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Tumor Specific Functional Nanomaterials for Bio-Applications

已有 1516 次阅读 2021-1-16 10:27 |系统分类:论文交流

Tumor Microenvironment-Specific Functional Nanomaterials for Biomedical Applications

Linlu Zhao【赵琳璐】1, Heng Liu【刘恒】1, Yanlong Xing【邢艳珑】1, Rui Wang【王锐】1, Ziyi Cheng【程子译】1, Chuanzhu Lv【吕传柱】1 ∗, Zhiyue Lv【吕志跃】1 2 3 ∗, and Fabiao Yu【于法标】1 ∗

1 Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Institute of Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China

2 Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou 571199, China

3 Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China

Copyright © 2020 American Scientific Publishers  All rights reserved  Printed in the United States of America

Journal of Biomedical Nanotechnology Vol. 16, 1325–1358, 2020  www.aspbs.com/jbn

Abstract: In recent years, great progress has been made to motivate the construction of tumor microenvironment (TME)-specific functional nanomaterials, which can effectively response to the intrinsic pathological and physicochemical factors in diseased regions to improve the specificity of imaging and drug delivery. Up to now, various nanoarchitectures have been designed to combat with cancer effectively and specifically. This review outlines the most up-to-date developments in TME-specific theranostic nanoplatforms based on multifunctional nanomaterials that hold the potential to achieve targeted recognition to tumor sites. Recent progress and achievements have also been summarized in nanosystems that can specifically response to TME, presenting different stimuli-sensitive strategies and their applications in drug delivery, tumor imaging, therapy and synergistic theranostics. This review aims to highlight the significance of functional nanomaterials in response to tumor stimulus for enhancing anticancer efficacy and promoting its development in extensive research fields ranging from nanoscience to biomedicine and clinical applications.

Keywords: Functional Nanomaterials, Cancer Therapy, Tumor Microenvironment, Drug Delivery, Activable Imaging.




Passive targeting strategy: the EPR effect

Size effect

Surface properties of nanoparticles

Active targeting utilizing TME-specific molecular markers

Targeting tumor blood vessels

Target cancer-associated stromal cells

Targeting tumor metastasis organs

Design of the acidic TME-responsive nanotheranostics






Combined Therapy

Enzyme-overexpression inspired functional nanomaterials

Enzymatic cleavage-based stimuli-responsive optical  nanoprobes

Enzyme-triggered drug release for targeted tumor therapy

Enzyme-responsive nanomaterials for imaging-guided  synergistic therapy

Oxidation-reduction regulated activatable nanosystem

ROS-responsive drug delivery nanosystems

GSH--responsive drug delivery nanosystems

Construction of efficient therapeutic nanomaterials based on  tumor-specific hypoxic microenvironment

Nanomaterials specific to hypoxia-responsive cargo  liberation.

Multifunctional nanotheranostic system combined with  hypoxia-activated therapy.

Conclusion and outlook




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Figure 2. (a) Stimuli-responsive programmed specific targeting nanosystems based on switchable surface charge, uncaged targeting molecules, conformation changeable targeting molecules, unshielded targeting molecules, and unbound targeting molecules. Reprinted with permission from [83] Wang, S. et al., 2016. Stimuli-Responsive Programmed Specific Targeting in Nanomedicine. ACS Nano, 10(3), pp. 2991-2994. Copyright © 2016, American Chemical Society. (b) Differently sized polymers were administered i.v. in mice bearing epidermoid carcinoma (A431) and prostate carcinoma (PC3) xenografts. Nanomedicine with sizes in the range of therapeutic antibodies show balanced properties with respect to passive accumulation, tissue penetration and active targeting. Reprinted with permission from [84], Tsvetkova, Y. et al., 2017. Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers. Nano Letter, 17(8), pp. 4665-4674. Copyright © 2017, American Chemical Society.


Figure 3. (a) Structure and working principle of the split i-motif based pH-activatable aptamer probe (pH-AAP) strategy for tumor imaging. Reprinted with permission from [93], Wang K. et al., 2018. Ultra-pH-responsive split i-motif based aptamer anchoring strategy for specific activatable imaging of acidic tumor microenvironment. Chemical Communications, 54(73), p.p. 10288-10291. Copyright @ The Royal Society of Chemistry. (b) Nanoprobe injected intravenously passes through the impaired blood vessel to enter cancerous tissue. Reprinted with permission from [95], Gao M. et al., 2018. Dual-ratiometric target-triggered fluorescent probe for simultaneous quantitative visualization of tumor microenvironment protease activity and pH in vivo. Journal of the American Chemical Society, 140 (1), p.p. 211-218. Copyright @ American Chemical Society. (c) Illustration of pH-PTT as a smart drug for specific Golgi apparatus activated PTT. Reprinted with permission from [98], Yi T. et al., 2017. A smart drug: a pH-responsive photothermal ablation agent for Golgi apparatus activated cancer therapy. Chemical Communications, 53(48), p.p. 6424-6427. Copyright @ The Royal Society of Chemistry. (d) Illustration of the self-assembled HSA/dc-IR825/GA NPs for synergistic molecular targeting-mediated mild-temperature PTT and chemotherapy. Reprinted with permission from [100], Wu F. et al., 2019. Molecular targeting-mediated mild-temperature photothermal therapy with a smart albumin-based nanodrug. Small, 15(33), p.p. 1900501. Copyright @ WILEY-VCH.


Figure 4. (a) Illustration of self-assembly for Catalase & Chitosan-Ce6 (C&C-Ce6) nanoparticles and the pH-triggered release of Catalase for rapid O2-release for effective PDT. Reprinted with permission from [103], Zhang Z. et al., 2017. pH-Responsive aerobic nanoparticles for effective photodynamic therapy. Theranostics, 7, p.p. 4537. Copyright @ Theranostics. (b) Schematic illustration of M-TPPa for dual-stage precisely targeting of early endosome and mitochondria to amplify photodynamic therapy. Reprinted with permission from [107], Wang Y. et al., 2019. A pH-Activatable nanoparticle for dual-stage precisely mitochondria-targeted photodynamic anticancer therapy. Biomaterials, 213, p.p. 119219. Copyright @ Elesvier. (c) Illustration of the charge reversal PPDC system with self-amplifiable drug release for tumor therapy in vivo. Reprinted with permission from [109], Yang H. et al., 2019. A pH/ROS cascade-responsive charge-reversal nanosystem with self-amplified drug release for synergistic oxidation-chemotherapy. Advanced Science, 6, p.p. 1801807. Copyright @ WILEY-VCH. (d) Illustration of the synthesis of the drug-loaded PEG-cZnO clusters as a drug delivery system and the subsequent cellular uptake for the effective delivery of the drug. Reprinted with permission from [111], Lin Y. et al., 2017. pH-Responsive ZnO nanocluster for lung cancer chemotherapy. ACS Applied Materials & Interfaces, 9, p.p. 5739. Copyright @ American Chemical Society. (e) Schematic illustration for the synthesis of antigens-loaded MOFs by a very simple “One-Step” process and illustration of enhanced antitumor response of the coloaded nanocarriers. Reprinted with permission from [115], Zhang J. et al., 2017. A simple and powerful co-delivery system based on pH-responsive metal-organic frameworks for enhanced cancer immunotherapy. Biomaterials, 122, p.p. 23. Copyright @ Elesvier. (f) Schematic representation of DLNP for effective cancer immunotherapy. Reprinted with permission from [117], Liu Y. et al., 2019. Dual-locking nanoparticles disrupt the PD-1/PD-L1 pathway for efficient cancer immunotherapy. Advanced Materials, 31, p.p. 1905751. Copyright @ WILEY-VCH.


Figure 5. (a) Illustration of the synthesis of NdIII-IP virus-like nanodrug and tumor acidity responsive shape-reversal spherical-shell camouflaged hierarchical nanoassembly (NdIII-IP-N=CH-PEG nanosphere); Accumulation of NdIII-IP-N=CH-PEG nanospheres in tumors via reduced immune clearance and prolonged blood circulation. Reprinted with permission from [120], Liu X. et al., 2019. Tumor microenvironment responsive shape-reversal self-targeting virus-inspired Nanodrug for imaging-guided near-infrared-II photothermal chemotherapy. ACS Nano, 13, p.p. 12912. Copyright @ American Chemical Society. (b) Illustration of construction of pH-Responsive Nanovesicles (pRNVs/HPPH/IND) via Co-assembly of HPPH, IND, and pH-responsive polypeptide and promotion of host immunity. Reprinted with permission from [122], Chen X. et al., 2020. Smart nanovesicle-mediated immunogenic cell death through tumor microenvironment modulation for effective photodynamic immunotherapy. ACS Nano, 14(1), p.p. 620-631. Copyright @ American Chemical Society.


Figure 6. (a) Schematic illustration of the Au–Se nanoprobes with cathepsin B and caspase-3 in a biosystem. Reprinted with permission from [134], Gao X. et al., 2020. Real-time in situ monitoring of signal molecules’ evolution in apoptotic pathway via Au–Se bond constructed nanoprobe. Biosensors and Bioelectronics, 147, p.p. 111755. Copyright @ Elsevier. (b) The structure and reaction mechanism of the MMP-9-cleavable FRET-based nanoprobe (left) and fluorescent imaging of MMP-9 activity and tumor microenvironment pH. Reprinted with permission from [137], Ma T. et al., 2018. Dual-Ratiometric Target-Triggered Fluorescent Probe for Simultaneous Quantitative Visualization of Tumor Microenvironment Protease Activity and pH in Vivo. Journal of the American Chemical Society, 140, p.p. 211-218. Copyright @ American Chemical Society. (c) Schematic illustration for the detection of MMP-2 based on a NSGO assembly-disassembly sensing principle. Reprinted with permission from [141], Yang J.-K. et al., 2019, Atomically-tailored graphene oxide displaying enhanced fluorescence for the improved optical sensing of MMP-2. Sensors & Actuators: B. Chemical, 284, p.p. 485–493. Copyright @ Elsevier.


Figure 7. Schematic for the Cleave-and-Bind Mechanism for the Logical Multiplex Detection of MMPs on Nanopillar Chip Reprinted with permission from [144], Gong T. et al., 2017. Optical interference-free Surface-Enhanced Raman Scattering CO-nanotags for logical multiplex detection of vascular disease-related biomarkers. ACS Nano, 11(3), p.p. 3365-3375. Copyright @ American Chemical Society.


Figure 8. (a) Magnetically actuated protease sensors. Thermosensitive liposomes, consisting of the lipids DPPC, MSPC, and DPSE-PEG, were encapsulated with magnetic nanoparticles and synthetic peptides. These peptide substrates are each coupled with a near- IR dye, Cy7, as a urinary reporter, and an N-terminal biotin enabling streptavidin-bead-based separation. Upon exposure to alternating magnetic fields (AMF), heat is dissipated by the coentrapped MNPs due to hysteresis losses, which in turn melts the thermosensitive bilayer. The permeabilized membrane allows peptides to diffuse to the exterior, where they are cleaved by proteases. Cleaved and uncleaved peptides clear into urine, where cleaved reporters are isolated using streptavidin-coated beads. Reprinted with permission from [149], Schuerle S. et al., 2016. Magnetically Actuated Protease Sensors for in Vivo Tumor Profiling. Nano Letters, 16(10), p.p. 6303-6310. Copyright @ American Chemical Society. (b) A Probe for Non-invasively Detecting MMP-2 Activity through Fluorescence/Photoacoustic Imaging. Reprinted with permission from [152], Yin L. et al., 2019. Quantitatively visualizing tumor-related protease activity in vivo using a ratiometric photoacoustic probe, Journal of the American Chemical Society, 141(7), p.p. 3265–3273. Copyright @ American Chemical Society.


Figure 9. Schematic Illustration of Enzyme-Triggered Morphology Transformation and Autocatalytic Growth of Nanofibers. (a) Molecular structure and self-assembly behavior of CPT-LFPR. (b) The fibrils accelerate the subsequent transformation into nanofibers based on autocatalytic growth mechanism. (c) Multiple intravenous injections of nanoparticles show the cumulative effect of fibrous prodrugs. Reprinted with permission from [127], Cheng D. et al., 2019. Autocatalytic morphology transformation platform for targeted drug accumulation. Journal of the American Chemical Society, 141(10), p.p. 4406-4411. Copyright @ American Chemical Society.


Figure 10. (a) Schematic illustration of the design strategy and synthesis route of the theranostic nanoprobe as an MMP2-activated platform for tumor-targeted precision imaging and site-specific phototherapies. Reprinted with permission from [158], Hu B. et al., 2019. Activatable smart nanoprobe for sensitive endogenous MMP2 detection and fluorescence imaging-guided phototherapies. Inorganic Chemistry Frontiers, 6, p.p. 820-828. Copyright @ Royal Society of Chemistry. (b) Schematic Illustration of MoS2-PEI-HA Nanosheets as a Multifunctional Platform for Targeting and Multiple-Stimuli-Responsive Therapy of MCF-7-ADR Cells Guided by PET Imaging. i) & ii) Synthesis of MoS2 nanosheets using a modified liquid exfoliation process in aqueous solution to produce single-layer MoS2 nanosheets and then modified with HA. iii) DOX loading process to obtain DOX@MoS2-PEI-HA. iv) MoS2-PEI-HA nanosheets for active CD44-targeting DOX delivery and MDR reversal through P-gp protein inhibition. v) MoS2-PEI-HA functionalized with NOTA-64Cu for PET imaging. Reprinted with permission from [161], Dong X. et al., 2018. Intelligent MoS2 nanotheranostic for targeted and enzyme-/pH-/ NIR-responsive drug delivery to overcome cancer chemotherapy resistance guided by PET imaging, 10, p.p. 4271-4284. Copyright @ American Chemical Society.


Figure 11. Schematic illustration of micelles formation and application of PTX-based prodrug. PEG-B-PTX was activated by H2O2 in tumor microenvironment and produced drug PTX release for tumor therapy. Reprinted with permission from [176], Dong, C., et al., 2020. Self-assembly of oxidation-responsive polyethylene glycol-paclitaxel prodrug for cancer chemotherapy. Journal of Controlled Release, 321, pp.529-539. Copyright @ Elsevier. 


Figure 12. Schematic illustration of the formation and application of dual-targeting prodrug nanoreactors (DT-PNs). DT-PNs was composed of cancer targeting amphiphiles (cRGD-PDMA-b-PCPTSM), mitochondria targeting amphiphiles (TPP-PDMA-b-PCPTSM) and CPT. Reprinted with permission from [178], Zhang, W., et al., 2019. Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy. Nature Communications, 10(1), pp.1704. Copyright @ Nature Publishing Group.


Figure 13. CPT-based GSH-responsive polydrug (FA-CSC-NPs) for imaging-guided combinational therapy. Schematic illustration of design and theranostic application of FA-CSC-NPs. (CSC: CR-(SS-CPT)2; PLGA: poly lactide-co-glycolide; SPC: soybean phosphatidylcholine; DSPE–PEG–FA:1,2-distearoyl-sn-glycero-3-phosphoethanolami ne-N-[folate(polyethylene glycol)-2000]). Reprinted with permission from [185], Yu, F., et al., 2018. Redox-responsive dual chemophotothermal therapeutic nanomedicine for imaging-guided combinational therapy. Journal of Materials Chemistry B, 6(33), pp.5362-5367. Copyright @ Royal Society of Chemistry.


Figure 14. Dually responsive polymer conjugate micelles for enhanced combinational delivery of Dox and Ce6 in a tumor-bearing mice model. Both drugs were co-loaded in the mPEG-PAsp-NI conjugate micelles. The NI moiety was converted to hydrophilic aminoimidazole under hypoxia, accompanied by the reduction of GSH. Upon laser irradiation, NI could be oxidized to aldehyde, resulting in micelle disassembly and cargo liberation. Reprinted with permission from [202], Zhao, Y., et al., 2019. Hypoxia- and singlet oxygen-responsive chemo-photodynamic Micelles featured with glutathione depletion and aldehyde production. Biomaterials Science, 7(1), pp.429-441. Copyright @ Royal Society of Chemistry.


Figure 15. Schematic illustration of the preparation of Lip/Ce6/TPZ nanoparticles and light-triggered hypoxia-activated photodynamic and chemotherapy combined cancer therapy. Reprinted with permission from [121], Zhang, X. et al., 2018. Light-triggered theranostic liposomes for tumor diagnosis and combined photodynamic and hypoxia-activated prodrug therapy. Biomaterials, 185, p.p. 301. Copyright @ Elesvier.


Figure 16. Schematic illustration of multi-stimuli responsive TENAB NPs for cancer synergistic therapy. Reprinted with permission from [207], Dong, X. et al., 2019. Photothermal-pH-hypoxia responsive multifunctional nanoplatform for cancer photo-chemo therapy with negligible skin phototoxicity. Biomaterials, 221, pp.119422. Copyright @ Elesvier.



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