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Hydroxyapatite-dextran methacrylate core/shell hybrid nanocarriers for combinatorial drug therapy

Published online by Cambridge University Press:  13 August 2020

S. Ram Prasad Open the ORCID record for S. Ram Prasad [Opens in a new window] ,
A. Jayakrishnan  and
T. S. Sampath Kumar
S. Ram Prasad
Affiliation:
Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai600 036, Tamil Nadu, India Medical Materials Laboratory, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Madras, Chennai600 036, Tamil Nadu, India
A. Jayakrishnan*
Affiliation:
Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai600 036, Tamil Nadu, India
T. S. Sampath Kumar*
Affiliation:
Medical Materials Laboratory, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Madras, Chennai600 036, Tamil Nadu, India
*
a)Address all correspondence to these authors. e-mail: jayakrishnan1953@gmail.com; jayakrishnana@rgcb.res.in
b)e-mail: tssk@iitm.ac.in
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Abstract

In this study, a hybrid dual drug-loaded hydroxyapatite-oxidized dextran methacrylate core–shell nanocarrier was formulated and explored for combinatorial delivery of doxorubicin (DOX) and methotrexate (MTX) to bone cancer. The synthesized nanocarrier was well characterized by different techniques. In vitro drug release studies in both acidic (pH 5) and alkaline (pH 7.4) conditions showed sequential release of MTX followed by DOX in a sustained manner for 10 days. Biocompatibility and cytotoxicity studies performed using drug-loaded nanoparticles (NPs) on fibroblast L929 cells and osteosarcoma MG63 cells (OMG63) showed that the NPs were highly biocompatible and showed concentration-dependent toxicity. Gene expression studies in OMG-63 cells exhibited the upregulation of caspase-3 and BAX which confirmed the apoptosis induced by dual drug-loaded NPs. The nanocarrier is expected to be a potential bone void filling material, as well as a platform for sequential delivery of DOX and MTX for the treatment of bone cancer.

Keywords

biomaterialcore/shellnanostructure
Type
Article
Information
Journal of Materials Research , Volume 35 , Issue 18 , 28 September 2020 , pp. 2451 - 2465
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Copyright
Copyright © Materials Research Society 2020

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Footnotes

c)

Present address: Raja Ramanna Fellow, Rajiv Gandhi Centre for Biotechnology, Jagathy, Trivandrum 695 014, Kerala, India

References

Ibrahim, T., Mercatali, L., and Amadori, D.: Bone and cancer: The osteoncology. Clin. Cases Miner. Bone Metab. 10, 121 (2013).Google ScholarPubMed
Buijs, J.T. and van der Pluijm, G.: Osteotropic cancers: From primary tumor to bone. Cancer Lett. 273, 177–193 (2009).CrossRefGoogle ScholarPubMed
Kimura, T.: Multidisciplinary approach for bone metastasis: A review. Cancers 10, 156 (2018).CrossRefGoogle ScholarPubMed
Gu, W., Wu, C., Chen, J., and Xiao, Y.: Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration. Int. J. Nanomedicine 8, 2305–2317 (2013).CrossRefGoogle ScholarPubMed
Macedo, F., Ladeira, K., Pinho, F., Saraiva, N., Bonito, N., Pinto, L., and Gonçalves, F.: Bone metastases: An overview. Oncol. Rev. 11, 321 (2017).Google ScholarPubMed
Hossen, S., Hossain, M.K., Basher, M.K., Mia, M.N., Rahman, M.T., and Uddin, M.J.: Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review. J. Adv. Res. 15, 1–18 (2019).CrossRefGoogle ScholarPubMed
Marques, C., Ferreira, J.M., Andronescu, E., Ficai, D., Sonmez, M., and Ficai, A.: Multifunctional materials for bone cancer treatment. Int. J. Nanomedicine 9, 2713–2725 (2014).Google ScholarPubMed
Alexandrino, E.M., Ritz, S., Marsico, F., Baier, G., Mailänder, V., Landfester, K., and Wurm, F.R.: Paclitaxel-loaded polyphosphate nanoparticles: A potential strategy for bone cancer treatment. J. Mater. Chem. B. 2, 1298 (2014).CrossRefGoogle ScholarPubMed
Ma, H., He, C., Cheng, Y., Yang, Z., Zang, J., Liu, J., and Chen, X.: Localized co-delivery of doxorubicin, cisplatin, and methotrexate by thermosensitive hydrogels for enhanced osteosarcoma treatment. ACS Appl. Mater. Interfaces 7, 27040–27048 (2015).CrossRefGoogle ScholarPubMed
Kemp, J.A., Shim, M.S., Heo, C.Y., and Kwon, Y.J.: “Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. Adv. Drug Deliv. Rev. 98, 3–18 (2016).CrossRefGoogle ScholarPubMed
Parhi, P., Mohanty, C., and Sahoo, S.K.: Nanotechnology-based combinational drug delivery: An emerging approach for cancer therapy. Drug Discov. Today. 17, 1044–1052 (2012).CrossRefGoogle ScholarPubMed
Wicki, A., Witzigmann, D., Balasubramanian, V., and Huwyler, J.: Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. J. Control. Release 28, 138–157 (2015).CrossRefGoogle Scholar
Hu, C.M., Aryal, S., and Zhang, L.: Nanoparticle-assisted combination therapies for effective cancer treatment. Ther. Deliv 1, 323–334 (2010).CrossRefGoogle ScholarPubMed
Qi, S.S., Sun, J.H., Yu, H.H., and Yu, S.Q.: Co-delivery nanoparticles of anti-cancer drugs for improving chemotherapy efficacy. Drug Deliv. 24, 1909–1926 (2017).CrossRefGoogle ScholarPubMed
Estanqueiro, M., Amaral, M.H., Conceicao, J., and Lobo, J.M.: Nanotechnological carriers for cancer chemotherapy: The state of the art. Colloids Surf. B: Biointerfaces 126, 631–648 (2015).CrossRefGoogle ScholarPubMed
Zhao, C.Y., Cheng, R., Yang, Z., and Tian, Z.M.: Nanotechnology for cancer therapy based on chemotherapy. Molecules. 23, 826 (2018).CrossRefGoogle ScholarPubMed
Sadat-Shojai, M., Khorasani, M.T., Dinpanah-Khoshdargi, E., and Jamshidi, A.: Synthesis methods for nanosized hydroxyapatite with diverse structures. Acta Biomater. 9, 7591–7621 (2013).CrossRefGoogle ScholarPubMed
Cheng, X. and Kuhn, L.: Chemotherapy drug delivery from calcium phosphate nanoparticles. Int. J. Nanomedicine 2, 667 (2007).Google ScholarPubMed
Yang, L., Sheldon, B.W., and Webster, T.J.: Nanophase ceramics for improved drug delivery. Am. Ceram. Soc. Bull. 89, 24–32 (2010).Google Scholar
Son, K.D. and Kim, Y.J.: Anticancer activity of drug-loaded calcium phosphate nanocomposites against human osteosarcoma. Biomater. Res. 21, 13 (2017).CrossRefGoogle ScholarPubMed
Li, W.M., Su, C.W., Chen, Y.W., and Chen, S.Y.: In situ DOX-calcium phosphate mineralized CPT-amphiphilic gelatin nanoparticle for intracellular controlled sequential release of multiple drugs. Acta Biomater. 15, 191–199 (2015).CrossRefGoogle ScholarPubMed
Lebugle, A., Rodrigues, A., Bonnevialle, P., Voigt, J.J., Canal, P., and Rodriguez, F.: Study of implantable calcium phosphate systems for the slow release of methotrexate. Biomaterials. 23, 3517–3522 (2002).CrossRefGoogle ScholarPubMed
Cipreste, M.F. and Sousa, E.M.B.: Poly(vinyl alcohol)/collagen/hydroxyapatite nanoparticles hybrid system containing yttrium-90 as a potential agent to treat osteosarcoma. J. Biomater. Nanobiotechnol. 5, 24–30 (2014).CrossRefGoogle Scholar
Rong, Z.J., Yang, L.J., Cai, B.T., Zhu, L.X., Cao, Y.L., Wu, G.F., and Zhang, Z.J.: Porous nano-hydroxyapatite/collagen scaffold containing drug-loaded ADM-PLGA microspheres for bone cancer treatment. J. Mater. Sci. Mater. Med. 27, 89 (2016).CrossRefGoogle ScholarPubMed
Wang, Y., Zhang, X., Yan, J., Xiao, Y., and Lang, M.: Surface modification of hydroxyapatite with poly(methyl methacrylate) via surface-initiated ATRP. Appl. Surf. Sci. 257, 6233–6238 (2011).CrossRefGoogle Scholar
Liu, Q., de Wijn, J.R., and Van Blitterswijk, C.A.: Covalent bonding of PMMA, PBMA, and poly (HEMA) to hydroxyapatite particles. J. Biomed. Mater. Res. 40, 257–263 (1998).3.0.CO;2-J>CrossRefGoogle Scholar
Liu, Q., de Wijn, J.R., de Groot, K., and van Blitterswijk, C.A.: Surface modification of nano-apatite by grafting organic polymer. Biomaterials 19, 1067–1072 (1998).CrossRefGoogle ScholarPubMed
Kango, S., Kalia, S., Celli, A., Njuguna, J., Habibi, Y., and Kumar, R.: Surface modification of inorganic nanoparticles for development of organic–inorganic nanocomposites – a review. Prog. Polym. Sci. 38, 1232–1261 (2013).CrossRefGoogle Scholar
Wei, J., He, P., Liu, A., Chen, X., Wang, X., and Jing, X.: Surface modification of hydroxyapatite nanoparticles with thermal-responsive PNIPAM by ATRP. Macromol. Biosci. 9, 1237–1246 (2009).CrossRefGoogle ScholarPubMed
Matsuda, A., Furuzono, T., Walsh, D., Kishida, A., and Tanaka, J.: Surface modification of a porous hydroxyapatite to promote bonded polymer coatings. J. Mater. Sci. Mater 14, 973–978 (2003).CrossRefGoogle ScholarPubMed
Prasad, S.R., Jayakrishnan, A., and Sampath Kumar, T.S.: Hydroxyapatite-poly(vinyl alcohol) core-shell nanoparticles for dual delivery of methotrexate and gemcitabine for bone cancer treatment. J. Drug Deliv. Sci. Technol. 51, 629–638 (2019).CrossRefGoogle Scholar
Dhaneshwar, S.S., Mini, K., Gairola, N., and Kadam, S.S.: Dextran: A promising macromolecular drug carrier. Indian J. Pharm. Sci. 68, 705 (2006).CrossRefGoogle Scholar
Cabral, J.D., Roxburgh, M., Shi, Z., Liu, L., McConnell, M., Williams, G., Evans, N., Hanton, L.R., Simpson, J., Moratti, S.C., and Robinson, B.H.: Synthesis, physiochemical characterization, and biocompatibility of a chitosan/dextran-based hydrogel for postsurgical adhesion prevention. J. Mater. Sci. Mater. Med. 25, 2743–2756 (2014).CrossRefGoogle ScholarPubMed
Varshosaz, J.: Dextran conjugates in drug delivery. Expert Opin. Drug Deliv. 9, 509–523 (2012).CrossRefGoogle ScholarPubMed
Feng, X., Li, D., Han, J., Zhuang, X., and Ding, J.: Schiff base bond-linked polysaccharide-doxorubicin conjugate for upregulated cancer therapy. Mater. Sci. Eng. C Mater. Biol. Appl. 76, 1121–1128 (2017).CrossRefGoogle ScholarPubMed
Doane, T. and Burda, C.: Nanoparticle mediated non-covalent drug delivery. Adv. Drug Deliv. Rev. 65, 607–621 (2013).CrossRefGoogle ScholarPubMed
Qiu, L., Hong, C.Y., and Pan, C.Y.: Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery. Int. J. Nanomedicine 10, 3623–3640 (2015).Google ScholarPubMed
Miao, T., Wang, J., Zeng, Y., Liu, G., and Chen, X.: Polysaccharide-based controlled release systems for therapeutics delivery and tissue engineering: From bench to bedside. Adv. Sci. 5, 700513 (2018).CrossRefGoogle ScholarPubMed
Zhang, Y., Huo, M., Zhou, J., Zou, A., Li, W., Yao, C., and Xie, S.: DDSolver: An add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 12, 263–271 (2010).CrossRefGoogle ScholarPubMed
Gierszewska-Drużyńska, M., and Ostrowska-Czubenko, J.: Mechanism of water diffusion into noncrosslinked and ionically crosslinked chitosan membranes. Prog. Chem. Appl. Chitin Deriv. 17, 63–70 (2012).Google Scholar
Basha, R.Y., Sampath Kumar, T.S., and Doble, M.: Dual delivery of tuberculosis drugs via cyclodextrin conjugated curdlan nanoparticles to infected macrophages. Carbohydr. Polym. 218, 53–62 (2019).CrossRefGoogle Scholar
International Organization for Standardization. ISO 10993-5. Biological Evaluation of Medical Devices – Part 5: Tests for In vitro Cytotoxicity (ISO, Geneva, 2009).Google Scholar
Chou, T.C.: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621–681 (2006).CrossRefGoogle ScholarPubMed
Song, W., Tang, Z., Li, M., Lv, S., Sun, H., Deng, M., Liu, H., and Chen, X.: Polypeptide-based combination of paclitaxel and cisplatin for enhanced chemotherapy efficacy and reduced side-effects. Acta Biomater. 10, 1392–1402 (2014).CrossRefGoogle ScholarPubMed
Rahimi, M., Safa, K.D., and Salehi, R.: Co-delivery of doxorubicin and methotrexate by dendritic chitosan-g-mPEG as a magnetic nanocarrier for multi-drug delivery in combination chemotherapy. Polym. Chem. 8, 7333–7350 (2017).CrossRefGoogle Scholar
Lowe, S.W. and Lin, A.W.: Apoptosis in cancer. Carcinogenesis. 21, 485–495 (2000).CrossRefGoogle ScholarPubMed
Kim, S.H. and Chu, C.C.: Synthesis and characterization of dextran–methacrylate hydrogels and structural study by SEM. J. Biomed. Mater. Res. 49(4), 517–27 (2000).3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Zhang, Y. and Lu, J.: A simple method to tailor spherical nanocrystal hydroxyapatite at low temperature. J. Nanoparticle Res. 9, 589–594 (2006).CrossRefGoogle Scholar
Francis, A.P., Gurudevan, S., and Jayakrishnan, A.: Synthetic polymannose as a drug carrier: synthesis, toxicity and anti-fungal activity of polymannose-amphotericin B conjugates. J. Biomater Sci. Polym. 29, 1529–1548 (2018).CrossRefGoogle ScholarPubMed
Balavigneswaran, C.K., Mahto, S.K., Subia, B., Prabhakar, A., Mitra, K., Rao, V., Ganguli, M., Ray, B., Maiti, P., and Misra, N.: Tailored chemical properties of 4-Arm star shaped poly(d,l-lactide) as cell adhesive three-dimensional scaffolds. Bioconjugate Chem. 28, 1236–1250 (2017).CrossRefGoogle ScholarPubMed
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