Published
How to Cite
Issue
Section
