Login Register Cart 0
Generic placeholder image

Current Drug Delivery

Editor-in-Chief

ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Gemcitabine-loaded Folic Acid Tagged Liposomes: Improved Pharmacokinetic and Biodistribution Profile

Author(s): Sambamoorthy Unnam*, Venkataraju Makam Panduragaiah, Manjappa Arehalli Sidramappa and Bhanoji Rao Muddana Eswara*

Volume 16, Issue 2, 2019

Page: [111 - 122] Pages: 12

DOI: 10.2174/1567201815666181024112252

Price: $65

Abstract

Background: Gemcitabine (GEM) is found effective in the treatment of many solid tumors. However, its use is restricted due to its small circulation half-life, fast metabolism and low capacity for selective tumor uptake. Folate receptors (FRs) have been recognized as cellular surface markers, which can be used for cancer targeting. PEGylated liposomes decorated with folic acid have been investigated for several anticancer agents not only to extend plasma half-life but also for tumor targeting via folic acid receptors which overexpressed on tumor cell surface.

Objective: Therefore, the objective of the present study was to prepare GEM-loaded folic acid tagged liposomes to improve the pharmacokinetics and tumor distribution of GEM.

Methods: The blank folate-targeted liposomes composed of HSPC/DSPE-mPEG2000/DSPE-mPEG-Folic acid were prepared first by thin film hydration technique. GEM was then loaded into liposomes by remote loading technique. The optimized liposomal formulations were evaluated in vitro for GEM release using dialysis technique, HeLa cell uptake using FACS technique, and cytotoxicity using MTT dye reduction assay. The comparative in vivo pharmacokinetic and biodistribution characteristics of radiolabeled (99mTc-labeled) plain GEM solution, and all liposomal formulations (conventional:CLs; stealth: SLs; folate targeted: FTLs) were evaluated in mice model.

Results: GEM-loaded FTLs showed sustained release profile, efficient uptake by HeLa cells and greater cytotoxicity. Further, FTLs displayed significantly improved pharmacokinetics, and biodistribution profile of loaded GEM.

Conclusion: In conclusion, the developed GEM-loaded folic acid receptor-targeted liposomal formulation could be a promising and potential alternative formulation for further development.

Keywords: Gemcitabine (GEM), liposomes, folic acid, folate receptor, drug delivery, cancer.

Next »
Graphical Abstract

[1]
Federico, C.; Morittu, V.M.; Britti, D.; Trapasso, E.; Cosco, D. Gemcitabine-loaded liposomes: Rationale, potentialities and future perspectives. Int. J. Nanomedicine, 2012, 7, 5423-5436.
[2]
Manjappa, A.S.; Goel, P.N.; Gude, R.P.; Murthy, R.S.R. Anti-neuropilin 1 antibody Fab′ fragment conjugated liposomal docetaxel for active targeting of tumours. J. Drug Target., 2014, 22(8), 698-711.
[3]
Manjappa, A.S.; Goel, P.N.; Vekataraju, M.P.; Rajesh, K.S.; Makwana, K.; Ukawala, M.; Nikam, Y.; Gude, R.P.; Murthy, R.S.R. Is an alternative drug delivery system needed for docetaxel? The role of controlling epimerization in formulations and beyond. Pharm. Res., 2013, 30(10), 2675-2693.
[4]
Urey, C.; Hilmersson, K.S.; Andersson, B.; Ansari, D.; Andersson, R. Development and in-vitro characterization of a gemcitabine-loaded MUC4-targeted immunoliposome against pancreatic ductal adenocarcinoma. Anticancer Res., 2017, 37(11), 6031-6039.
[5]
Ringhieri, P.; Mannucci, S.; Conti, G.; Nicolato, E.; Fracasso, G.; Marzola, P.; Morelli, G.; Accardo, A. Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells. Int. J. Nanomedicine, 2017, 12, 501-514.
[6]
Manjappa, A.S.; Chaudhari, K.R.; Venkataraju, M.P.; Dantuluri, P.; Nanda, B.; Sidda, C.; Sawant, K.K.; Murthy, R.S.R. Antibody derivatization and conjugation strategies: Application in preparation of stealth immunoliposome to target chemotherapeutics to tumor. J. Control. Release, 2011, 150(1), 2-22.
[7]
Elnakat, H.; Ratnam, M. Role of folate receptor genes in reproduction and related cancers. Front. Biosci., 2006, 11, 506-519.
[8]
Hilgenbrink, A.R.; Low, P.S. Folate receptor-mediated drug targeting: From therapeutics to diagnostics. J. Pharm. Sci., 2005, 94, 2135-2146.
[9]
Kim, S.H.; Jeong, J.H.; Mok, H.; Lee, S.H.; Kim, S.W.; Park, T.G. Folate receptor targeted delivery of polyelectrolyte complex micelles prepared from ODN-PEG-folate conjugate and cationic lipids. Biotechnol. Prog., 2007, 23, 232-237.
[10]
Qiu, L.; Dong, C.; Kan, X. Lymphoma-targeted treatment using a folic acid-decorated vincristine-loaded drug delivery system. Drug Des. Devel. Ther., 2018, 12, 863-872.
[11]
Zhang, S.; Liu, Y.; Gan, Y.; Qiu, N.; Gu, Y.; Zhu, H. Conjugates of TAT and folate with DOX-loaded chitosan micelles offer effective intracellular delivery ability. Pharm. Dev. Technol., 2018, 24, 1-23.
[12]
Moghimipour, E.; Rezaei, M.; Ramezani, Z.; Kouchak, M.; Amini, M.; Angali, K.A.; Dorkoosh, F.A.; Handali, S. Folic acid-modified liposomal drug delivery strategy for tumor targeting of 5-fluorouracil. Eur. J. Pharm. Sci., 2018, 114, 166-174.
[13]
Jain, A.; Jain, S.K. Advances in tumor targeted liposomes. Curr. Mol. Med., 2018, 18(1), 44-57.
[14]
Gazzano, E.; Rolando, B.; Chegaev, K.; Salaroglio, I.C.; Kopecka, J.; Pedrini, I.; Saponara, S.; Sorge, M.; Buondonno, I.; Stella, B.; Marengo, A.; Valoti, M.; Brancaccio, M.; Fruttero, R.; Gasco, A.; Arpicco, S.; Riganti, C. Folate-targeted liposomal nitrooxy-doxorubicin: An effective tool against P-glycoprotein-positive and folate receptor-positive tumors. J. Control. Release, 2018, 270, 37-52.
[15]
Kabilova, T.O.; Shmendel, E.V.; Gladkikh, D.V.; Chernolovskaya, E.L.; Markov, O.V.; Morozova, N.G.; Maslov, M.A.; Zenkova, M.A. Targeted delivery of nucleic acids into xenograft tumors mediated by novel folate-equipped liposomes. Eur. J. Pharm. Biopharm., 2018, 123, 59-70.
[16]
Goren, D.; Horowitz, A.T.; Tzemach, D.; Tarshish, M.; Zalipsky, S.; Gabizon, A. Nuclear delivery of doxorubicin via folate-targeted liposomes with bypass of multidrug-resistance efflux pump. Clin. Cancer Res., 2000, 6, 1949-1957.
[17]
Mamot, C.; Drummond, D.C.; Hong, K.; Kirpotin, D.B.; Park, J.W. Liposome-based approaches to overcome anticancer drug resistance. Drug Resist. Updat., 2003, 6, 271-279.
[18]
Gemcitabine. USP DI. Volume 1. Drug information for the health care professional. Update monographs. Englewood, Colorado: Micromedex, Inc.; 18th October 1999.
[19]
Hertel, L.W.; Boder, G.B.; Kroin, J.S.; Rinzel, S.M.; Poore, G.A.; Todd, G.C.; Grindey, G.B. Evaluation of the antitumor activity of gemcitabine (2′, 2′-difluoro-2′-deoxycytidine). Cancer Res., 1990, 50(14), 4417-4422.
[20]
Haran, G.; Cohen, R.; Bar, L.K.; Barenholz, Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim. Biophys. Acta, 1993, 1151, 201-215.
[21]
Pan, X.G.; Zheng, X.; Shi, G.F.; Wang, H.Q.; Ratnam, M.; Lee, R.J. Strategy for the treatment of acute myelogenous leukemia based on folate receptor-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid. Blood, 2002, 100, 594-602.
[22]
Klibanov, A.L.; Maruyama, K.; Toechilin, V.P.; Huang, L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett., 1990, 268, 235-237.
[23]
Allen, T.M. Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends Pharma. Sci., 1994, 15, 215-220.
[24]
Manjappa, A.S.; Kumbhar, P.S.; Khopade, P.S.; Patil, A.B.; Disouza, J.I. Mixed micelles as nano polymer therapeutics of docetaxel: Increased in vitro cytotoxicity and decreased in vivo toxicity. Curr. Drug Deliv., 2018, 15(4), 564-575.
[25]
Richardson, V.J.; Jeyasingh, K.; Jewkes, R.F.; Ryman, B.E.; Tattersall, M.H. Properties of [99mTc] technetium-labeled liposomes in normal and tumour-bearing rats. Biochem. Soc. Trans., 1977, 5(1), 290-291.
[26]
Arulsudar, N.; Subramanian, N.; Mishra, P.; Chuttani, K.; Sharma, R.K.; Murthy, R.S.R. Preparation, characterization, and biodistribution study of technetium 99m labelled leuprolide acetate-loaded liposomes in ehrlich ascites tumor-bearing mice. AAPS PharmSci, 2004, 6(1), E5.
[27]
Snehalatha, M.; Venugopal, K.; Saha, R.N.; Babbar, A.K.; Sharma, R.K. Etoposide loaded PLGA and PCL nanoparticles II: Biodistribution and pharmacokinetics after radiolabelling with Tc-99m. Drug Deliv., 2008, 15(5), 277-287.
[28]
Reddy, L.H.; Sharma, R.K.; Chuttani, K.; Mishra, A.K.; Murthy, R.S.R. Etoposide incorporated tripalmitin nanoparticles with different surface charge: Formation, characterization, radiolabeling and biodistribution studies. AAPS J., 2004, 6(3), e23.
[29]
Patel, A.; Tyagi, A.; Sharma, R.K.; Thakkar, H. A gamma scintigraphy study to investigate uterine targeting efficiency of raloxifene-loaded liposomes administered intravaginally in New Zealand white female rabbits. Drug Deliv., 2016, 23(9), 3330-3338.
[30]
Pace, E.; Melis, M.; Siena, L.; Bucchieri, F.; Vignola, A.M.; Profita, M.; Gjomarkaj, M.; Bonsignore, G. Effects of gemcitabine on cell proliferation and apoptosis in non-small-cell-lung cancer (NSCLC) cell lines. Cancer Chemother. Pharmacol., 2000, 46, 467-476.
[31]
Hui, Y.; Reitz, J. Gemcitabine: A cytidine analog active against solid tumors. Am. J. Health Syst. Pharm., 1997, 54, 162-170.
[32]
Immordino, M.L.; Dosio, F.; Cattel, L. Stealth liposomes: Review of the basic science, rationale, and clinical applications, existing and potential. Int. J. Nanomedicine, 2006, 1(3), 297-315.
[33]
Affram, K.; Udofot, O.; Singh, M.; Krishnan, S.; Reams, R.; Rosenberg, J.; Agyare, E. Smart thermosensitive liposomes for effective solid tumor therapy and in vivo imaging. PLoS One, 2017, 12(9), e0185116.
[34]
Minh Le, V.; Nho, T.D.T.; Ly, H.T.; Sang Vo, T.; Nguyen, H.D.; Phung, T.T.H.; Zou, A.; Liu, J. Enhanced anticancer efficacy and tumor targeting through folate-PEG modified nanoliposome loaded with 5-fluorouracil. Adv. Nat. Sci.: Nanosci. Nanotechnol., 2017, 8 015008 (7pp)
[35]
Lohade, A.A.; Jain, R.R.; Iyer, K.; Roy, S.K.; Shimpi, H.H.; Pawar, Y.; Rajan, M.G.; Menon, M.D. A novel folate-targeted nanoliposomal system of doxorubicin for cancer targeting. AAPS PharmSciTech, 2016, 17(6), 1298-1311.
[36]
Xu, H.; Paxton, J.; Lim, J.; Li, Y.; Zhang, W.; Duxfield, L.; Wu, Z. Development of high-content gemcitabine PEGylated liposomes and their cytotoxicity on drug-resistant pancreatic tumour cells. Pharm. Res., 2014, 31(10), 2583-2592.
[37]
Sriraman, S.K.; Pan, J.; Sarisozen, C.; Luther, E.; Torchilin, V. Enhanced cytotoxicity of folic acid-targeted liposomes co-loaded with C6 ceramide and doxorubicin: In vitro evaluation on HeLa, A2780-ADR and H69-AR Cells. Mol. Pharm., 2016, 13(2), 428-437.
[38]
Majumdar, D.; Saha, C.N.; Bhattacharya, S. 99mTechnetium radiolebeling and biodistribution studies of some peptide based ligands. World J. Med. Sci, 2011, 6, 105-110.
[39]
Moustapha, M.E.; Shweeta, H.A.; Motaleb, M.A. Technetium-labeled danofloxacin complex as a model for infection imaging. Arab. J. Chem., 2016, 9(2), S1928-S1934.
[40]
Paolino, D.; Cosco, D.; Racanicchi, L.; Trapasso, E.; Celia, C.; Iannone, M.; Puxeddu, E.; Costante, G.; Filetti, S.; Russo, D.; Fresta, M. Gemcitabine-loaded PEGylated unilamellar liposomes vs GEMZAR®: Biodistribution, pharmacokinetic features and in vivo antitumor activity. J. Control. Release, 2010, 144(2), 144-150.
[41]
Storniolo, A.M.; Allerheiligen, S.R.B.; Pearce, H.L. Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin. Oncol., 1997, 24(2 suppl 7), S7-2-S7-7.
[42]
Reddy, L.H.; Couvreur, P. Novel approaches to deliver gemcitabine to cancers. Curr. Pharm. Des., 2008, 14, 1124-1137.
[43]
Pawar, H.; Surapaneni, S.K.; Tikoo, K.; Singh, C.; Burman, R.; Gill, M.S.; Suresh, S. Folic acid functionalized long-circulating co-encapsulated docetaxel and curcumin solid lipid nanoparticles: In vitro evaluation, pharmacokinetic and biodistribution in rats. Drug Deliv., 2016, 23(4), 1453-1468.
[44]
Li, X.; Wang, D.; Zhang, J.; Pan, W. Preparation and pharmacokinetics of docetaxel based on nanostructured lipid carriers. J. Pharm. Pharmacol., 2009, 61, 1485-1492.
[45]
Gaber, M.; Medhat, W.; Hany, M.; Saher, N.; Fang, J.Y.; Elzoghby, A. Protein-lipid nanohybrids as emerging platforms for drug and gene delivery: Challenges and outcomes. J. Control. Release, 2017, 254, 75-91.

Rights & Permissions Print Cite
Article Metrics
93
8
1
© 2024 Bentham Science Publishers | Privacy Policy