Biodegradable Guar Gum Nanoparticles as Carrier for Tamoxifen Citrate in Treatment of Breast Cancer
Author(s)
Jayanta K. Sarmah1*,
Saibal Kanti Bhattacharjee2,
Samhita Roy3,
Ranadeep Mahanta4,
Rita Mahanta3
Affiliation(s)
1 School of Engineering and Technology, Kaziranga University, Jorhat, India. 2 Department of Chemistry, Gauhati University, Guwahati, India. 3 Department of Zoology, Cotton College, Guwahati, India. 4 Department of Biochemistry, Jorhat Medical College, Jorhat, India.
1 School of Engineering and Technology, Kaziranga University, Jorhat, India. 2 Department of Chemistry, Gauhati University, Guwahati, India. 3 Department of Zoology, Cotton College, Guwahati, India. 4 Department of Biochemistry, Jorhat Medical College, Jorhat, India.
ABSTRACT
We prepared, characterized and studied the biodistribution of tamoxifen citrate (TMX) loaded cross-linked guar gum (GG) nanoparticles (NPs). NPs were prepared via a single step emulsion process and particle size evaluated. The extent of tissue distribution and retention following oral administration of TMX loaded GG NPs and TMX tablet in female albino mice was analyzed over a period of 48 hours. Till 48 hours, the particles remained detectable in both mammary and ovary tissue (estrogen receptors). Uptake and retention of TMX from NPs and tablet in mammary gland and ovary tissue changed with time. Results showed that the uptake and retention of NPs was more in the mammary gland between 24 - 48 hours (11.2% at 24 h; 4.65% at 48 h). As mammary gland is the target organ in breast cancer therapy, it may be concluded that the cross-linked GG NPs are capable of releasing the drug at the target and minimize the uptake and retention in non target tissue, the ovary (7.98% at 24 h; 1.9% at 48 h). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with time were measured. No abnormal changes in the liver enzymes were observed. GG NPs under study can be used as a drug carrier system for treating cancer.
We prepared, characterized and studied the biodistribution of tamoxifen citrate (TMX) loaded cross-linked guar gum (GG) nanoparticles (NPs). NPs were prepared via a single step emulsion process and particle size evaluated. The extent of tissue distribution and retention following oral administration of TMX loaded GG NPs and TMX tablet in female albino mice was analyzed over a period of 48 hours. Till 48 hours, the particles remained detectable in both mammary and ovary tissue (estrogen receptors). Uptake and retention of TMX from NPs and tablet in mammary gland and ovary tissue changed with time. Results showed that the uptake and retention of NPs was more in the mammary gland between 24 - 48 hours (11.2% at 24 h; 4.65% at 48 h). As mammary gland is the target organ in breast cancer therapy, it may be concluded that the cross-linked GG NPs are capable of releasing the drug at the target and minimize the uptake and retention in non target tissue, the ovary (7.98% at 24 h; 1.9% at 48 h). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with time were measured. No abnormal changes in the liver enzymes were observed. GG NPs under study can be used as a drug carrier system for treating cancer.
Cite this paper
Sarmah, J. , Bhattacharjee, S. , Roy, S. , Mahanta, R. and Mahanta, R. (2014) Biodegradable Guar Gum Nanoparticles as Carrier for Tamoxifen Citrate in Treatment of Breast Cancer. Journal of Biomaterials and Nanobiotechnology, 5, 220-228. doi: 10.4236/jbnb.2014.54026.
Sarmah, J. , Bhattacharjee, S. , Roy, S. , Mahanta, R. and Mahanta, R. (2014) Biodegradable Guar Gum Nanoparticles as Carrier for Tamoxifen Citrate in Treatment of Breast Cancer. Journal of Biomaterials and Nanobiotechnology, 5, 220-228. doi: 10.4236/jbnb.2014.54026.
References
[1] www.who.int/topics/cancer/ [2] Rabinow, B.E. (2004) Nanosuspensions in Drug Delivery. Nature Reviews Drug Discovery, 39, 785-796.
http://dx.doi.org/10.1038/nrd1494 [3] Meibohm, B. and Derendorf, H. (2002) Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development. Journal of Pharmaceutical Sciences, 91, 18-31.
http://dx.doi.org/10.1002/jps.1167 [4] Scaglione, F. (2002) Can PK/PD Be Used in Everyday Clinical Practice. International Journal of Antimicrobial Agents, 19, 349-353.
http://dx.doi.org/10.1016/S0924-8579(02)00020-1 [5] Duncan, R., Coatsworth, J.K. and Burtles, S. (1998) Preclinical Toxicology of a Novel Polymeric Antitumour Agent: HPMA Copolymer-Doxorubicin (PK1). Human & Experimental Toxicology, 17, 93-104.
http://dx.doi.org/10.1191/096032798678908378 [6] Hopewel, J.W., Duncan, R., Wilding, D. and Chakrabarti, K. (2001) Preclinical Evaluation of the Cardiotoxicity of PK2: A Novel HPMA Copolymer-Doxorubicin-Galactosamine Conjugate Antitumour Agent. Human & Experimental Toxicology, 20, 461-470.
http://dx.doi.org/10.1191/096032701682693017 [7] Mahmood, I. (2001) Interspecies Scaling of Maximum Tolerated Dose of Anticancer Drugs: Relevance to Starting Dose for Phase I Clinical Trials. American Journal of Therapeutics, 8, 109-116.
http://dx.doi.org/10.1097/00045391-200103000-00005 [8] Howell, S.B. (2001) Clinical Applications of a Novel Sustained-Release Injectable Drug Delivery System: DepoFoam Technology. Cancer Journal, 7, 219-227. [9] Maeda, H. (2001) The Enhanced Permeability and Retention (EPR) Effect in Tumor Vasculature: The Key Role of Tumor-Selective Macromolecular Drug Targeting. Advances in Enzyme Regulation, 41, 189-207.
http://dx.doi.org/10.1016/S0065-2571(00)00013-3 [10] Park, J.W. (2002) Liposome Based Drug Delivery in Breast Cancer Treatment. Breast Cancer Research, 4, 95-99.
http://dx.doi.org/10.1186/bcr432 [11] Goldenberg, D.M. (2002) Targeted Therapy of Cancer with Radiolabeled Antibodies. Journal of Nuclear Medicine, 43, 693-713. [12] Schipper, N.G.M., Varum, K.M. and Artursson, P. (1996) Chitosan as Absorption Enhancers for Poorly Absorbable Drugs: Influence of Molecular Weight and Degree of Acetylation on Drug Transport across Human Intestinal Epithelia (Caco-29 Cells). Pharmaceutical Research, 13, 1686-1692.
http://dx.doi.org/10.1023/A:1016444808000 [13] Martin, E.A., Brown, K., Gaskell, M., Al-Azzawi, F., Garner, R.C., Boocock, D.J., Mattock, E., Pring, D.W., Dingley, K., Turteltaub, K.W., Smith, L.L. and White, I.N.H. (2003) Tamoxifen DNA Damage Detected in Human Endometrium Using Accelerator Mass Spectrometry. Cancer Research, 63, 8461-8465. [14] Lashley, M.R., Niedzinski, E.J., Rogers, J.M., Denison, M.S. and Nantz, M.H. (2002) Synthesis and Estrogen Receptor Affinity of a 4-Hydroxytamoxifen-Labeled Ligand for Diagnostic Imaging. Bioorganic & Medicinal Chemistry, 10, 4075-4082.
http://dx.doi.org/10.1016/S0968-0896(02)00329-2 [15] Marcsek, Z., Kocsis, Z., Jakab, M., Szende, B. and Tompa, A. (2004) The Efficacy of Tamoxifen in Estrogen Receptor-Positive Breast Cancer Cells Is Enhanced by a Medical Nutriment. Cancer Biotherapy & Radiopharmaceuticals, 19, 746-753.
http://dx.doi.org/10.1089/cbr.2004.19.746 [16] Heres-Pulido, E.M., Duenas-Garcia, I., Castaneda-Partida, L., Sanchez-Garcia, A., Contreras-Sousa, M., Duran-Dias, A. and Ulrich, G. (2004) Genotoxicity of Tamoxifen Citrate and 4-Nitroquinoline-1-Oxide in the Wing Spot Test Drosophila Melanogaster. Mutagenesis, 19, 187-193.
http://dx.doi.org/10.1093/mutage/geh020 [17] Chodak, G.W. and Kolvenbag, G.J.C.M. (2001) Will the Experience with Tamoxifen in Breast Cancer Help Define the Role of Antiandrogens in Prostate Cancer? Prostate Cancer and Prostatic Diseases, 4, 72-80.
http://dx.doi.org/10.1038/sj.pcan.4500518 [18] Krishnaiah, Y.S.R., Karthikeyan, R.S. and Satyanarayana, V. (2002) A Three-Layer Guar Gum Matrix Tablet for Oral Controlled Delivery of Highly Soluble Metoprolol Tartrate. International Journal of Pharmaceutics, 241, 353-366.
http://dx.doi.org/10.1016/S0378-5173(02)00273-9 [19] Toti, U.S. and Aminabhavi, T.M. (2004) Modified Guar Gum Matrix Tablet for Controlled Release of Diltiazem Hydrochloride. Journal of Controlled Release, 95, 567-577.
http://dx.doi.org/10.1016/j.jconrel.2003.12.019 [20] Soppirnath, K.S. and Aminabhavi, T.M. (2002) Water Transport and Drug Release Study from Cross-Linked Polyacrylamide Grafted Guar Gum Hydrogel Microspheres for the Controlled Release Application. European Journal of Pharmaceutics and Biopharmaceutics, 53, 87-98.
http://dx.doi.org/10.1016/S0939-6411(01)00205-3 [21] Wassel, G.M., Omar, S.M. and Ammar, N.M. (1989) Application of Guar Flour and Prepared Guaran in Tablet Manufacture. Journal of Drug Research, 18, 1-8. [22] Sarmah, J.K., Mahanta, R., Bhattacharjee, S.K., Mahanta, R. and Biswas, A. (2011) Controlled Release of Tamoxifen Citrate Encapsulated in Cross-Linked Guar Gum Nanoparticles. International Journal of Biological Macromolecules, 49, 390-396.
http://dx.doi.org/10.1016/j.ijbiomac.2011.05.020 [23] Sarmah, J.K., Bhattacharjee, S.K., Mahanta, R. and Mahanta, R. (2009) Preparation of Cross-Linked Guar Gum Nanospheres Containing Tamoxifen Citrate by Single Step Emulsion in Situ Polymer Cross-Linking Method. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 65, 329-334. [24] Gliko-Kabir, I., Yagen, B., Penhasi, A. and Rubinstein, A. (2000) Phosphated Crosslinked Guar for Colon-Specific Drug Delivery: I. Preparation and Physicochemical Characterization. Journal of Controlled Release, 63, 121-127.
http://dx.doi.org/10.1016/S0168-3659(99)00179-0 [25] Gliko-Kabir, I., Yagen, B., Penhasi, A. and Rubinstein, A. (1998) Low Swelling, Crosslinked Guar and Its Potential Use as Colon-Specific Drug Carrier. Pharmaceutical Research, 15, 1019-1025.
http://dx.doi.org/10.1023/A:1011921925745 [26] Krishnaiah, Y.S.R., Seetha Devi, A., Nageswara Rao, L., Bhaskar Reddy, P.R., Karthikeyan, R.S. and Satyanarayana, V. (2001) Guar Gum as a Carrier for Colon Specific Delivery; Influence of Metronidazole and Tinidazole on in Vitro Release of Albendazole from Guar Gum Matrix Tablets. Journal of Pharmacy and Pharmaceutical Sciences, 4, 235-243. [27] Gliko-Kabir, I., Yagen, B., Baluom, M. and Rubinstein, A. (2000) Phosphated Crosslinked Guar for Colon-Specific Drug Delivery. II. In Vitro and in Vivo Evaluation in the Rat. Journal of Controlled Release, 63, 129-134.
http://dx.doi.org/10.1016/S0168-3659(99)00180-7 [28] Hard, G.C., Iatropoulos, M.J., Jordan, K., Radi, L., Kaltenberg, O.P., Imondi, A.R. and Williams, G.M. (1993) Major Difference in the Hepatocarcinogenicity and DNA Adduct Forming Ability between Toremifene and Tamoxifen in Female Crl: CD (BR) Rats. Cancer Research, 53, 4534-4541. [29] Albukhari, A.A., Gashlan, H.M., El-Beshbishy, H.A., Nagy, A.A. and Abdel-Naim, A.B. (2009) Caffeic Acid Phenethyl Ester Protects against Tamoxifen-Induced Hepatotoxicity in Rats. Food and Chemical Toxicology, 47, 1689-1695.
http://dx.doi.org/10.1016/j.fct.2009.04.021 [30] Elefsiniotis, I.S., Pantazis, K.D., Ilias, A., Pallis, L., Mariolis, A., Glynou, I., Kada, H. and Moulakakis, A. (2004) Tamoxifen Induced Hepatotoxicity in Breast Cancer Patients with Pre-Existing Liver Steatosis: The Role of Glucose Intolerance. European Journal of Gastroenterology & Hepatology, 16, 593-598.
http://dx.doi.org/10.1097/00042737-200406000-00013 [31] Jain, A.K., Swarnakar, N.K., Godugu, C., Singh, R.P. and Jain, S. (2011) The Effect of the Oral Administration of Polymeric Nanoparticles on the Efficacy and Toxicity of Tamoxifen. Biomaterials, 32, 503-515.
http://dx.doi.org/10.1016/j.biomaterials.2010.09.037
[1] www.who.int/topics/cancer/ [2] Rabinow, B.E. (2004) Nanosuspensions in Drug Delivery. Nature Reviews Drug Discovery, 39, 785-796.
http://dx.doi.org/10.1038/nrd1494 [3] Meibohm, B. and Derendorf, H. (2002) Pharmacokinetic/Pharmacodynamic Studies in Drug Product Development. Journal of Pharmaceutical Sciences, 91, 18-31.
http://dx.doi.org/10.1002/jps.1167 [4] Scaglione, F. (2002) Can PK/PD Be Used in Everyday Clinical Practice. International Journal of Antimicrobial Agents, 19, 349-353.
http://dx.doi.org/10.1016/S0924-8579(02)00020-1 [5] Duncan, R., Coatsworth, J.K. and Burtles, S. (1998) Preclinical Toxicology of a Novel Polymeric Antitumour Agent: HPMA Copolymer-Doxorubicin (PK1). Human & Experimental Toxicology, 17, 93-104.
http://dx.doi.org/10.1191/096032798678908378 [6] Hopewel, J.W., Duncan, R., Wilding, D. and Chakrabarti, K. (2001) Preclinical Evaluation of the Cardiotoxicity of PK2: A Novel HPMA Copolymer-Doxorubicin-Galactosamine Conjugate Antitumour Agent. Human & Experimental Toxicology, 20, 461-470.
http://dx.doi.org/10.1191/096032701682693017 [7] Mahmood, I. (2001) Interspecies Scaling of Maximum Tolerated Dose of Anticancer Drugs: Relevance to Starting Dose for Phase I Clinical Trials. American Journal of Therapeutics, 8, 109-116.
http://dx.doi.org/10.1097/00045391-200103000-00005 [8] Howell, S.B. (2001) Clinical Applications of a Novel Sustained-Release Injectable Drug Delivery System: DepoFoam Technology. Cancer Journal, 7, 219-227. [9] Maeda, H. (2001) The Enhanced Permeability and Retention (EPR) Effect in Tumor Vasculature: The Key Role of Tumor-Selective Macromolecular Drug Targeting. Advances in Enzyme Regulation, 41, 189-207.
http://dx.doi.org/10.1016/S0065-2571(00)00013-3 [10] Park, J.W. (2002) Liposome Based Drug Delivery in Breast Cancer Treatment. Breast Cancer Research, 4, 95-99.
http://dx.doi.org/10.1186/bcr432 [11] Goldenberg, D.M. (2002) Targeted Therapy of Cancer with Radiolabeled Antibodies. Journal of Nuclear Medicine, 43, 693-713. [12] Schipper, N.G.M., Varum, K.M. and Artursson, P. (1996) Chitosan as Absorption Enhancers for Poorly Absorbable Drugs: Influence of Molecular Weight and Degree of Acetylation on Drug Transport across Human Intestinal Epithelia (Caco-29 Cells). Pharmaceutical Research, 13, 1686-1692.
http://dx.doi.org/10.1023/A:1016444808000 [13] Martin, E.A., Brown, K., Gaskell, M., Al-Azzawi, F., Garner, R.C., Boocock, D.J., Mattock, E., Pring, D.W., Dingley, K., Turteltaub, K.W., Smith, L.L. and White, I.N.H. (2003) Tamoxifen DNA Damage Detected in Human Endometrium Using Accelerator Mass Spectrometry. Cancer Research, 63, 8461-8465. [14] Lashley, M.R., Niedzinski, E.J., Rogers, J.M., Denison, M.S. and Nantz, M.H. (2002) Synthesis and Estrogen Receptor Affinity of a 4-Hydroxytamoxifen-Labeled Ligand for Diagnostic Imaging. Bioorganic & Medicinal Chemistry, 10, 4075-4082.
http://dx.doi.org/10.1016/S0968-0896(02)00329-2 [15] Marcsek, Z., Kocsis, Z., Jakab, M., Szende, B. and Tompa, A. (2004) The Efficacy of Tamoxifen in Estrogen Receptor-Positive Breast Cancer Cells Is Enhanced by a Medical Nutriment. Cancer Biotherapy & Radiopharmaceuticals, 19, 746-753.
http://dx.doi.org/10.1089/cbr.2004.19.746 [16] Heres-Pulido, E.M., Duenas-Garcia, I., Castaneda-Partida, L., Sanchez-Garcia, A., Contreras-Sousa, M., Duran-Dias, A. and Ulrich, G. (2004) Genotoxicity of Tamoxifen Citrate and 4-Nitroquinoline-1-Oxide in the Wing Spot Test Drosophila Melanogaster. Mutagenesis, 19, 187-193.
http://dx.doi.org/10.1093/mutage/geh020 [17] Chodak, G.W. and Kolvenbag, G.J.C.M. (2001) Will the Experience with Tamoxifen in Breast Cancer Help Define the Role of Antiandrogens in Prostate Cancer? Prostate Cancer and Prostatic Diseases, 4, 72-80.
http://dx.doi.org/10.1038/sj.pcan.4500518 [18] Krishnaiah, Y.S.R., Karthikeyan, R.S. and Satyanarayana, V. (2002) A Three-Layer Guar Gum Matrix Tablet for Oral Controlled Delivery of Highly Soluble Metoprolol Tartrate. International Journal of Pharmaceutics, 241, 353-366.
http://dx.doi.org/10.1016/S0378-5173(02)00273-9 [19] Toti, U.S. and Aminabhavi, T.M. (2004) Modified Guar Gum Matrix Tablet for Controlled Release of Diltiazem Hydrochloride. Journal of Controlled Release, 95, 567-577.
http://dx.doi.org/10.1016/j.jconrel.2003.12.019 [20] Soppirnath, K.S. and Aminabhavi, T.M. (2002) Water Transport and Drug Release Study from Cross-Linked Polyacrylamide Grafted Guar Gum Hydrogel Microspheres for the Controlled Release Application. European Journal of Pharmaceutics and Biopharmaceutics, 53, 87-98.
http://dx.doi.org/10.1016/S0939-6411(01)00205-3 [21] Wassel, G.M., Omar, S.M. and Ammar, N.M. (1989) Application of Guar Flour and Prepared Guaran in Tablet Manufacture. Journal of Drug Research, 18, 1-8. [22] Sarmah, J.K., Mahanta, R., Bhattacharjee, S.K., Mahanta, R. and Biswas, A. (2011) Controlled Release of Tamoxifen Citrate Encapsulated in Cross-Linked Guar Gum Nanoparticles. International Journal of Biological Macromolecules, 49, 390-396.
http://dx.doi.org/10.1016/j.ijbiomac.2011.05.020 [23] Sarmah, J.K., Bhattacharjee, S.K., Mahanta, R. and Mahanta, R. (2009) Preparation of Cross-Linked Guar Gum Nanospheres Containing Tamoxifen Citrate by Single Step Emulsion in Situ Polymer Cross-Linking Method. Journal of Inclusion Phenomena and Macrocyclic Chemistry, 65, 329-334. [24] Gliko-Kabir, I., Yagen, B., Penhasi, A. and Rubinstein, A. (2000) Phosphated Crosslinked Guar for Colon-Specific Drug Delivery: I. Preparation and Physicochemical Characterization. Journal of Controlled Release, 63, 121-127.
http://dx.doi.org/10.1016/S0168-3659(99)00179-0 [25] Gliko-Kabir, I., Yagen, B., Penhasi, A. and Rubinstein, A. (1998) Low Swelling, Crosslinked Guar and Its Potential Use as Colon-Specific Drug Carrier. Pharmaceutical Research, 15, 1019-1025.
http://dx.doi.org/10.1023/A:1011921925745 [26] Krishnaiah, Y.S.R., Seetha Devi, A., Nageswara Rao, L., Bhaskar Reddy, P.R., Karthikeyan, R.S. and Satyanarayana, V. (2001) Guar Gum as a Carrier for Colon Specific Delivery; Influence of Metronidazole and Tinidazole on in Vitro Release of Albendazole from Guar Gum Matrix Tablets. Journal of Pharmacy and Pharmaceutical Sciences, 4, 235-243. [27] Gliko-Kabir, I., Yagen, B., Baluom, M. and Rubinstein, A. (2000) Phosphated Crosslinked Guar for Colon-Specific Drug Delivery. II. In Vitro and in Vivo Evaluation in the Rat. Journal of Controlled Release, 63, 129-134.
http://dx.doi.org/10.1016/S0168-3659(99)00180-7 [28] Hard, G.C., Iatropoulos, M.J., Jordan, K., Radi, L., Kaltenberg, O.P., Imondi, A.R. and Williams, G.M. (1993) Major Difference in the Hepatocarcinogenicity and DNA Adduct Forming Ability between Toremifene and Tamoxifen in Female Crl: CD (BR) Rats. Cancer Research, 53, 4534-4541. [29] Albukhari, A.A., Gashlan, H.M., El-Beshbishy, H.A., Nagy, A.A. and Abdel-Naim, A.B. (2009) Caffeic Acid Phenethyl Ester Protects against Tamoxifen-Induced Hepatotoxicity in Rats. Food and Chemical Toxicology, 47, 1689-1695.
http://dx.doi.org/10.1016/j.fct.2009.04.021 [30] Elefsiniotis, I.S., Pantazis, K.D., Ilias, A., Pallis, L., Mariolis, A., Glynou, I., Kada, H. and Moulakakis, A. (2004) Tamoxifen Induced Hepatotoxicity in Breast Cancer Patients with Pre-Existing Liver Steatosis: The Role of Glucose Intolerance. European Journal of Gastroenterology & Hepatology, 16, 593-598.
http://dx.doi.org/10.1097/00042737-200406000-00013 [31] Jain, A.K., Swarnakar, N.K., Godugu, C., Singh, R.P. and Jain, S. (2011) The Effect of the Oral Administration of Polymeric Nanoparticles on the Efficacy and Toxicity of Tamoxifen. Biomaterials, 32, 503-515.
http://dx.doi.org/10.1016/j.biomaterials.2010.09.037