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Research Article

Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy

Yulin Li1,5,§( ), Liudi Wang1,§, Guoqiang Zhong1,§, Guoying Wang1,§, Yanzhao Zhu4,§, Jian Li2, Lan Xiao6, Yanhui Chu4, Yan Wu4( ), Kaichun Li2( ), Jie Gao3( )
Engineering Research Centre for Biomedical Materials of Ministry of Education, The Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Material Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
Department of Oncology Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China
Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
College of Life Sciences Mudanjiang Medical University, Mudanjiang 157011, China
Wenzhou Institute of Shanghai University, Wenzhou 325000, China
Centre for Biomedical Technologies, Queensland University of Technology, Brisbane, QLD 4059, Australia

§ Yulin Li, Liudi Wang, Guoqiang Zhong, Guoying Wang, and Yanzhao Zhu contributed equally to this work.

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Graphical Abstract

By crosslinking laponite (LP) with gelatin for doxorubicin delivery, gelatin/laponite/doxorubicin (GLD) nanoparticles are developed. They show strong colloidal stability and reduced protein absorption, as demonstrated by superior penetration in both in vitro three-dimensional (3D) tumor spheroids and in vivo tumor models. The intracellular low pH and matrix metallopeptidase-2 (MMP-2) further cause doxorubicin release after endocytosis by tumor cells, leading to a higher inhibitory potential against cancer cells.

Abstract

There are several limitations to the application of nanoparticles in the treatment of cancer, including their low drug loading, poor colloidal stability, insufficient tumor penetration, and uncontrolled release of the drug. Herein, gelatin/laponite (LP)/doxorubicin (GLD) nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery. GLD shows high doxorubicin encapsulation efficacy (99%) and strong colloidal stability, as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles. When gelatin from 115 nm GLD reaches the tumor site, matrix metallopeptidase-2 (MMP-2) from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis. As demonstrated by superior penetration in both in vitro three-dimensional (3D) tumor spheroids (138-fold increase compared to the free drug) and in vivo tumor models. The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells, leading to a higher inhibitory potential against cancer cells. The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model. MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD, offering a useful method for anticancer therapy.

Keywords

sequentially triggered drug releasesize-transformablenanoparticlestumor penetrationanticancer therapydrug delivery

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References

[1]

Mu, W. W.; Chu, Q. H.; Liu, Y. J.; Zhang, N. A review on Nano-based drug delivery system for cancer chemoimmunotherapy. Nano-Micro Lett. 2020, 12, 142.
Crossref Google Scholar
[2]

Zhang, M. M.; Gao, S.; Yang, D. J.; Fang, Y.; Lin, X. J.; Jin, X. C.; Liu, Y. L.; Liu, X.; Su, K. X.; Shi, K. Influencing factors and strategies of enhancing nanoparticles into tumors in vivo. Acta Pharm. Sin. B 2021, 11, 2265–2285.
Crossref Google Scholar
[3]

Mitchell, M. J.; Billingsley, M. M.; Haley, R. M.; Wechsler, M. E.; Peppas, N. A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 2021, 20, 101–124.
Crossref Google Scholar
[4]

Niu, Y. M.; Zhu, J. H.; Li, Y.; Shi, H. H.; Gong, Y. X.; Li, R.; Huo, Q.; Ma, T.; Liu, Y. Size shrinkable drug delivery nanosystems and priming the tumor microenvironment for deep intratumoral penetration of nanoparticles. J. Control. Release 2018, 277, 35–47.
Crossref Google Scholar
[5]

Di, J. W.; Gao, X.; Du, Y. M.; Zhang, H.; Gao, J.; Zheng, A. P. Size, shape, charge and “stealthy” surface: Carrier properties affect the drug circulation time in vivo. Asian J. Pharm. Sci. 2021, 16, 444–458.
Crossref Google Scholar
[6]

Tan, J.; Li, H.; Hu, X. X.; Abdullah, R.; Xie, S. T.; Zhang, L. L.; Zhao, M. M.; Luo, Q.; Li, Y. Z.; Sun, Z. J. et al. Size-tunable assemblies based on ferrocene-containing DNA polymers for spatially uniform penetration. Chem 2019, 5, 1775–1792.
Crossref Google Scholar
[7]

Chen, Y. X.; Liu, X. J.; Yuan, H. F.; Yang, Z. G.; von Roemeling, C. A.; Qie, Y.; Zhao, H.; Wang, Y. F.; Jiang, W.; Kim, B. Y. S. Therapeutic remodeling of the tumor microenvironment enhances nanoparticle delivery. Adv. Sci. 2019, 6, 1802070.
Crossref Google Scholar
[8]

Ding, J. X.; Chen, J. J.; Gao, L. Q.; Jiang, Z. Y.; Zhang, Y.; Li, M. Q.; Xiao, Q. C.; Lee, S. S.; Chen, X. S. Engineered nanomedicines with enhanced tumor penetration. Nano Today 2019, 29, 100800.
Crossref Google Scholar
[9]

Guo, S. J.; Xu, C. C.; Yin, H. R.; Hill, J.; Pi, F. M.; Guo, P. X. Tuning the size, shape and structure of RNA nanoparticles for favorable cancer targeting and immunostimulation. WIREs Nanomed. Nanobiotechnol. 2020, 12, e1582.
Crossref Google Scholar
[10]

Cheng, G. H.; Zong, W.; Guo, H. Z.; Li, F. Y.; Zhang, X.; Yu, P.; Ren, F. X.; Zhang, X. L.; Shi, X. E.; Gao, F. et al. Programmed size-changeable nanotheranostic agents for enhanced imaging-guided chemo/photodynamic combination therapy and fast elimination. Adv. Mater. 2021, 33, 2100398.
Crossref Google Scholar
[11]

Sun, T. M.; Zhang, Y. S.; Pang, B.; Hyun, D. C.; Yang, M. X.; Xia, Y. N. Engineered nanoparticles for drug delivery in cancer therapy. Angew. Chem., Int. Ed. 2014, 53, 12320–12364.
Crossref Google Scholar
[12]

Jiang, H.; Guo, Y. D.; Wei, C. Y.; Hu, P.; Shi, J. L. Nanocatalytic innate immunity activation by mitochondrial DNA oxidative damage for tumor-specific therapy. Adv. Mater. 2021, 33, 2008065.
Crossref Google Scholar
[13]

Mai, B. T.; Fernandes, S.; Balakrishnan, P. B.; Pellegrino, T. Nanosystems based on magnetic nanoparticles and thermo- or pH-responsive polymers: An update and future perspectives. Acc. Chem. Res. 2018, 51, 999–1013.
Crossref Google Scholar
[14]

Li, X. L.; Xu, F. N.; He, Y.; Li, Y.; Hou, J. W.; Yang, G.; Zhou, S. B. A hierarchical structured ultrafine fiber device for preventing postoperative recurrence and metastasis of breast cancer. Adv. Funct. Mater. 2020, 30, 2004851.
Crossref Google Scholar
[15]

Zhou, Z. X.; Vázquez-González, M.; Willner, I. Stimuli-responsive metal-organic framework nanoparticles for controlled drug delivery and medical applications. Chem. Soc. Rev. 2021, 50, 4541–4563.
Crossref Google Scholar
[16]

Yang, Y. F.; Zhang, J. P. Highly stable lithium-sulfur batteries based on laponite nanosheet-coated celgard separators. Adv. Energy Mater. 2018, 8, 1801778.
Crossref Google Scholar
[17]

Chen, G. X.; Li, D.; Li, J. C.; Cao, X. Y.; Wang, J. H.; Shi, X. Y.; Guo, R. Targeted doxorubicin delivery to hepatocarcinoma cells by lactobionic acid-modified laponite nanodisks. New J. Chem. 2015, 39, 2847–2855.
Crossref Google Scholar
[18]

Takahashi, T.; Yamada, Y.; Kataoka, K.; Nagasaki, Y. Preparation of a novel PEG-clay hybrid as a DDS material: Dispersion stability and sustained release profiles. J. Control. Release 2005, 107, 408–416.
Crossref Google Scholar
[19]

Echave, M. C.; del Burgo, L. S.; Pedraz, J. L.; Orive, G. Gelatin as biomaterial for tissue engineering. Curr. Pharm. Des. 2017, 23, 3567–3584.
Crossref Google Scholar
[20]

Xu, P. W.; Jiang, F. L.; Zhang, H. B.; Yin, R. X.; Cen, L.; Zhang, W. J. Calcium carbonate/gelatin methacrylate microspheres for 3D cell culture in bone tissue engineering. Tissue Eng. Part C: Methods 2020, 26, 418–432.
Crossref Google Scholar
[21]

Zhou, X.; Tenaglio, S.; Esworthy, T.; Hann, S. Y.; Cui, H. T.; Webster, T. J.; Fenniri, H.; Zhang, L. G. Three-dimensional printing biologically inspired DNA-based gradient scaffolds for cartilage tissue regeneration. ACS Appl. Mater. Interfaces 2020, 12, 33219–33228.
Crossref Google Scholar
[22]

Liu, J. H.; Yan, L. W.; Yang, W.; Lan, Y.; Zhu, Q. Y.; Xu, H. J.; Zheng, C. B.; Guo, R. Controlled-release neurotensin-loaded silk fibroin dressings improve wound healing in diabetic rat model. Bioact. Mater. 2019, 4, 151–159.
Crossref Google Scholar
[23]

Qu, S. Q.; Dai, C. C.; Yang, F. F.; Huang, T. T.; Xu, T. L.; Zhao, L.; Li, Y. W.; Hao, Z. H. A comparison of two methods for the preparation cefquinome-loaded gelatin microspheres for lung targeting. Pharm. Res. 2018, 35, 43.
Crossref Google Scholar
[24]

Diba, M.; Pape, B.; Klymov, A.; Zhang, Y.; Song, J. K.; Löwik, D. W. P. M.; Seyednejad, H.; Leeuwenburgh, S. C. G. Nanostructured raspberry-like gelatin microspheres for local delivery of multiple biomolecules. Acta Biomater. 2017, 58, 67–79.
Crossref Google Scholar
[25]

Ceylan, H.; Yasa, I. C.; Yasa, O.; Tabak, A. F.; Giltinan, J.; Sitti, M. 3D-printed biodegradable microswimmer for theranostic cargo delivery and release. ACS Nano 2019, 13, 3353–3362.
Crossref Google Scholar
[26]

Fang, T.; Zhang, J.; Zuo, T.; Wu, G.; Xu, Y.; Yang, Y.; Yang, J.; Shen, Q. Chemo-photothermal combination cancer therapy with ROS scavenging, extracellular matrix depletion, and tumor immune activation by telmisartan and diselenide-paclitaxel prodrug loaded nanoparticles. ACS Appl. Mater. Interfaces 2020, 12, 31292–31308.
Crossref Google Scholar
[27]

Chen, X. J.; Zou, J. F.; Zhang, K.; Zhu, J. J.; Zhang, Y.; Zhu, Z. H.; Zheng, H. Y.; Li, F. Z.; Piao, J. G. Photothermal/matrix metalloproteinase-2 dual-responsive gelatin nanoparticles for breast cancer treatment. Acta Pharm. Sini. B 2021, 11, 271–282.
Crossref Google Scholar
[28]

Bellat, V.; Ting, R.; Southard, T. L.; Vahdat, L.; Molina, H.; Fernandez, J.; Aras, O.; Stokol, T.; Law, B. Functional peptide nanofibers with unique tumor targeting and enzyme-induced local retention properties. Adv. Funct. Mater. 2018, 28, 1803969.
Crossref Google Scholar
[29]

Adib, A. A.; Sheikhi, A.; Shahhosseini, M.; Simeunović, A.; Wu, S.; Castro, C. E.; Zhao, R.; Khademhosseini, A.; Hoelzle, D. J. Direct-write 3D printing and characterization of a GelMA-based biomaterial for intracorporeal tissue engineering. Biofabrication 2020, 12, 045006.
Crossref Google Scholar
[30]

Pawar, N.; Bohidar, H. B. Anisotropic domain growth and complex coacervation in nanoclay-polyelectrolyte solutions. Adv. Colloid Interface Sci. 2011, 167, 12–23.
Crossref Google Scholar
[31]

Karimi, F.; Taheri Qazvini, N.; Namivandi-Zangeneh, R. Fish gelatin/laponite biohybrid elastic coacervates: A complexation kinetics–structure relationship study. Int. J. Biol. Macromol 2013, 61, 102–113.
Crossref Google Scholar
[32]

Viseras, C.; Cerezo, P.; Sanchez, R.; Salcedo, I.; Aguzzi, C. Current challenges in clay minerals for drug delivery. Appl. Clay Sci. 2010, 48, 291–295.
Crossref Google Scholar
[33]

Wu, W. T.; Dong, Z.; He, J. S.; Yu, J.; Zhang, J. Transparent cellulose/laponite nanocomposite films. J. Mater. Sci. 2016, 51, 4125–4133.
Crossref Google Scholar
[34]

Ivanenkov, Y. A.; Machulkin, A. E.; Garanina, A. S.; Skvortsov, D. A.; Uspenskaya, A. A.; Deyneka, E. V.; Trofimenko, A. V.; Beloglazkina, E. K.; Zyk, N. V.; Koteliansky, V. E. et al. Synthesis and biological evaluation of doxorubicin-containing conjugate targeting PSMA. Bioorg. Med. Chem. Lett. 2019, 29, 1246–1255.
Crossref Google Scholar
[35]

Dai, Y. L.; Yang, D. M.; Ma, P. A.; Kang, X. J.; Zhang, X.; Li, C. X.; Hou, Z. Y.; Cheng, Z. Y.; Lin, J. Doxorubicin conjugated NaYF4: Yb3+/Tm3+ nanoparticles for therapy and sensing of drug delivery by luminescence resonance energy transfer. Biomaterials 2012, 33, 8704–8713.
Crossref Google Scholar
[36]

Zheng, L.; Zhou, B. J.; Qiu, X. F.; Xu, X.; Li, G.; Lee, W. Y. W.; Jiang, J.; Li, Y. L. Direct assembly of anticancer drugs to form laponite-based nanocomplexes for therapeutic co-delivery. Mater. Sci. Eng. C 2019, 99, 1407–1414.
Crossref Google Scholar
[37]

Fan, Y.; Wang, Q. J.; Lin, G. M.; Shi, Y. B.; Gu, Z. L.; Ding, T. T. Combination of using prodrug-modified cationic liposome nanocomplexes and a potentiating strategy via targeted co-delivery of gemcitabine and docetaxel for CD44-overexpressed triple negative breast cancer therapy. Acta Biomater. 2017, 62, 257–272.
Crossref Google Scholar
[38]

Meng, H.; Xue, M.; Xia, T.; Zhao, Y. L.; Tamanoi, F.; Stoddart, J. F.; Zink, J. I.; Nel, A. E. Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. J. Am. Chem. Soc. 2010, 132, 12690–12697.
Crossref Google Scholar
[39]

Fang, C.; Bhattarai, N.; Sun, C.; Zhang, M. Q. Functionalized nanoparticles with long-term stability in biological media. Small 2009, 5, 1637–1641.
Crossref Google Scholar
[40]

Wang, X. Y.; Wang, X. F.; Wang, M. Z.; Zhang, D.; Yang, Q.; Liu, T.; Lei, R.; Zhu, S. F.; Zhao, Y. L.; Chen, C. Y. Probing adsorption behaviors of BSA onto chiral surfaces of nanoparticles. Small 2018, 14, 1703982.
Crossref Google Scholar
[41]

Zhang, Y. Z.; Cui, H. G.; Zhang, R. Q.; Zhang, H. B.; Huang, W. Nanoparticulation of prodrug into medicines for cancer therapy. Adv. Sci. 2021, 8, 2101454.
Crossref Google Scholar
[42]

Li, M. Q.; Tang, Z. H.; Lv, S. X.; Song, W. T.; Hong, H.; Jing, X. B.; Zhang, Y. Y.; Chen, X. S. Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. Biomaterials 2014, 35, 3851–3864.
Crossref Google Scholar
[43]

Higuchi, T.; Takeuchi, A.; Munesue, S.; Yamamoto, N.; Hayashi, K.; Kimura, H.; Miwa, S.; Inatani, H.; Shimozaki, S.; Kato, T. et al. Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression. Cancer Med. 2018, 7, 1944–1954.
Crossref Google Scholar
[44]

Yang, Y. M.; Yue, C. X.; Han, Y.; Zhang, W.; He, A. N.; Zhang, C. L.; Yin, T.; Zhang, Q.; Zhang, J. J.; Yang, Y. et al. Tumor-responsive small molecule self-assembled nanosystem for simultaneous fluorescence imaging and chemotherapy of lung cancer. Adv. Funct. Mater. 2016, 26, 8735–8745.
Crossref Google Scholar
[45]

Zhang, P. H.; Wang, Y.; Lian, J.; Shen, Q.; Wang, C.; Ma, B. H.; Zhang, Y. C.; Xu, T. T.; Li, J. X.; Shao, Y. P. et al. Engineering the surface of smart nanocarriers using a pH-/thermal-/GSH-responsive polymer zipper for precise tumor targeting therapy in vivo. Adv. Mater. 2017, 29, 1702311.
Crossref Google Scholar
[46]

Schroeder, A.; Heller, D. A.; Winslow, M. M.; Dahlman, J. E.; Pratt, G. W.; Langer, R.; Jacks, T.; Anderson, D. G. Treating metastatic cancer with nanotechnology. Nat. Rev. Cancer 2012, 12, 39–50.
Crossref Google Scholar
[47]

Zhuang, J. L.; Zhang, J.; Wu, M. H.; Zhang, Y. Q. A dynamic 3D tumor spheroid chip enables more accurate nanomedicine uptake evaluation. Adv. Sci. 2019, 6, 1901462.
Crossref Google Scholar
[48]

Rodrigues, T.; Kundu, B.; Silva-Correia, J.; Kundu, S. C.; Oliveira, J. M.; Reis, R. L.; Correlo, V. M. Emerging tumor spheroids technologies for 3D in vitro cancer modeling. Pharmacol. Therapeut. 2018, 184, 201–211.
Crossref Google Scholar
[49]

Ruan, S. B.; Yuan, M. Q.; Zhang, L.; Hu, G. L.; Chen, J. T.; Cun, X. L.; Zhang, Q. Y.; Yang, Y. T.; He, Q.; Gao, H. L. Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles. Biomaterials 2015, 37, 425–435.
Crossref Google Scholar
[50]

Kim, J.; Jo, C.; Lim, W. G.; Jung, S.; Lee, Y. M.; Lim, J.; Lee, H.; Lee, J.; Kim, W. J. Programmed nanoparticle-loaded nanoparticles for deep-penetrating 3D cancer therapy. Adv. Mater. 2018, 30, 1707557.
Crossref Google Scholar
[51]

Zhang, Z. W.; Wang, H.; Tan, T.; Li, J.; Wang, Z. W.; Li, Y. P. Rational design of nanoparticles with deep tumor penetration for effective treatment of tumor metastasis. Adv. Funct. Mater. 2018, 28, 1801840.
Crossref Google Scholar
Nano Research
Volume 16 Issue 8,
August 2023
Pages 11186-11196
DOI: 10.1007/s12274-023-5833-5
Cite this article:
Li Y, Wang L, Zhong G, et al. Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy. Nano Research, 2023, 16(8): 11186-11196. https://doi.org/10.1007/s12274-023-5833-5
Topics:
Drug delivery

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Received: 01 March 2023
Revised: 09 May 2023
Accepted: 11 May 2023
Published: 25 July 2023
© Tsinghua University Press 2023
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