Tissue Distribution and Systemic Toxicity Evaluation of Raloxifene Targeted Polymeric Micelles of Poly (Styrene-Maleic Acid)-Poly (Amide- Ether-Ester-Imide)-Poly (Ethylene Glycol) Loaded With Docetaxel in Breast Cancer Bearing Mice

Author(s): Jaleh Varshosaz*, Farshid Hassanzadeh, Batool Hashemi-Beni, Mohsen Minaiyan, Saeedeh Enteshari.

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 14 , Issue 3 , 2019

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Background: Due to the low water solubility of Docetaxel (DTX), it is formulated with ethanol and Tween 80 with lots of side effects. For this reason, special attention has been paid to formulate it in new drug nano-carriers.

Objective: The goal of this study was to evaluate the safety, antitumor activity and tissue distribution of the novel synthesized Raloxifene (RA) targeted polymeric micelles.

Methods: DTX-loaded RA-targeted polymeric micelles composed of poly(styrene-maleic acid)- poly(amide-ether-ester-imide)-poly(ethylene glycol) (SMA-PAEE-PEG) were prepared and their antitumor activity was studied in MC4-L2 tumor-bearing mice compared with non-targeted micelles and free DTX. Safety of the micelles was studied by Hematoxylin and Eosin (H&E) staining of tumors and major organs of the mice. The drug accumulation in the tumor and major organs was measured by HPLC method.

Results: The results showed better tumor growth inhibition and increased survival of mice treated with DTX-loaded in targeted micelles compared to the non-targeted micelles and free DTX. Histopathological studies, H&E staining of tumors and immunohistochemical examination showed the potential of DTX-loaded RA-targeted micelles to inhibit tumor cells proliferation. The higher accumulation of the DTX in the tumor tissue after injection of the micelles compared to the free DTX may indicate the higher uptake of the targeted micelles by the G-Protein-Coupled Estrogen Receptors (GPER).

Conclusion: The results indicate that RA-conjugated polymeric micelles may be a strong and effective drug delivery system for DTX therapy and uptake of the drug into tumor cells, and overcome the disadvantages and side effects of conventional DTX.

Keywords: Docetaxel, G-protein-coupled estrogen receptors, histopathology, raloxifene targeted micelles, safety, tissue distribution.

Oyewumi MO, Yokel RA, Jay M, Coakley T, Mumper RJ. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Control Release 2004; 95(3): 613-26.
[http://dx.doi.org/10.1016/j.jconrel.2004.01.002] [PMID: 15023471]
Song H, Geng H, Ruan J, Wang K, Bao CH, Wang J, et al. Development of polysorbate 80/Phospholipid mixed micellar formation for docetaxel and assessment of its in vivo distribution in animal models. Nanoscale Res Lett 2011; 6(1): 354.
[http://dx.doi.org/10.1186/1556-276X-6-354] [PMID: 21711889]
Gao J, Ren Y, Wu L, Yu S. Pharmaceutical composition containing docetaxel-cyclodextrin inclusion complex and its preparing process. EP2080524 . (2006).
Palepu N. Docetaxel formulations with lipoic acid. US7772274 . (2009).
Palepu NR, Bulusu BT. Solubilized formulation of docetaxel without Tween 80. EP2170319 . (2007).
Yanasarn N, Sloat BR, Cui Z. Nanoparticles engineered from lecithin-in-water emulsions as a potential delivery system for docetaxel. Int J Pharm 2009; 379(1): 174-80.
[http://dx.doi.org/10.1016/j.ijpharm.2009.06.004] [PMID: 19524029]
Zhai G, Wu J, Xiang G, Wenxue M, Bo Y, Hong L, et al. Preparation, characterization and pharmacokinetics of folate receptor-targeted liposomes for docetaxel delivery. J Nanosci Nanotechnol 2009; 9(3): 2155-61.
[http://dx.doi.org/10.1166/jnn.2009.450] [PMID: 19435095]
Yousefi A, Esmaeili F, Rahimian S, Atyabi F, Dinarvand R. Preparation and in vitro evaluation of a pegylated nano-liposomal formulation containing docetaxel. Sci Pharm 2009; 77(2): 453-64.
Zhang H, Li RY, Lu X, Mou ZZ, Lin GM. Docetaxel-loaded liposomes: Preparation, pH sensitivity, pharmacokinetics, and tissue distribution. J Zhejiang Univ Sci B 2012; 13(12): 981-9.
[http://dx.doi.org/10.1631/jzus.B1200098] [PMID: 23225853]
Kim GH, Lee JY, Kang YM, Kang KN, Kim E, Kim D, et al. Preparation and characterization of self-emulsified docetaxel. J Nanomater 2011; 2011: 7.
Naik S, Patel D, Surti N, Misra A. Preparation of PEGylated liposomes of docetaxel using supercritical fluid technology. J Supercrit Fluids 2010; 54(1): 110-9.
Gan CW, Chien S, Feng SS. Nanomedicine: Enhancement of chemotherapeutical efficacy of docetaxel by using a biodegradable nanoparticle formulation. Curr Pharm Des 2010; 16(21): 2308-20.
[http://dx.doi.org/10.2174/138161210791920487] [PMID: 20618152]
Wright J. Docetaxel polymeric nanoparticles and methods of treating cancers using same. US20160151298 . (2013).
Liversidge G, Jenkins S, Liversidge E. Nanoparticulate formulations of docetaxel and analogues thereof. WO2006091780 . (2005).
Garrec DL, Gori S, Karkan D, Luo L, Lessard DG, Smith D, et al. Preparation, characterization, cytotoxicity and biodistribution of docetaxel-loaded polymeric micelle formulations. J Drug Deliv Sci Technol 2005; 15(2): 115-20.
Musumeci T, Ventura CA, Giannone I, Ruozi B, Montenegro L, Pignatello R, et al. PLA/PLGA nanoparticles for sustained release of docetaxel. Int J Pharm 2006; 325(1-2): 172-9.
[http://dx.doi.org/10.1016/j.ijpharm.2006.06.023] [PMID: 16887303]
Severin E, Zykova I, Gulenko V. Docetaxel-based prolongedrelease cancer treatment drugs. WO2013171382 . (2012).
Li SD, Ernsting MJ. Cellulose-based nanoparticles for drug delivery. WO2014015422 . (2012).
Liu XC, Sha Y, Zhang ZL. Docetaxel nanometer lipid injection, preparation method and purpose thereof. CN101548947 . (2009).
Summa J. Nanoparticles comprising docetaxel for treating cancers having a k-ras mutation. CA2946155 . (2014).
We Z, Zhang XG, Yang M, Yang YC. Novel docetaxel injection pharmaceutical composition and application thereof. CN102309444 . (2010).
Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 2008; 5(4): 505-15.
[http://dx.doi.org/10.1021/mp800051m] [PMID: 18672949]
Koopaei MN, Dinarvand R, Amini M, Rabbani H, Emami S, Ostad SN, et al. Docetaxel immunonanocarriers as targeted delivery systems for HER 2-positive tumor cells: Preparation, characterization, and cytotoxicity studies. Int J Nanomedicine 2011; 6: 1903-12.
[PMID: 21931485]
Singh RP, Sharma G, Agrawal P, Pandey BL, Koch B, Muthu MS. Transferrin receptor targeted PLA-TPGS micelles improved efficacy and safety in docetaxel delivery. Int J Biol Macromol 2016; 83: 335-44.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.11.081] [PMID: 26657586]
Esmaeili F, Ghahremani MH, Ostad SN, Atyabi F, Seyedabadi M, Malekshahi MR, et al. Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA-PEG-folate conjugate. J Drug Target 2008; 16(5): 415-23.
[http://dx.doi.org/10.1080/10611860802088630] [PMID: 18569286]
Alexis F, Zhang L, Radovic-Moreno AF, et al. Poly (amino acid) targeting moieties. WO2008124639 . (2007).
Feng JF, Hu KL, Chen WY, Liu M. Target nano lipid core micelle used for carrying docetaxel, and preparation method and applications thereof. CN103505442 . (2012).
Kim JH, Hong ST, Chung HJ, Joo MK, Cho HG, Hong J. Targeting-enhanced anticancer nanoparticles and preparation methods of same. US9662401. (2013).
Li YX, Yu W, Zhu Q, Teng LS, Zhou YL. Herceptinmodified docetaxel-loaded triple targeting nanoparticle carrier system. CN104840957 . (2015).
Xi SG, Zhang HQ, Dou JF. Docetaxel transferrin acceptortargeted liposome preparation. CN102836127 . (2012).
Cheng SB, Graeber CT, Quinn JA, Filardo EJ. Retrograde transport of the transmembrane estrogen receptor, G-protein-coupled-receptor-30 (GPR30/GPER) from the plasma membrane towards the nucleus. Steroids 2011; 76(9): 892-6.
[http://dx.doi.org/10.1016/j.steroids.2011.02.018] [PMID: 21354433]
Lappano R, Pisano A, Maggiolini M. GPER function in breast cancer: An overview. Front Endocrinol (Lausanne) 2014; 5: 66.
[http://dx.doi.org/10.3389/fendo.2014.00066] [PMID: 24834064]
Prossnitz ER, Sklar LA, Oprea TI, Arterburn JB. GPR30: A novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci 2008; 29(3): 116-23.
[http://dx.doi.org/10.1016/j.tips.2008.01.001] [PMID: 18262661]
Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 2005; 146(2): 624-32.
[http://dx.doi.org/10.1210/en.2004-1064] [PMID: 15539556]
Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 1997; 45(3): 607-17.
[http://dx.doi.org/10.1006/geno.1997.4972] [PMID: 9367686]
Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res 2006; 12(21): 6359-66.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-0860] [PMID: 17085646]
Smith HO, Leslie KK, Singh M, Qualls CR, Revankar CM, Joste NE, et al. GPR30: A novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol 2007; 196(4): 386. e1-9
Smith HO, Arias-Pulido H, Kuo DY, Howard T, Qualls CR, Lee SJ, et al. GPR30 predicts poor survival for ovarian cancer. Gynecol Oncol 2009; 114(3): 465-71.
[http://dx.doi.org/10.1016/j.ygyno.2009.05.015] [PMID: 19501895]
Enteshari S, Varshosaz J, Minayian M, Hassanzadeh F. Antitumor activity of raloxifene-targeted poly(styrene maleic acid)-poly (amide-ether-ester-imide) co-polymeric nanomicelles loaded with docetaxel in breast cancer-bearing mice. Invest New Drugs 2018; 36(2): 206-16.
[http://dx.doi.org/10.1007/s10637-017-0533-1] [PMID: 29177974]
Varshosaz J, Enteshari S, Hassanzadeh F, Hashemi-Beni B, Minaiyan M, Mirsafaei R. Synthesis, in vitro characterization, and anti-tumor effects of novel polystyrene-poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice. Drug Dev Ind Pharm 2018; 44(7): 1139-57.
[http://dx.doi.org/10.1080/03639045.2018.1438462] [PMID: 29436875]
Gao X, Wang S, Wang B, Deng S, Liu X, Zhang X, et al. Improving the anti-ovarian cancer activity of docetaxel with biodegradable self-assembly micelles through various evaluations. Biomaterials 2015; 53: 646-58.
[http://dx.doi.org/10.1016/j.biomaterials.2015.02.108] [PMID: 25890760]
Oyelere AK, El-Sayed MA, Dreaden EC. Targeted cellular delivery of nanoparticles. US20110077581 . (2009).
Li SD, Wang AJ, Lai CK. Drug delivery system targeting to estrogen receptor over-expressed cells. US7820204 . (2002).
Nemzek JA, Bolgos GL, Williams BA, Remick DG. Differences in normal values for murine white blood cell counts and other hematological parameters based on sampling site. Inflamm Res 2001; 50(10): 523-7.
[http://dx.doi.org/10.1007/PL00000229] [PMID: 11713907]
Yang Y, Pan D, Luo K, Li L, Gu Z. Biodegradable and amphiphilic block copolymer-doxorubicin conjugate as polymeric nanoscale drug delivery vehicle for breast cancer therapy. Biomaterials 2013; 34(33): 8430-43.
[http://dx.doi.org/10.1016/j.biomaterials.2013.07.037] [PMID: 23896006]
Wang T, Yang S, Mei LA, Parmar CK, Gillespie JW, Praveen KP, et al. Paclitaxel-loaded PEG-PE-based micellar nanopreparations targeted with tumor-specific landscape phage fusion protein enhance apoptosis and efficiently reduce tumors. Mol Cancer Ther 2014; 13(12): 2864-75.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0052] [PMID: 25239936]
Wang Y, Chen L, Tan L, Zhao Q, Luo F, Wei Y, et al. PEG-PCL based micelle hydrogels as oral docetaxel delivery systems for breast cancer therapy. Biomaterials 2014; 35(25): 6972-85.
[http://dx.doi.org/10.1016/j.biomaterials.2014.04.099] [PMID: 24836952]
Wang X, Li J, Wang Y, Cho KJ, Kim G, Gjyrezi A, et al. HFT-T, a targeting nanoparticle, enhances specific delivery of paclitaxel to folate receptor-positive tumors. ACS Nano 2009; 3(10): 3165-74.
[http://dx.doi.org/10.1021/nn900649v] [PMID: 19761191]
Lee ES, Na K, Bae YH. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor. J Control Release 2005; 103(2): 405-18.
[http://dx.doi.org/10.1016/j.jconrel.2004.12.018] [PMID: 15763623]
Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, et al. International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: Recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 2011; 103(22): 1656-64.
[http://dx.doi.org/10.1093/jnci/djr393] [PMID: 21960707]
Wang Y, Yang T, Wang X, Dai W, Wang J, Zhang X, et al. Materializing sequential killing of tumor vasculature and tumor cells via targeted polymeric micelle system. J Control Release 2011; 149(3): 299-306.
[http://dx.doi.org/10.1016/j.jconrel.2010.10.027] [PMID: 21044651]
Liu L, Sun L, Wu Q, Guo W, Li L, Chen Y, et al. Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis. Int J Pharm 2013; 443(1-2): 175-82.
[http://dx.doi.org/10.1016/j.ijpharm.2012.12.032] [PMID: 23287774]
Xu P, Meng Q, Sun H, Yin Q, Yu H, Zhang Z, et al. Shrapnel nanoparticles loading docetaxel inhibit metastasis and growth of breast cancer. Biomaterials 2015; 64: 10-20.
[http://dx.doi.org/10.1016/j.biomaterials.2015.06.017] [PMID: 26106797]
Cho YW, Park SA, Han TH, Son DH, Park JS, Oh SJ, et al. In vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: Mechanisms, key factors, and their implications. Biomaterials 2007; 28(6): 1236-47.
[http://dx.doi.org/10.1016/j.biomaterials.2006.10.002] [PMID: 17126900]
Zhang C, Qu G, Sun Y, Wu X, Yao Z, Guo Q, et al. Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel. Biomaterials 2008; 29(9): 1233-41.
[http://dx.doi.org/10.1016/j.biomaterials.2007.11.029] [PMID: 18093646]
Liu J, Li H, Chen D, Jin X, Zhao X, Zhang C, et al. In vivo evaluation of novel chitosan graft polymeric micelles for delivery of paclitaxel. Drug Deliv 2011; 18(3): 181-9.
[http://dx.doi.org/10.3109/10717544.2010.520355] [PMID: 20942638]
Gabizon A, Shmeeda H, Horowitz AT, Zalipsky S. Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates. Adv Drug Deliv Rev 2004; 56(8): 1177-92.
[http://dx.doi.org/10.1016/j.addr.2004.01.011] [PMID: 15094214]
Khalid MN, Simard P, Hoarau D, Dragomir A, Leroux JC. Long circulating poly(ethylene glycol)-decorated lipid nanocapsules deliver docetaxel to solid tumors. Pharm Res 2006; 23(4): 752-8.
[http://dx.doi.org/10.1007/s11095-006-9662-5] [PMID: 16550475]
Li FY, Li C. Docetaxel drug-loading nanoparticles, preparation method and application thereof. CN105078900A. (2015).
Chandran SS, Ray S, Pomper MG, Denmeade SR, Mease RC. Prostate Specific Membrane Antigen (PSMA) targeted nanoparticles for therapy of prostate cancer. US9422234 . (2007).
Xin T, Gu XJ. Docetaxel carrying micelle preparation. CN105267972 . (2014).
Harada M, Saito H, Kato Y. Docetaxel polymer derivative, method for producing same and use of same. WO2009142326 . (2009).
Yu JG, Qiu LG, Ma JJ. Biodegradable polymer-docetaxel bonding drug and preparation method thereof. CN105688225 . (2014).
Seo MH, Lee SW. Preparation method of polymeric micellar nanoparticles composition containing a poorly water-soluble drug. EP2376062 . (2008).

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Year: 2019
Page: [280 - 291]
Pages: 12
DOI: 10.2174/1574892814666190919163731
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