Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Formulation, Optimization and In vitro / In vivo Characterization of Spray Dried Doxorubicin Loaded Folic Acid Conjugated Gelatin Nanoparticles

Author(s): Harjit Singh, Bharat Khurana, Daisy Arora and Sukhbir Kaur*

Volume 14, Issue 3, 2021

Published on: 05 May, 2020

Page: [367 - 380] Pages: 14

DOI: 10.2174/1874467213666200505095143

Price: $65

Abstract

Aim: Formulation, optimization and anticancer activity of spray-dried Doxorubicin loaded folic acid conjugated Gelatin nanoparticles (DOX-FA-GN).

Methods: Doxorubicin loaded gelatin nanoparticles (DOX-GN) were prepared by the Coacervation phase separation method, optimized using DoE and then conjugated with folic acid by covalent coupling to formulate Doxorubicin loaded folic acid conjugated nanoparticles (DOX-FA-GN). The formulated nanoparticles were characterized to evaluate its physicochemical properties. Cellular uptake and cell viability studies were carried out using MTT assay and biodistribution studies were carried out in Wistar rats.

Results: Particle size, PDI and entrapment efficiency for optimized DOX-GN were found to be 152.3 ± 9.3 nm 0.294 ± 0.1 and 86.9± 3.4% while for DOX-FA-GN, 193.9 ± 12.3 nm 0.247 ± 0.2 and 84 ± 3.6%. The cytotoxic studies showed a cell viability of 75.1% for DOX-GN and 29.5% DOX-FA-GN. Biodistribution studies were found to be statistically insignificant for conjugated nanoparticles with excellent flow properties. Significantly higher DOX distribution in the lungs was observed in the case of DOX-FA-GN.

Conclusion: There was a higher uptake of DOX on HeLa cells with DOX-FA-GN compared to DOX-GN. Also, the biodistribution of Dox in the lungs of Wistar rats was higher in conjugated nanoparticles as compared to unconjugated nanoparticles.

Keywords: Doxorubicin, spray-dried, MTT assay, cellular uptake studies, doxorubicin-folic acid gelatin nanoparticles, targeted delivery, HPLC.

Graphical Abstract

[1]
Soylar, P.; Özer, A.; Doğan Yüksekol, Ö.; Ulucan, M. Knowledge, attitude, and practice regarding cancer screening tests among health workers in a university hospital in Turkey. J. Cancer Educ., 2019, 1-6.
[http://dx.doi.org/10.1007/s13187-019-01517-2] [PMID: 30937881]
[2]
Gridelli, C.; Rossi, A.; Carbone, D.P.; Guarize, J.; Karachaliou, N.; Mok, T.; Petrella, F.; Spaggiari, L.; Rosell, R. Non-small-cell lung cancer. Nat. Rev. Dis. Primers, 2015, 1(1), 15009.
[http://dx.doi.org/10.1038/nrdp.2015.9] [PMID: 27188576]
[3]
Karachaliou, N.; Pilotto, S.; Lazzari, C.; Bria, E.; de Marinis, F.; Rosell, R. Cellular and molecular biology of small cell lung cancer: An overview. Transl. Lung Cancer Res., 2016, 5(1), 2-15.
[PMID: 26958489]
[4]
Pleasance, E.D.; Stephens, P.J.; O’Meara, S.; McBride, D.J.; Meynert, A.; Jones, D.; Lin, M.L.; Beare, D.; Lau, K.W.; Greenman, C.; Varela, I.; Nik-Zainal, S.; Davies, H.R.; Ordoñez, G.R.; Mudie, L.J.; Latimer, C.; Edkins, S.; Stebbings, L.; Chen, L.; Jia, M.; Leroy, C.; Marshall, J.; Menzies, A.; Butler, A.; Teague, J.W.; Mangion, J.; Sun, Y.A.; McLaughlin, S.F.; Peckham, H.E.; Tsung, E.F.; Costa, G.L.; Lee, C.C.; Minna, J.D.; Gazdar, A.; Birney, E.; Rhodes, M.D.; McKernan, K.J.; Stratton, M.R.; Futreal, P.A.; Campbell, P.J. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature, 2010, 463(7278), 184-190.
[http://dx.doi.org/10.1038/nature08629] [PMID: 20016488]
[5]
Parsons, A.; Daley, A.; Begh, R.; Aveyard, P. Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ, 2010, 340, b5569.
[http://dx.doi.org/10.1136/bmj.b5569] [PMID: 20093278]
[6]
Kumar, N.; Salar, R.K.; Prasad, M.; Ranjan, K. Synthesis, characterization and anticancer activity of vincristine loaded folic acid-chitosan conjugated nanoparticles on NCI-H460 non-small cell lung cancer cell line. Egypt. J. Basic Appl. Sci, 2018, 5(1), 87-99.
[http://dx.doi.org/10.1016/j.ejbas.2017.11.002]
[7]
Kenfield, S.A.; Wei, E.K.; Stampfer, M.J.; Rosner, B.A.; Colditz, G.A. Comparison of aspects of smoking among the four histological types of lung cancer. Tob. Control, 2008, 17(3), 198-204.
[http://dx.doi.org/10.1136/tc.2007.022582] [PMID: 18390646]
[8]
Brambilla, E. Pugatch B, Geisinger K.; Gal A.; Sheppard MN.; Guinee DG. Large cell carcinoma. In: World Health Organization Classification of Tumours Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart; Travis, W.; Brambilla, E.; Müller-Hermelink, H., Eds.; WHO Press: Geneva, 2004; pp. 45-50.
[9]
Kumar, A.; Gautam, B.; Dubey, C.; Tripathi, P.K. A review: role of doxorubicin in treatment of cancer. Int. J. Pharm. Sci. Res., 2014, 5(10), 4105.
[10]
Sivarajakumar, R.; Mallukaraj, D.; Kadavakollu, M.; Neelakandan, N.; Chandran, S.; Bhojaraj, S.; Reddy Karri, V.V. Nanoparticles for the treatment of lung cancers. J. Young Pharm., 2018, 10(3)
[http://dx.doi.org/10.5530/jyp.2018.10.62]
[11]
Sahu, S.K.; Mallick, S.K.; Santra, S.; Maiti, T.K.; Ghosh, S.K.; Pramanik, P. In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery. J. Mater. Sci. Mater. Med., 2010, 21(5), 1587-1597.
[http://dx.doi.org/10.1007/s10856-010-3998-4] [PMID: 20111985]
[12]
Engin, K.; Leeper, D.B.; Cater, J.R.; Thistlethwaite, A.J.; Tupchong, L.; McFarlane, J.D. Extracellular pH distribution in human tumours. Int. J. Hyperthermia, 1995, 11(2), 211-216.
[http://dx.doi.org/10.3109/02656739509022457] [PMID: 7790735]
[13]
Kumar, M.N.; Muzzarelli, R.A.A.; Muzzarelli, C.; Sashiwa, H.; Domb, A.J. Chitosan chemistry and pharmaceutical perspectives. Chem. Rev., 2004, 104(12), 6017-6084.
[http://dx.doi.org/10.1021/cr030441b] [PMID: 15584695]
[14]
Bittleman, K.R.; Dong, S.; Roman, M.; Lee, Y.W. Folic acid-conjugated cellulose nanocrystals show high folate-receptor binding affinity and uptake by kb and breast cancer cells. ACS Omega, 2018, 3(10), 13952-13959.
[http://dx.doi.org/10.1021/acsomega.8b01619] [PMID: 30411055]
[15]
Dixit, N.; Vaibhav, K.; Pandey, R.S.; Jain, U.K.; Katare, O.P.; Katyal, A.; Madan, J. Improved cisplatin delivery in cervical cancer cells by utilizing folate-grafted non-aggregated gelatin nanoparticles. Biomed. Pharmacother., 2015, 69, 1-10.
[http://dx.doi.org/10.1016/j.biopha.2014.10.016] [PMID: 25661330]
[16]
Grenha, A.; Seijo, B.; Remuñán-López, C. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur. J. Pharm. Sci., 2005, 25(4-5), 427-437.
[http://dx.doi.org/10.1016/j.ejps.2005.04.009] [PMID: 15893461]
[17]
Karathanasis, E.; Ayyagari, A.L.; Bhavane, R.; Bellamkonda, R.V.; Annapragada, A.V. Preparation of in vivo cleavable agglomerated liposomes suitable for modulated pulmonary drug delivery. J. Control. Release, 2005, 103(1), 159-175.
[http://dx.doi.org/10.1016/j.jconrel.2004.11.009] [PMID: 15710508]
[18]
Lee, WH.; Loo, CY.; Traini, D.; Young, PM. Inhalation of nanoparticle-based drug for lung cancer treatment: advantages and challenges. Asian J. Pharm. Sci., 2015, 10(6), 481-489.
[19]
Zhu, Q.; Jia, L.; Gao, Z.; Wang, C.; Jiang, H.; Zhang, J.; Dong, L. A tumor environment responsive doxorubicin-loaded nanoparticle for targeted cancer therapy. Mol. Pharm., 2014, 11(10), 3269-3278.
[http://dx.doi.org/10.1021/mp4007776] [PMID: 24735448]
[20]
Salar, R.K.; Kumar, N. Synthesis and characterization of vincristine loaded folic acid–chitosan conjugated nanoparticles. Res. Eff. Technol., 2016, 2, 199-214.
[http://dx.doi.org/10.1016/j.reffit.2016.10.006]
[21]
Bourguignon, N.; Attallah, C.; Karp, P.; Booth, R.; Peñaherrera, A.; Payés, C.; Oggero, M.; Pérez, M.S.; Helguera, G.; Lerner, B. Production of monoclonal antibodies in microfluidic devices. Integr. Biol., 2018, 10(3), 136-144.
[http://dx.doi.org/10.1039/c7ib00200a] [PMID: 29488523]
[22]
Zhang, J.; Chen, X.G.; Peng, W.B.; Liu, C.S. Uptake of oleoyl-chitosan nanoparticles by A549 cells. Nanomedicine (Lond.), 2008, 4(3), 208-214.
[http://dx.doi.org/10.1016/j.nano.2008.03.006] [PMID: 18508414]
[23]
Rezazadeh, M.; Davatsaz, Z.; Emami, J.; Hasanzadeh, F.; Jahanian-Najafabadi, A. Preparation and characterization of spray-dried inhalable powders containing polymeric micelles for pulmonary delivery of paclitaxel in lung cancer. J. Pharm. Pharm. Sci., 2018, 21(1s), 200s-214s.
[http://dx.doi.org/10.18433/jpps30048] [PMID: 30321135]
[24]
Kaur, P.; Garg, T.; Rath, G.; Murthy, R.S.; Goyal, A.K. Development, optimization and evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of drug resistance lung cancer using Box-Behnken design. Drug Deliv., 2016, 23(6), 1912-1925.
[PMID: 25544602]
[25]
Sharma, N.; Madan, P.; Lin, S. Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: A co-surfactant study. Asian J. Pharm. Sci., 2016, 11(3), 404-416.
[26]
Madan, J.; Dhiman, N.; Sardana, S.; Aneja, R.; Chandra, R.; Katyal, A. Long-circulating poly(ethylene glycol)-grafted gelatin nanoparticles customized for intracellular delivery of noscapine: preparation, in-vitro characterization, structure elucidation, pharmacokinetics, and cytotoxicity analyses. Anticancer Drugs, 2011, 22(6), 543-555.
[http://dx.doi.org/10.1097/CAD.0b013e32834159b8] [PMID: 21471809]
[27]
Shen, Z.; Li, Y.; Kohama, K.; Oneill, B.; Bi, J. Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres. Pharmacol. Res., 2011, 63(1), 51-58.
[http://dx.doi.org/10.1016/j.phrs.2010.10.012] [PMID: 21035550]
[28]
Ghaffari, S.B.; Sarrafzadeh, M.H.; Fakhroueian, Z.; Khorramizadeh, M.R. Flower-like curcumin-loaded folic acid-conjugated ZnO-MPA-βcyclodextrin nanostructures enhanced anticancer activity and cellular uptake of curcumin in breast cancer cells. Mater. Sci. Eng., 2019, C109827
[http://dx.doi.org/10.1016/j.msec.2019.109827]
[29]
Jain, S.; Mathur, R.; Das, M.; Swarnakar, N.K.; Mishra, A.K. Synthesis, pharmacoscintigraphic evaluation and antitumor efficacy of methotrexate-loaded, folate-conjugated, stealth albumin nanoparticles. Nanomedicine (Lond.), 2011, 6(10), 1733-1754.
[http://dx.doi.org/10.2217/nnm.11.53] [PMID: 22087800]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy