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Engineering of ultrasound contracts agents-focused cabazitaxel-loaded microbubbles nanomaterials induces cell proliferation and enhancing apoptosis in cancer cells

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Abstract

Tumour-induced sentinel lymph node diagnosis and metastatic therapeutic techniques are limited by current strategies nowadays. Herein, we combined iron oxide nanomaterials with chemotherapy drugs in poly(lactic-co-glycolic acid) multifunctional microbubbles (MMBs) to develop and visualize tumour lymph node treatment. Fabrication and loading of perfluorocarbon gas-filled PLGA microbubbles with co-encapsulated cabazitaxel (CTX) and Fe3O4 nanomaterials were accomplished. Ultrasound (US) imaging enhancement and US-induced drug delivery have been investigated in vitro and in vivo to improve the outcomes. The MMBs had a mean size of 881.45 ± 70.19 nm, with a narrow size dispersion and a smooth surface. It was also shown that the amount of Fe3O4 nanomaterials in the MBs did not affect the CTX drug loading efficiency or encapsulation. Our outcomes showed that these MMBs could improve ultrasound imaging in vitro and in vivo and improve tumour lymph node signals. Biomarkers of tumour proliferation profile and micro blood/lymphatic vessel density were used to assess the anti-tumour efficacy of MMBs-mediated chemotherapy in vivo. These markers were consistently lower after MMBs + sonication treatment than controls. The tumour cell apoptosis index was shown to be highest following MMBs plus sonication treatment, which is in line with this finding. A cabazitaxel-loaded PLGA-Fe3O4 nanomaterials therapeutic and diagnostic agent for low-frequency US-triggered US imaging of the lymph node metastasis has been developed successfully. It may provide an approach for the chemotherapy and imaging of primary metastasis tumours.

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References

  • Azzali G (2003) Transendothelial transport and migration in vessels of the apparatus lymphaticus periphericus absorbens (ALPA). Int Rev Cytol 230:42–89

    Google Scholar 

  • Balaji S, Mohamed Subarkhan MK, Ramesh R, Wang H, Semeril D (2020) Synthesis and structure of arene Ru(II) N∧O-chelating complexes: in vitro cytotoxicity and cancer cell death mechanism. Organometallics 39:1366–1375. https://doi.org/10.1021/acs.organomet.0c00092

    Article  CAS  Google Scholar 

  • Berg D (2006) In vivo detection of iron and neuromelanin by transcranial sonography–a new approach for early detection of substantia nigra damage. J Neural Transm 113:775–780

    Article  CAS  Google Scholar 

  • Chen Y, Liang Y, Jiang P, Li F, Yu B, Yan F (2019) Lipid/PLGA hybrid microbubbles as a versatile platform for noninvasive image-guided targeted drug delivery. ACS Appl Mater Interfaces 11:41842–41852

    Article  CAS  Google Scholar 

  • Chen M, Lv Z, Qian F, Wang Y, Xing X, Zhou K, Wang J, Huang S, Han S-T, Zhou Y (2021) Phototunable memories and reconfigurable logic applications based on natural melanin. J Mater Chem C 9:3569–3577. https://doi.org/10.1039/D1TC00052G

    Article  CAS  Google Scholar 

  • Danafar H (2018) Preparation and characterization of PCL-PEG-PCL copolymeric nanoparticles as polymersomes for delivery hydrophilic drugs. Iran J Pharm Sci 14:21–32

    Google Scholar 

  • Devulapally R, Lee T, Barghava-Shah A, Sekar TV, Foygel K, Bachawal SV, Willmann JK, Paulmurugan R (2018) Ultrasound-guided delivery of thymidine kinase–nitroreductase dual therapeutic genes by PEGylated-PLGA/PEI nanoparticles for enhanced triple negative breast cancer therapy. Nanomedicine 13:1051–1066

    Article  CAS  Google Scholar 

  • Di Salvo DN (2001) A new view of the neonatal brain: clinical utility of supplemental neurologic US imaging windows. Radiographics 21:943–955

    Article  Google Scholar 

  • Di Ianni T, Bose RJC, Sukumar UK, Bachawal S, Wang H, Telichko A, Herickhoff C, Robinson E, Baker S, Vilches-Moure JG (2019) Ultrasound/microbubble-mediated targeted delivery of anticancer microRNA-loaded nanoparticles to deep tissues in pigs. J Control Release 309:1–10

    Article  CAS  Google Scholar 

  • Ding Y, Li Z, Jaklenec A, Hu Q (2021) Vaccine delivery systems toward lymph nodes. Adv Drug Deliv Rev 179:113914

    Article  CAS  Google Scholar 

  • Eide PK, Vatnehol SAS, Emblem KE, Ringstad G (2018) Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep 8:1–10

    Article  Google Scholar 

  • Ferrara KW, Merritt CRB, Burns PN, Foster FS, Mattrey RF, Wickline SA (2000) Evaluation of tumor angiogenesis with US: imaging, Doppler, and contrast agents. Acad Radiol 7:824–839

    Article  CAS  Google Scholar 

  • Gong Y, Xing X, Wang Y, Lv Z, Zhou Y, Han S-T (2021) Emerging MXenes for functional memories. Small Sci 1:2100006. https://doi.org/10.1002/smsc.202100006

    Article  Google Scholar 

  • Huang S, Ziegler CGK, Austin J, Mannoun N, Vukovic M, Ordovas-Montanes J, Shalek AK, von Andrian UH (2021) Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential. Cell 184:441–459

    Article  CAS  Google Scholar 

  • Jung SJ (2012) Protocol development for observation of the primo vascular system in lymphatic system. J Acupunct Meridian Stud 5:234–240

    Article  Google Scholar 

  • Kato T, Prevo R, Steers G, Roberts H, Leek RD, Kimura T, Kameoka S, Nishikawa T, Kobayashi M, Jackson DG (2005) A quantitative analysis of lymphatic vessels in human breast cancer, based on LYVE-1 immunoreactivity. Br J Cancer 93:1168–1174

    Article  CAS  Google Scholar 

  • Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Gatter KC, Harris AL, Jackson DG (2005) LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer. J Clin Pathol 58:202–206

    Article  CAS  Google Scholar 

  • Kumar SU, Telichko AV, Wang H, Hyun D, Johnson EG, Kent MS, Rebhun RB, Dahl JJ, Culp WTN, Paulmurugan R (2020) Acoustically driven microbubbles enable targeted delivery of microRNA-loaded nanoparticles to spontaneous hepatocellular neoplasia in canines. Adv Ther 3:2000120

    Article  CAS  Google Scholar 

  • Lee C, Jeong S, Jang C, Bae H, Kim YH, Park I, Kim SK, Koh GY (2019) Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation. Science 363:644–649

    Article  CAS  Google Scholar 

  • Li Y, Wu M, Zhang N, Tang C, Jiang P, Liu X, Yan F, Zheng H (2018) Mechanisms of enhanced antiglioma efficacy of polysorbate 80-modified paclitaxel-loaded PLGA nanoparticles by focused ultrasound. J Cell Mol Med 22:4171–4182

    Article  CAS  Google Scholar 

  • Liu Z, Lammers T, Ehling J, Fokong S, Bornemann J, Kiessling F, Gätjens J (2011) Iron oxide nanoparticle-containing microbubble composites as contrast agents for MR and ultrasound dual-modality imaging. Biomaterials 32:6155–6163

    Article  CAS  Google Scholar 

  • Liu J, Li H-J, Luo Y-L, Xu C-F, Du X-J, Du J-Z, Wang J (2019a) Enhanced primary tumor penetration facilitates nanoparticle draining into lymph nodes after systemic injection for tumor metastasis inhibition. ACS Nano 13:8648–8658

    Article  CAS  Google Scholar 

  • Liu H, Ren F, Zhou X, Ma C, Wang T, Zhang H, Sun Q, Li Z (2019b) Ultra-sensitive detection and inhibition of the metastasis of breast cancer cells to adjacent lymph nodes and distant organs by using long-persistent luminescence nanoparticles. Anal Chem 91:15064–15072

    Article  CAS  Google Scholar 

  • Lv Z, Chen M, Qian F, Roy VAL, Ye W, She D, Wang Y, Xu Z-X, Zhou Y, Han S-T (2019) Mimicking neuroplasticity in a hybrid biopolymer transistor by dual modes modulation. Adv Funct Mater 29:1902374. https://doi.org/10.1002/adfm.201902374

    Article  CAS  Google Scholar 

  • Lv Z, Wang Y, Chen J, Wang J, Zhou Y, Han S-T (2020) Semiconductor quantum dots for memories and neuromorphic computing systems. Chem Rev 120:3941–4006. https://doi.org/10.1021/acs.chemrev.9b00730

    Article  CAS  Google Scholar 

  • Mohamed Kasim MS, Sundar S, Rengan R (2018) Synthesis and structure of new binuclear ruthenium(II) arene benzil bis(benzoylhydrazone) complexes: investigation on antiproliferative activity and apoptosis induction. Inorg Chem Front 5:585–596. https://doi.org/10.1039/C7QI00761B

    Article  CAS  Google Scholar 

  • Mohamed Subarkhan MK, Ramesh R, Liu Y (2016) Synthesis and molecular structure of arene ruthenium(II) benzhydrazone complexes: impact of substitution at the chelating ligand and arene moiety on antiproliferative activity. New J Chem. https://doi.org/10.1039/c6nj01936f

    Article  Google Scholar 

  • Mohan N, Mohamed Subarkhan MK, Ramesh R (2018) Synthesis, antiproliferative activity and apoptosis-promoting effects of arene ruthenium(II) complexes with N, O chelating ligands. J Organomet Chem. https://doi.org/10.1016/j.jorganchem.2018.01.022

    Article  Google Scholar 

  • Najibi AJ, Mooney DJ (2020) Cell and tissue engineering in lymph nodes for cancer immunotherapy. Adv Drug Deliv Rev 161–162:42–62

    Article  CAS  Google Scholar 

  • Ohtani O, Ohtani Y (2008) Structure and function of rat lymph nodes. Arch Histol Cytol 71:69–76

    Article  Google Scholar 

  • Prat F, Centarti M, Sibille A, El Fadil FA, Henry L, Chapelon J, Cathignol D (1995) Extracorporeal high-intensity focused ultrasound for VX2 liver tumors in the rabbit. Hepatology 21:832–836

    CAS  Google Scholar 

  • Price RJ (2018) Targeted delivery of controlled release nanoparticles to brain tumors using contrast agent microbubbles and high-intensity focused ultrasound

  • Sanz-Ortega L, Rojas JM, Marcos A, Portilla Y, Stein JV, Barber DF (2019) T cells loaded with magnetic nanoparticles are retained in peripheral lymph nodes by the application of a magnetic field. J Nanobiotechnol 17:1–20

    Article  CAS  Google Scholar 

  • SathiyaKamatchi T, Mohamed Subarkhan MK, Ramesh R, Wang H, Małecki JG (2020) Investigation into antiproliferative activity and apoptosis mechanism of new arene Ru(II) carbazole-based hydrazone complexes. Dalt Trans 49:11385–11395. https://doi.org/10.1039/D0DT01476A

    Article  CAS  Google Scholar 

  • Schreuder A, Jacobs C, Scholten ET, van Ginneken B, Schaefer-Prokop CM, Prokop M (2020) Typical CT features of intrapulmonary lymph nodes: a review. Radiol Cardiothorac Imaging 2:e190159

    Article  Google Scholar 

  • Schudel A, Chapman AP, Yau M-K, Higginson CJ, Francis DM, Manspeaker MP, Avecilla ARC, Rohner NA, Finn MG, Thomas SN (2020) Programmable multistage drug delivery to lymph nodes. Nat Nanotechnol 15:491–499

    Article  CAS  Google Scholar 

  • Shen X, Li T, Xie X, Feng Y, Chen Z, Yang H, Wu C, Deng S, Liu Y (2020) PLGA-based drug delivery systems for remotely triggered cancer therapeutic and diagnostic applications. Front Bioeng Biotechnol 8:381

    Article  Google Scholar 

  • Shi H, Yan R, Wu L, Sun Y, Liu S, Zhou Z, He J, Ye D (2018) Tumor-targeting CuS nanoparticles for multimodal imaging and guided photothermal therapy of lymph node metastasis. Acta Biomater 72:256–265

    Article  CAS  Google Scholar 

  • Som PM, Francois M (2017) The current concepts of the embryology of the lymphatic system. Neurographics 7:129–150

    Article  Google Scholar 

  • Sonamuthu J, Cai Y, Liu H, Kasim MSM, Vasanthakumar VR, Pandi B, Wang H, Yao J (2020) MMP-9 responsive dipeptide-tempted natural protein hydrogel-based wound dressings for accelerated healing action of infected diabetic wound. Int J Biol Macromol 153:1058–1069. https://doi.org/10.1016/j.ijbiomac.2019.10.236

    Article  CAS  Google Scholar 

  • Steiner DF, MacDonald R, Liu Y, Truszkowski P, Hipp JD, Gammage C, Thng F, Peng L, Stumpe MC (2018) Impact of deep learning assistance on the histopathologic review of lymph nodes for metastatic breast cancer. Am J Surg Pathol 42:1636

    Article  Google Scholar 

  • Subarkhan MKM, Ramesh R (2016) Ruthenium(II) arene complexes containing benzhydrazone ligands: Synthesis, structure and antiproliferative activity. Inorg Chem Front 3:1245–1255. https://doi.org/10.1039/c6qi00197a

    Article  CAS  Google Scholar 

  • Wang X, Niu D, Li P, Wu Q, Bo X, Liu B, Bao S, Su T, Xu H, Wang Q (2015) Dual-enzyme-loaded multifunctional hybrid nanogel system for pathological responsive ultrasound imaging and T 2-weighted magnetic resonance imaging. ACS Nano 9:5646–5656

    Article  CAS  Google Scholar 

  • Wang L, Chen S, Zhu Y, Zhang M, Tang S, Li J, Pei W, Huang B, Niu C (2018) Triple-modal imaging-guided chemo-photothermal synergistic therapy for breast cancer with magnetically targeted phase-shifted nanoparticles. ACS Appl Mater Interfaces 10:42102–42114

    Article  CAS  Google Scholar 

  • Willmann JK, Paulmurugan R, Chen K, Gheysens O, Rodriguez-Porcel M, Lutz AM, Chen IY, Chen X, Gambhir SS (2008) US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice. Radiology 246:508–518

    Article  Google Scholar 

  • Witte MH, Bernas MJ, Martin CP, Witte CL (2001) Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55:122–145

    Article  CAS  Google Scholar 

  • Xin Y, Qi Q, Mao Z, Zhan X (2017) PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: in vitro and in vivo investigations. Int J Pharm 528:47–54

    Article  CAS  Google Scholar 

  • Xu Y, Niu C, An S, Tang S, Xiao P, Peng Q, Wang L (2017) Thermal-sensitive magnetic nanoparticles for dual-modal tumor imaging and therapy. RSC Adv 7:40791–40802

    Article  CAS  Google Scholar 

  • Yu X, Dai Y, Zhao Y, Qi S, Liu L, Lu L, Luo Q, Zhang Z (2020) Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic anti-tumor immune response. Nat Commun 11:1–14

    CAS  Google Scholar 

  • Zaki NM, Hafez MM (2012) Enhanced antibacterial effect of ceftriaxone sodium-loaded chitosan nanoparticles against intracellular Salmonella typhimurium. Aaps Pharmscitech 13:411–421

    Article  CAS  Google Scholar 

  • Zhang C, Li X, Zhang Z, Lei S, Fan P, Xiao Q (2019a) The potential role of carbon nanoparticles-assisted biopsy for sentinel lymph nodes of incidental thyroid carcinoma. Gland Surg 8:370

    Article  Google Scholar 

  • Zhang Y, Yong L, Luo Y, Ding X, Xu D, Gao X, Yan S, Wang Q, Luo J, Pu D (2019b) Enhancement of HIFU ablation by sonosensitizer-loading liquid fluorocarbon nanoparticles with pre-targeting in a mouse model. Sci Rep 9:1–18

    Google Scholar 

  • Zhu J (2020) Imaging lymphatic system using high frame rate contrast enhanced and super-resolution ultrasound: in vitro, in vivo and clinical study

  • Zhuang J, Fan K, Gao L, Lu D, Feng J, Yang D, Gu N, Zhang Y, Liang M, Yan X (2012) Ex vivo detection of iron oxide magnetic nanoparticles in mice using their intrinsic peroxidase-mimicking activity. Mol Pharm 9:1983–1989

    Article  CAS  Google Scholar 

  • Zukancic D, Suys EJA, Pilkington EH, Algarni A, Al-Wassiti H, Truong NP (2020) The importance of poly (ethylene glycol) and lipid structure in targeted gene delivery to lymph nodes by lipid nanoparticles. Pharmaceutics 12:1068

    Article  CAS  Google Scholar 

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Liu, H., Bai, L., Chen, Z. et al. Engineering of ultrasound contracts agents-focused cabazitaxel-loaded microbubbles nanomaterials induces cell proliferation and enhancing apoptosis in cancer cells. Appl Nanosci 12, 1829–1838 (2022). https://doi.org/10.1007/s13204-022-02376-y

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