Construction of hollow polydopamine nanoparticle based drug sustainable release system and its application in bone regeneration

Abstract

Nanomaterial-based drug sustainable release systems have been tentatively applied to bone regeneration. They, however, still face disadvantages of high toxicity, low biocompatibility, and low drug-load capacity. In view of the low toxicity and high biocompatibility of polymer nanomaterials and the excellent load capacity of hollow nanomaterials with high specific surface area, we evaluated the hollow polydopamine nanoparticles (HPDA NPs), in order to find an optimal system to effectively deliver the osteogenic drugs to improve treatment of bone defect. Data demonstrated that the HPDA NPs synthesized herein could efficiently load four types of osteogenic drugs and the drugs can effectively release from the HPDA NPs for a relatively longer time in vitro and in vivo with low toxicity and high biocompatibility. Results of qRT-PCR, ALP, and alizarin red S staining showed that drugs released from the HPDA NPs could promote osteogenic differentiation and proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. Image data from micro-CT and H&E staining showed that all four osteogenic drugs released from the HPDA NPs effectively promoted bone regeneration in the defect of tooth extraction fossa in vivo, especially tacrolimus. These results suggest that the HPDA NPs, the biodegradable hollow polymer nanoparticles with high drug load rate and sustainable release ability, have good prospect to treat the bone defect in future clinical practice.

References

[1] Fan W, Yung B, Huang P, Chen X. Nanotechnology for multimodal synergistic cancer therapy. Chem. Rev., 2017, 117: 13566-13638.

[2] Cheng L, Wang C, Feng L, Yang K, Liu Z. Functional nanomaterials for phototherapies of cancer. Chem. Rev., 2014, 114: 10869-10939.

[3] Yang X, Yang M, Pang B, Vara M, Xia Y. Gold nanomaterials at work in biomedicine. Chem. Rev., 2015, 115: 10410-10488.

[4] Natarajan JV, Nugraha C, Ng XW, Venkatraman S. Sustained-release from nanocarriers: a review. J. Control. Release, 2014, 193: 122-138.

[5] Lvov Y, Wang W, Zhang L, Fakhrullin R. Halloysite clay nanotubes for loading and sustained release of functional compounds. Adv. Mater., 2016, 28: 1227-1250.

[6] Duan W, . Esterase-responsive polypeptide vesicles as fast-response and sustained-release nanocompartments for fibroblast-exempt drug delivery. Biomacromolecules, 2020, 21: 5093-5103.

[7] Adepu S, Khandelwal M. Ex-situ modification of bacterial cellulose for immediate and sustained drug release with insights into release mechanism. Carbohydr. Polym., 2020, 249: 116816.

[8] Hu J, Miszuk JM, Stein KM, Sun H. Nanoclay promotes mouse cranial bone regeneration mainly through modulating drug binding and sustained release. Appl. Mater. Today, 2020, 21: 100860.

[9] Cavallaro G, . Nanohydrogel formation within the halloysite lumen for triggered and sustained release. ACS Appl. Mater. Interfaces, 2018, 10: 8265-8273.

[10] Liu J-Y, . Biomass-derived multilayer-structured microparticles for accelerated hemostasis and bone repair. Adv. Sci., 2020, 7: 2002243.

[11] Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem. Rev., 2016, 116: 2602-2663.

[12] Stebbins ND, Faig JJ, Yu W, Guliyev R, Uhrich KE. Polyactives: controlled and sustained bioactive release via hydrolytic degradation. Biomater. Sci., 2015, 3: 1171-1187.

[13] Ma L-L, . Supramolecular control of photocycloadditions in solution: in situ stereoselective synthesis and release of cyclobutanes. Angew. Chem. Int. Ed., 2019, 58: 3986-3991.

[14] Chen W-H, . Stimuli-responsive nucleic acid-based polyacrylamide hydrogel-coated metal-organic framework nanoparticles for controlled drug release. Adv. Funct. Mater., 2018, 28: 1705137.

[15] Loira-Pastoriza C, Todoroff J, Vanbever R. Delivery strategies for sustained drug release in the lungs. Adv. Drug Deliv. Rev., 2014, 75: 81-91.

[16] Razavi M, . Controlled nutrient delivery to pancreatic islets using polydopamine-coated mesoporous silica nanoparticles. Nano Lett., 2020, 20: 7220-7229.

[17] Deng C, . Template-free synthesis of chemically asymmetric silica nanotubes for selective cargo loading and sustained drug release. Chem. Mater., 2019, 31: 4291-4298.

[18] Hu X, . Stimuli-responsive polymersomes for biomedical applications. Biomacromolecules, 2017, 18: 649-673.

[19] Liu S, . Tumor microenvironment-responsive nanoshuttles with sodium citrate modification for hierarchical targeting and improved tumor theranostics. ACS Appl. Mater. Interfaces, 2019, 11: 25730-25739.

[20] Yao C, . Near-infrared upconversion mesoporous cerium oxide hollow biophotocatalyst for concurrent pH-/H₂O₂-responsive O₂-evolving synergetic cancer therapy. Adv. Mater., 2018, 30: 1704833.

[21] Yang G, . Hollow MnO₂ as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses. Nat. Commun., 2017, 8

[22] Nel A, Xia T, Madler L, Li N. Toxic potential of materials at the nanolevel. Science, 2006, 311: 622-627.

[23] Yuan Z, . Dual-controlled release of icariin/Mg²⁺ from biodegradable microspheres and their synergistic upregulation effect on bone regeneration. Adv. Healthc. Mater., 2020, 9: 2000211.

[24] Yang K, . Cooperative assembly of magneto-nanovesicles with tunable wall thickness and permeability for MRI-guided drug delivery. J. Am. Chem. Soc., 2018, 140: 4666-4677.

[25] Shen S, Wu Y, Liu Y, Wu D. High drug-loading nanomedicines: progress, current status, and prospects. Int. J. Nanomed., 2017, 12: 4085-4109.

[26] Teng Z, . Mesoporous organosilica hollow nanoparticles: synthesis and applications. Adv. Mater., 2019, 31: 1707612.

[27] Ding B, Zheng P, Ma P-A, Lin J. Manganese oxide nanomaterials: synthesis, properties, and theranostic applications. Adv. Mater., 2020, 32: 1905823.

[28] Xiang S, . Chelation competition induced polymerization (CCIP): a binding energy based strategy for nonspherical polymer nanocontainers’ fabrication. Chem. Mater., 2017, 29: 6536-6543.

[29] Xiang S, . Chelation competition induced polymerization (CCIP): construction of integrated hollow polydopamine nanocontainers with tailorable functionalities. Chem. Commun., 2016, 52: 10155.

[30] Tao K, . Targeted multifunctional nanomaterials with MRI, chemotherapy and photothermal therapy for the diagnosis and treatment of bladder cancer. Biomater. Sci., 2020, 8: 342-352.

[31] Xiang S, . Design and synthesis of dodecahedral carbon nanocages incorporated with Fe₃O₄. RSC Adv., 2017, 7: 13257.

[32] Wang C, . Iron oxide@polypyrrole nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy with synergistic antitumor effect. ACS Nano, 2013, 7: 6782-6795.

[33] Prasadh S, Manakari V, Parande G, Wong RCW, Gupta M. Hollow silica reinforced magnesium nanocomposites with enhanced mechanical and biological properties with computational modeling analysis for mandibular reconstruction. Int. J. Oral. Sci., 2020, 12: 31.

[34] He J, . Chitosan-coated hydroxyapatite and drug-loaded polytrimethylene carbonate/polylactic acid scaffold for enhancing bone regeneration. Carbohydr. Polym., 2021, 253: 117198.

[35] Suresh S, Castro LF, Dey S, Robey PG, Noguchi CT. Erythropoietin modulates bone marrow stromal cell differentiation. Bone Res., 2019, 7: 21.

[36] Ji M, . A novel porous aspirin-loaded (GO/CTS-HA)_n nanocomposite films: synthesis and multifunction for bone tissue engineering. Carbohydr. Polym., 2016, 153: 124-132.

[37] Bu W, . Ascorbic acid-PEI carbon dots with osteogenic effects as miR-2861 carriers to effectively enhance bone regeneration. ACS Appl. Mater. Interfaces, 2020, 12: 50287-50302.

[38] Nabavi MH, . A collagen-based hydrogel containing tacrolimus for bone tissue engineering. Drug Deliv. Transl. Res., 2020, 10: 108-121.

[39] Venkatesan N, . Biodegradable polymerized simvastatin stimulates bone formation. Acta Biomater., 2019, 93: 192-199.

[40] Wan L, . EPO promotes bone repair through enhanced cartilaginous callus formation and angiogenesis. PLoS ONE, 2014, 9: 111830.

[41] Xu X, . An injectable and thermosensitive hydrogel: promoting periodontal regeneration by controlled-release of aspirin and erythropoietin. Acta Biomater., 2019, 93: 235-246.

[42] Liu A, . Macrophage-derived small extracellular vesicles promote biomimetic mineralized collagen-mediated endogenous bone regeneration. Int. J. Oral. Sci., 2020, 12: 33.

[43] Yahiro Y, . BMP-induced Atoh8 attenuates osteoclastogenesis by suppressing Runx2 transcriptional activity and reducing the Rankl/Opg expression ratio in osteoblasts. Bone Res., 2020, 8: 32.

[44] Steffen U, Schett G, Bozec A. How autoantibodies regulate osteoclast induced bone loss in rheumatoid arthritis. Front. Immunol., 2019, 10: 1483.

[45] Solakoglu Ö, . Characterization of circulating DNA in plasma of patients after allogeneic bone grafting. Clin. Oral. Invest., 2019, 23: 4243-4253.

[46] Jones KJ, Cash BM. Matrix-induced autologous chondrocyte implantation with autologous bone grafting for osteochondral lesions of the femoral trochlea. Arthrosc. Tech., 2019, 8: 259-266.

Funding

National Natural Science Foundation of China (National Science Foundation of China)(81870741, 81920108012, 21774045)