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.

CONTENTS

CONTENTS

Introduction

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

Imaging

PTT

PDT

Chemotherapy

Immunotherapy

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

Acknowledgements

Reference

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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.

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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.

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