Combined cancer therapeutics—Tackling the complexity of the tumor microenvironment

Advanced Review

Catarina Roma‐Rodrigues, Luís R. Raposo, Rúben Valente, Alexandra R. Fernandes, Pedro V. Baptista

Published Online: Feb 10 2021

DOI: 10.1002/wnan.1704

Full article on Wiley Online Library: HTML PDF

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Abstract Cancer treatment has yet to find a “silver bullet” capable of selectively and effectively kill tumor cells without damaging healthy cells. Nanomedicine is a promising field that can combine several moieties in one system to produce a multifaceted nanoplatform. The tumor microenvironment (TME) is considered responsible for the ineffectiveness of cancer therapeutics and the difficulty in the translation from the bench to bed side of novel nanomedicines. A promising approach is the use of combinatorial therapies targeting the TME with the use of stimuli‐responsive nanomaterials which would increase tumor targeting. Contemporary combined strategies for TME‐targeting nanoformulations are based on the application of external stimuli therapies, such as photothermy, hyperthermia or ultrasounds, in combination with stimuli‐responsive nanoparticles containing a core, usually composed by metal oxides or graphene, and a biocompatible stimuli‐responsive coating layer that could also contain tumor targeting moieties and a chemotherapeutic agent to enhance the therapeutic efficacy. The obstacles that nanotherapeutics must overcome in the TME to accomplish an effective therapeutic cargo delivery and the proposed strategies for improved nanotherapeutics will be reviewed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies

Tumor microenvironment (TME) characteristics and composition. The metabolism reprograming of tumor cells result in acidification of the TME, and in the increased production of glutathione (GSH) to counteract the increased ROS production. The rapid proliferation of tumor cells creates hypoxic regions that stimulates the formation of an immature and chaotic vascular network. The inflammatory signals at the TME trigger the formation of cancer associated fibroblasts and polarization of tumor associated macrophages. The presence of lymphoid lineage cells is preponderant for tumor prognosis

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Stimuli‐responsive nanoparticles are mainly composed by two distinct layers, an internal core and the coating layer (P. Liu, Xie, et al., 2020; van der Meel et al., 2019). The internal core is frequently composed by metal oxides, graphene or other biocompatible polymers. The coating layer could be composed by biocompatible stimuli responsive or targeting molecules, such as polyethylene glycol (PEG), hyaluronic acid (HA) or MnO₂, that under acidic conditions or high concentrations of reactive oxygen species (ROS) found in tumor microenvironment (TME), detach from the core. Chemotherapeutic agents, such as doxorubicin, cisplatin or paclitaxel, are frequently attached or adsorbed to the coating layer to enhance the therapeutic effect of the nanoformulation. External stimuli, such as light, ultrasound or magnetic field enhance the release of coating layer and the solubilization of the materials from the core

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References

Alves,, A. d. C. S., Lavayen,, V., Figueiro,, F., Dallemole,, D. R., de Fraga Dias,, A., Ce,, R., Battastini,, A. M. O., Guterres,, S. S., & Pohlmann,, A. R. (2020). Chitosan‐coated lipid‐core nanocapsules functionalized with Gold‐III and bevacizumab induced in vitro cytotoxicity against C6 cell line and in vivo potent antiangiogenic activity. Pharmaceutical Research, 37(6), 91. https://doi.org/10.1007/s11095-020-02804-0
Anderson,, N. M., & Simon,, M. C. (2020). The tumor microenvironment. Current Biology, 30(16), R921–R925. https://doi.org/10.1016/j.cub.2020.06.081
Avolio,, R., Matassa,, D. S., Criscuolo,, D., Landriscina,, M., & Esposito,, F. (2020). Modulation of mitochondrial metabolic reprogramming and oxidative stress to overcome chemoresistance in cancer. Biomolecules, 10(1), 135. https://doi.org/10.3390/biom10010135
Bachmann,, M., Pontarin,, G., & Szabo,, I. (2019). The contribution of mitochondrial ion channels to cancer development and progression. Cellular Physiology and Biochemistry, 53, 63–78. https://doi.org/10.33594/000000198
Barnes,, T. A., & Amir,, E. (2017). HYPE or HOPE: The prognostic value of infiltrating immune cells in cancer. British Journal of Cancer, 117(4), 451–460. https://doi.org/10.1038/bjc.2017.220
Beik,, J., Khateri,, M., Khosravi,, Z., Kamrava,, S. K., Kooranifar,, S., Ghaznavi,, H., & Shakeri‐Zadeh,, A. (2019). Gold nanoparticles in combinatorial cancer therapy strategies. Coordination Chemistry Reviews, 387, 299–324. https://doi.org/10.1016/j.ccr.2019.02.025
Cai,, L. H., Hu,, C. L., Liu,, S. N., Zhou,, Y., Pang,, M. L., & Lin,, J. (2020). A covalent organic framework‐based multifunctional therapeutic platform for enhanced photodynamic therapy via catalytic cascade reactions. Science China Materials, 64, 488–497. https://doi.org/10.1007/s40843-020-1428-0
Chakraborty,, S., Hosen,, M. I., Ahmed,, M., & Shekhar,, H. U. (2018). Onco‐multi‐OMICS approach: A new frontier in cancer research. BioMed Research International, 2018, 9836256. https://doi.org/10.1155/2018/9836256
Chauhan,, V. P., & Jain,, R. K. (2013). Strategies for advancing cancer nanomedicine. Nature Materials, 12(11), 958–962. https://doi.org/10.1038/nmat3792
Chen,, D. S., & Mellman,, I. (2017). Elements of cancer immunity and the cancer‐immune set point. Nature, 541(7637), 321–330. https://doi.org/10.1038/nature21349
Chen,, P. M., Pan,, W. Y., Wu,, C. Y., Yeh,, C. Y., Korupalli,, C., Luo,, P. K., Chou,, C. J., Chia,, W. T., & Sung,, H. W. (2020). Modulation of tumor microenvironment using aTLR‐7/8 agonist‐loaded nanoparticle system that exerts low‐temperature hyperthermia and immunotherapy for in situ cancer vaccination. Biomaterials, 230, 119629. https://doi.org/10.1016/j.biomaterials.2019.119629
Cheng,, N., Bai,, X., Shu,, Y., Ahmad,, O., & Shen,, P. (2021). Targeting tumor‐associated macrophages as an antitumor strategy. Biochemical Pharmacology, 183, 114354. https://doi.org/10.1016/j.bcp.2020.114354
Comito,, G., Ippolito,, L., Chiarugi,, P., & Cirri,, P. (2020). Nutritional exchanges within tumor microenvironment: Impact for cancer aggressiveness. Frontiers in Oncology, 10, 396. https://doi.org/10.3389/fonc.2020.00396
Cruz,, M. M., Ferreira,, L. P., Alves,, A. F., Mendo,, S. G., Ferreira,, P., Godinho,, M., & Carvalho,, M. D. (2017). Nanoparticles for magnetic hyperthermia. In Nanostructures for cancer therapy, Elsevier (pp. 485–511). https://doi.org/10.1016/b978-0-323-46144-3.00019-2
Das,, R. P., Gandhi,, V. V., Singh,, B. G., & Kunwar,, A. (2019). Passive and active drug targeting: Role of nanocarriers in rational design of anticancer formulations. Current Pharmaceutical Design, 25(28), 3034–3056. https://doi.org/10.2174/1381612825666190830155319
De Palma,, M., Biziato,, D., & Petrova,, T. V. (2017). Microenvironmental regulation of tumour angiogenesis. Nature Reviews. Cancer, 17(8), 457–474. https://doi.org/10.1038/nrc.2017.51
Ding,, C., Tong,, L., Feng,, J., & Fu,, J. (2016). Recent advances in stimuli‐responsive release function drug delivery systems for tumor treatment. Molecules, 21(12), 1715. https://doi.org/10.3390/molecules21121715
Dong,, X., Yang,, A., Bai,, Y., Kong,, D., & Lv,, F. (2020). Dual fluorescence imaging‐guided programmed delivery of doxorubicin and CpG nanoparticles to modulate tumor microenvironment for effective chemo‐immunotherapy. Biomaterials, 230, 119659. https://doi.org/10.1016/j.biomaterials.2019.119659
Du,, P., Yan,, J., Long,, S., Xiong,, H., Wen,, N., Cai,, S., Wang,, Y., Peng,, W., Liu,, Z., & Liu,, Y. (2020). Tumor microenvironment and NIR laser dual‐responsive release of berberine 9‐O‐pyrazole alkyl derivative loaded in graphene oxide nanosheets for chemo‐photothermal synergetic cancer therapy. Journal of Materials Chemistry B, 8(18), 4046–4055. https://doi.org/10.1039/d0tb00489h
Dzobo,, K., & Dandara,, C. (2020). Architecture of cancer‐associated fibroblasts in tumor microenvironment: Mapping their origins, heterogeneity, and role in cancer therapy resistance. OMICS, 24(6), 314–339. https://doi.org/10.1089/omi.2020.0023
Estrela,, J. M., Ortega,, A., & Obrador,, E. (2006). Glutathione in cancer biology and therapy. Critical Reviews in Clinical Laboratory Sciences, 43(2), 143–181. https://doi.org/10.1080/10408360500523878
Frattaruolo,, L., Brindisi,, M., Curcio,, R., Marra,, F., Dolce,, V., & Cappello,, A. R. (2020). Targeting the mitochondrial metabolic network: A promising strategy in cancer treatment. International Journal of Molecular Sciences, 21(17), 6014. https://doi.org/10.3390/ijms21176014
Ganguly,, D., Chandra,, R., Karalis,, J., Teke,, M., Aguilera,, T., Maddipati,, R., Wachsmann,, M. B., Ghersi,, M., Siravegna,, G., Zeh,, H. J., 3rd, Brekken,, R., Ting,, D. T., & Ligorio,, M. (2020). Cancer‐associated fibroblasts: Versatile players in the tumor microenvironment. Cancers (Basel), 12(9), 2652. https://doi.org/10.3390/cancers12092652
Giesel,, F. L., Kratochwil,, C., Lindner,, T., Marschalek,, M. M., Loktev,, A., Lehnert,, W., Debus,, J., Jager,, D., Flechsig,, P., Altmann,, A., Mier,, W., & Haberkorn,, U. (2019). (68)Ga‐FAPI PET/CT: Biodistribution and preliminary dosimetry estimate of 2 DOTA‐containing FAP‐targeting agents in patients with various cancers. Journal of Nuclear Medicine, 60(3), 386–392. https://doi.org/10.2967/jnumed.118.215913
Gilligan,, K. E., & Dwyer,, R. M. (2017). Engineering exosomes for cancer therapy. International Journal of Molecular Sciences, 18(6), 1122. https://doi.org/10.3390/ijms18061122
González‐Silva,, L., Quevedo,, L., & Varela,, I. (2020). Tumor functional heterogeneity unraveled by scRNA‐seqtechnologies. Trends in Cancer, 6, 13–19. https://doi.org/10.1016/j.trecan.2019.11.010
Graner,, M. W., Schnell,, S., & Olin,, M. R. (2018). Tumor‐derived exosomes, microRNAs, and cancer immune suppression. Seminars in Immunopathology, 40(5), 505–515. https://doi.org/10.1007/s00281-018-0689-6
Hanahan,, D., & Weinberg,, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70. https://doi.org/10.1016/s0092-8674(00)81683-9
Hanahan,, D., & Weinberg,, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013
Hannon,, G., Lysaght,, J., Liptrott,, N. J., & Prina‐Mello,, A. (2019). Immunotoxicity considerations for next generation cancer nanomedicines. Advanced Science, 6(19), 1900133. https://doi.org/10.1002/advs.201900133
He,, T., Qin,, X., Jiang,, C., Jiang,, D., Lei,, S., Lin,, J., Zhu,, W. G., Qu,, J., & Huang,, P. (2020). Tumor pH‐responsive metastable‐phase manganese sulfide nanotheranostics for traceable hydrogen sulfide gas therapy primed chemodynamic therapy. Theranostics, 10(6), 2453–2462. https://doi.org/10.7150/thno.42981
Hejmady,, S., Pradhan,, R., Alexander,, A., Agrawal,, M., Singhvi,, G., Gorain,, B., Tiwari,, S., Kesharwani,, P., & Dubey,, S. K. (2020). Recent advances in targeted nanomedicine as promising antitumor therapeutics. Drug Discovery Today, 25(12), 2227–2244. https://doi.org/10.1016/j.drudis.2020.09.031
Helmlinger,, G., Yuan,, F., Dellian,, M., & Jain,, R. K. (1997). Interstitial pH and pO2 gradients in solid tumors in vivo: High‐resolution measurements reveal a lack of correlation. Nature Medicine, 3(2), 177–182. https://doi.org/10.1038/nm0297-177
Hou,, M., Zhong,, Y., Zhang,, L., Xu,, Z., Kang,, Y., & Xue,, P. (2020). Polydopamine (PDA)‐activated cobalt sulfide nanospheres responsive to tumor microenvironment (TME) for chemotherapeutic‐enhanced photothermal therapy. Chinese Chemical Letters. https://doi.org/10.1016/j.cclet.2020.08.009
Hua,, S., de Matos,, M. B. C., Metselaar,, J. M., & Storm,, G. (2018). Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercialization, 9, 790. https://doi.org/10.3389/fphar.2018.00790
Huang,, J., Huang,, Y., Xue,, Z., & Zeng,, S. (2020). Tumor microenvironment responsive hollow mesoporous Co9S8@MnO2‐ICG/DOX intelligent nanoplatform for synergistically enhanced tumor multimodal therapy. Biomaterials, 262, 120346. https://doi.org/10.1016/j.biomaterials.2020.120346
Huber,, V., Camisaschi,, C., Berzi,, A., Ferro,, S., Lugini,, L., Triulzi,, T., Tuccitto,, A., Tagliabue,, E., Castelli,, C., & Rivoltini,, L. (2017). Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in Cancer Biology, 43, 74–89. https://doi.org/10.1016/j.semcancer.2017.03.001
Ioannidis,, J. P. A., Kim,, B. Y. S., & Trounson,, A. (2018). How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation. Nature Biomedical Engineering, 2(11), 797–809. https://doi.org/10.1038/s41551-018-0314-y
Jayasingam,, S. D., Citartan,, M., Thang,, T. H., Mat Zin,, A. A., Ang,, K. C., & Ch`ng,, E. S. (2020). Evaluating the polarization of tumor‐associated macrophages into M1 and M2 phenotypes in human cancer tissue: Technicalities and challenges in routine clinical practice. Frontiers in Oncology, 9, 1512–1512. https://doi.org/10.3389/fonc.2019.01512
Jia,, N., Li,, W., Liu,, D., Wu,, S., Song,, B., Ma,, J., Chen,, D., & Hu,, H. (2020). Tumor microenvironment stimuli‐responsive nanoparticles for programmed anticancer drug delivery. Molecular Pharmaceutics, 17(5), 1516–1526. https://doi.org/10.1021/acs.molpharmaceut.9b01189
Jin,, R., Yang,, J., Ding,, P., Li,, C., Zhang,, B., Chen,, W., Zhao,, Y. D., Cao,, Y., & Liu,, B. (2020). Antitumor immunity triggered by photothermal therapy and photodynamic therapy of a 2D MoS2 nanosheet‐incorporated injectable polypeptide‐engineered hydrogel combinated with chemotherapy for 4T1 breast tumor therapy. Nanotechnology, 31(20), 205102. https://doi.org/10.1088/1361-6528/ab72b9
Jing,, X., Zhi,, Z., Zhang,, N., Song,, H., Xu,, Y., Zhou,, G., Wang,, D., Shao,, Y., & Meng,, L. (2020). Multistage tumor microenvironment‐responsive theranostic nanopeanuts: Toward multimode imaging guided chemo‐photodynamic therapy. Chemical Engineering Journal, 385, 123893. https://doi.org/10.1016/j.cej.2019.123893
Junttila,, M. R., & de Sauvage,, F. J. (2013). Influence of tumour micro‐environment heterogeneity on therapeutic response. Nature, 501(7467), 346–354. https://doi.org/10.1038/nature12626
Kang,, H., Kim,, H., Lee,, S., Youn,, H., & Youn,, B. (2019). Role of metabolic reprogramming in epithelial(−)mesenchymal transition (EMT). International Journal of Molecular Sciences, 20(8), 2042. https://doi.org/10.3390/ijms20082042
Kanzaki,, R., & Pietras,, K. (2020). Heterogeneity of cancer‐associated fibroblasts: Opportunities for precision medicine. Cancer Science, 111, 2708–2717. https://doi.org/10.1111/cas.14537
Kim,, J., Jo,, Y. U., & Na,, K. (2020). Photodynamic therapy with smart nanomedicine. Archives of Pharmacal Research, 43(1), 22–31. https://doi.org/10.1007/s12272-020-01214-5
Klein,, D. (2018). The tumor vascular endothelium as decision maker in cancer therapy. Frontiers in Oncology, 8, 367. https://doi.org/10.3389/fonc.2018.00367
Kumar,, A., & Deep,, G. (2020). Hypoxia in tumor microenvironment regulates exosome biogenesis: Molecular mechanisms and translational opportunities. Cancer Letters, 479, 23–30. https://doi.org/10.1016/j.canlet.2020.03.017
Kv,, R., Liu,, T. I., Lu,, I. L., Liu,, C. C., Chen,, H. H., Lu,, T. Y., Chiang,, W. H., & Chiu,, H. C. (2020). Tumor microenvironment‐responsive and oxygen self‐sufficient oil droplet nanoparticles for enhanced photothermal/photodynamic combination therapy against hypoxic tumors. Journal of Controlled Release, 328, 87–99. https://doi.org/10.1016/j.jconrel.2020.08.038
Lagopati,, N., Evangelou,, K., Falaras,, P., Tsilibary,, E. C., Vasileiou,, P. V. S., Havaki,, S., Angelopoulou,, A., & Gorgoulis,, V. G. (2020). Nanomedicine: Photo‐activated nanostructured titanium dioxide, as a promising anticancer agent. Pharmacology %26 Therapeutics, 107795. https://doi.org/10.1016/j.pharmthera.2020.107795
Lamouille,, S., Xu,, J., & Derynck,, R. (2014). Molecular mechanisms of epithelial–mesenchymal transition. Nature Reviews. Molecular Cell Biology, 15(3), 178–196. https://doi.org/10.1038/nrm3758
Larue,, L., Myrzakhmetov,, B., Ben‐Mihoub,, A., Moussaron,, A., Thomas,, N., Arnoux,, P., Baros,, F., Vanderesse,, R., Acherar,, S., & Frochot,, C. (2019). Fighting hypoxia to improve PDT. Pharmaceuticals (Basel), 12(4). https://doi.org/10.3390/ph12040163
Li,, F., Qin,, Y., Lee,, J., Liao,, H., Wang,, N., Davis,, T. P., Qiao,, R., & Ling,, D. (2020). Stimuli‐responsive nano‐assemblies for remotely controlled drug delivery. Journal of Controlled Release, 322, 566–592. https://doi.org/10.1016/j.jconrel.2020.03.051
Li,, H., Yan,, W., Suo,, X., Peng,, H., Yang,, X., Li,, Z., Zhang,, J., & Liu,, D. (2019). Nucleus‐targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia‐activated chemotherapy. Biomaterials, 200, 1–14. https://doi.org/10.1016/j.biomaterials.2019.01.048
Li,, Y., An,, L., Lin,, J., Tian,, Q., & Yang,, S. (2019). Smart nanomedicine agents for cancer, triggered by pH, glutathione, H₂O₂, or H₂S. International Journal of Nanomedicine, 14, 5729–5749. https://doi.org/10.2147/IJN.S210116
Li,, Y., Hong,, W., Zhang,, H., Zhang,, T. T., Chen,, Z., Yuan,, S., Peng,, P., Xiao,, M., & Xu,, L. (2020). Photothermally triggered cytosolic drug delivery of glucose functionalized polydopamine nanoparticles in response to tumor microenvironment for the GLUT1‐targeting chemo‐phototherapy. Journal of Controlled Release, 317, 232–245. https://doi.org/10.1016/j.jconrel.2019.11.031
Li,, Y., Lin,, J., Wang,, P., Luo,, Q., Lin,, H., Zhang,, Y., Hou,, Z., Liu,, J., & Liu,, X. (2019). Tumor microenvironment responsive shape‐reversal self‐targeting virus‐inspired nanodrug for imaging‐guided near‐infrared‐II photothermal chemotherapy. ACS Nano, 13(11), 12912–12928. https://doi.org/10.1021/acsnano.9b05425
Li,, Y., Liu,, J., Gao,, L., Liu,, Y., Meng,, F., Li,, X., & Qin,, F. X. (2020). Targeting the tumor microenvironment to overcome immune checkpoint blockade therapy resistance. Immunology Letters, 220, 88–96. https://doi.org/10.1016/j.imlet.2019.03.006
Liang,, J. H., Zheng,, Y., Wu,, X. W., Tan,, C. P., Ji,, L. N., & Mao,, Z. W. (2020). A tailored multifunctional anticancer nanodelivery system for ruthenium‐based photosensitizers: Tumor microenvironment adaption and remodeling. Advanced Science, 7(1), 1901992. https://doi.org/10.1002/advs.201901992
Liberti,, M. V., & Locasale,, J. W. (2016). The Warburg effect: How does it benefit cancer cells? Trends in Biochemical Sciences, 41(3), 211–218. https://doi.org/10.1016/j.tibs.2015.12.001
Liu,, C., Wang,, D., Zhang,, S., Cheng,, Y., Yang,, F., Xing,, Y., Xu,, T., Dong,, H., & Zhang,, X. (2019). Biodegradable biomimic copper/manganese silicate nanospheres for chemodynamic/photodynamic synergistic therapy with simultaneous glutathione depletion and hypoxia relief. ACS Nano, 13(4), 4267–4277. https://doi.org/10.1021/acsnano.8b0938
Liu,, P., Xie,, X., Liu,, M., Hu,, S., Ding,, J., & Zhou,, W. (2020). A smart MnO₂‐doped graphene oxide nanosheet for enhanced chemo‐photodynamic combinatorial therapy via simultaneous oxygenation and glutathione depletion. Acta Pharmaceutica Sinica B. https://doi.org/10.1016/j.apsb.2020.07.021
Liu,, Y., Jing,, J., Jia,, F., Su,, S., Tian,, Y., Gao,, N., Yang,, C., Zhang,, R., Wang,, W., & Zhang,, X. (2020). Tumor microenvironment‐responsive theranostic nanoplatform for in situ self‐boosting combined phototherapy through intracellular reassembly. ACS Applied Materials %26 Interfaces, 12(6), 6966–6977. https://doi.org/10.1021/acsami.9b22097
Logozzi,, M., Mizzoni,, D., Bocca,, B., Di Raimo,, R., Petrucci,, F., Caimi,, S., Alimonti,, A., Falchi,, M., Cappello,, F., Campanella,, C., Bavisotto,, C. C., David,, S., Bucchieri,, F., Angelini,, D. F., Battistini,, L., & Fais,, S. (2019). Human primary macrophages scavenge AuNPs and eliminate it through exosomes. A natural shuttling for nanomaterials. European Journal of Pharmaceutics and Biopharmaceutics, 137, 23–36. https://doi.org/10.1016/j.ejpb.2019.02.014
Marino,, A., Almici,, E., Migliorin,, S., Tapeinos,, C., Battaglini,, M., Cappello,, V., Marchetti,, M., de Vito,, G., Cicchi,, R., Pavone,, F. S., & Ciofani,, G. (2019). Piezoelectric barium titanatena nostimulators for the treatment of glioblastoma multiforme. Journal of Colloid and Interface Science, 538, 449–461. https://doi.org/10.1016/j.jcis.2018.12.014
Marino,, A., Battaglini,, M., De Pasquale,, D., Degl`Innocenti,, A., & Ciofani,, G. (2018). Ultrasound‐activated piezoelectric nanoparticles inhibit proliferation of breast cancer cells. Scientific Reports, 8(1), 6257. https://doi.org/10.1038/s41598-018-24697-1
Mi,, P. (2020). Stimuli‐responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics. Theranostics, 10(10), 4557–4588. https://doi.org/10.7150/thno.38069
Mokhtari,, R. B., Homayouni,, T. S., Baluch,, N., Morgatskaya,, E., Kumar,, S., Das,, B., & Yeger,, H. (2015). Combination therapy in combating cancer. Oncotarget, 8(23), 38022–38043. https://doi.org/10.18632/oncotarget.16723
Montaseri,, H., Kruger,, C. A., & Abrahamse,, H. (2020). Review: Organic nanoparticle based active targeting for photodynamic therapy treatment of breast cancer cells. Oncotarget, 11, 2120–2136. https://doi.org/10.18632/oncotarget.27596. PMID: 32547709; PMCID: PMC7275783.
Mortezaee,, K. (2020). Redox tolerance and metabolic reprogramming in solid tumors. Cell Biology International. https://doi.org/10.1002/cbin.11506
Nandigama,, R., Upcin,, B., Aktas,, B. H., Ergun,, S., & Henke,, E. (2018). Restriction of drug transport by the tumor environment. Histochemistry and Cell Biology, 150(6), 631–648. https://doi.org/10.1007/s00418-018-1744-z
Netea‐Maier,, R. T., Smit,, J. W. A., & Netea,, M. G. (2018). Metabolic changes in tumor cells and tumor‐associated macrophages: A mutual relationship. Cancer Letters, 413, 102–109. https://doi.org/10.1016/j.canlet.2017.10.037
Ojha,, T., Pathak,, V., Shi,, Y., Hennink,, W. E., Moonen,, C. T. W., Storm,, G., Kiessling,, F., & Lammers,, T. (2017). Pharmacological and physical vessel modulation strategies to improve EPR‐mediated drug targeting to tumors. Advanced Drug Delivery Reviews, 119, 44–60. https://doi.org/10.1016/j.addr.2017.07.007
Ou,, M., Pan,, C., Yu,, Y., Wang,, X., Zhou,, Y., Zhang,, H., Cheng,, Q., Wu,, M., Ji,, X., & Mei,, L. (2020). Two‐dimensional highly oxidized ilmenite nanosheets equipped with Z‐scheme heterojunction for regulating tumor microenvironment and enhancing reactive oxygen species generation. Chemical Engineering Journal, 390, 124524. https://doi.org/10.1016/j.cej.2020.124524
Overchuk,, M., Harmatys,, K. M., Sindhwani,, S., Rajora,, M. A., Koebel,, A., Charron,, D. M., Syed,, A. M., Chen,, J., Pomper,, M. G., Wilson,, B. C., Chan,, W. C. W., & Zheng,, G. (2020). Subtherapeutic photodynamic treatment facilitates tumor nanomedicine delivery and overcomes desmoplasia. Nano Letters. https://doi.org/10.1021/acs.nanolett.0c03731
Palmer,, A. C., & Sorger,, P. K. (2017). Combination cancer therapy can confer benefit via patient‐to‐patient variability without drug additivity or synergy. Cell, 171(7), 1678–1691 e1613. https://doi.org/10.1016/j.cell.2017.11.009
Pan,, S., Pei,, L., Zhang,, A., Zhang,, Y., Zhang,, C., Huang,, M., Liu,, B., Wang,, L., Ma,, L., Zhang,, Q., & Cui,, D. (2020). Passion fruit‐like exosome‐PMA/Au‐BSA@Ce6 nanovehicles for real‐time fluorescence imaging and enhanced targeted photodynamic therapy with deep penetration and superior retention behavior in tumor. Biomaterials, 230, 119606. https://doi.org/10.1016/j.biomaterials.2019.119606
Pavlova,, N. N., & Thompson,, C. B. (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. https://doi.org/10.1016/j.cmet.2015.12.006
Pedrosa,, P., Heuer‐Jungemann,, A., Kanaras,, A. G., Fernandes,, A. R., & Baptista,, P. V. (2017). Potentiating angiogenesis arrest in vivo via laser irradiation of peptide functionalised gold nanoparticles. Journal of Nanobiotechnology, 15(1), 85. https://doi.org/10.1186/s12951-017-0321-2
Peng,, J., Yang,, Q., Xiao,, Y., Shi,, K., Liu,, Q., Hao,, Y., Yang,, F., Han,, R., & Qian,, Z. (2019). Tumor microenvironment responsive drug‐dye‐peptide nanoassembly for enhanced tumor‐targeting, penetration, and photo‐chemo‐immunotherapy. Advanced Functional Materials, 29(19). https://doi.org/10.1002/adfm.201900004
Pickup,, M. W., Mouw,, J. K., & Weaver,, V. M. (2014). The extracellular matrix modulates the hallmarks of cancer. EMBO Reports, 15, 1243–1253. https://doi.org/10.15252/embr.201439246
Poudel,, K., Banstola,, A., Tran,, T. H., Thapa,, R. K., Gautam,, M., Ou,, W., Pham,, L. M., Maharjan,, S., Jeong,, J. H., Ku,, S. K., Choi,, H. G., Yong,, C. S., & Kim,, J. O. (2020). Hyaluronic acid wreathed, trio‐stimuli receptive and on‐demand triggerable nanoconstruct for anchored combinatorial cancer therapy. Carbohydrate Polymers, 249, 116815. https://doi.org/10.1016/j.carbpol.2020.116815
Qu,, D., Qin,, Y., Liu,, Y., Liu,, T., Liu,, C., Han,, T., Chen,, Y., Ma,, C., & Li,, X. (2020). Fever‐inducible lipid nanocomposite for boosting cancer therapy through synergistic engineering of a tumor microenvironment. ACS Applied Materials %26 Interfaces, 12(29), 32301–32311. https://doi.org/10.1021/acsami.0c06949
Rabanel,, J.‐M., Adibnia,, V., Tehrani,, S. F., Sanche,, S., Hildgen,, P., Banquy,, X., & Ramassamy,, C. (2019). Nanoparticle heterogeneity: An emerging structural parameter influencing particle fate in biological media? Nanoscale, 11(2), 383–406. https://doi.org/10.1039/C8NR04916E
Roma‐Rodrigues,, C., Mendes,, R., Baptista,, P. V., & Fernandes,, A. R. (2019). Targeting tumor microenvironment for cancer therapy. International Journal of Molecular Sciences, 20(4), 840. https://doi.org/10.3390/ijms20040840
Roma‐Rodrigues,, C., Pombo,, I., Raposo,, L., Pedrosa,, P., Fernandes,, A. R., & Baptista,, P. V. (2019). Nanotheranostics targeting the tumor microenvironment. Frontiers in Bioengineering and Biotechnology, 7, 197. https://doi.org/10.3389/fbioe.2019.00197
Runa,, F., Hamalian,, S., Meade,, K., Shisgal,, P., Gray,, P. C., & Kelber,, J. A. (2017). Tumor microenvironment heterogeneity: Challenges and opportunities. Current Molecular Biology Reports, 3(4), 218–229. https://doi.org/10.1007/s40610-017-0073-7
Sahai,, E., Astsaturov,, I., Cukierman,, E., DeNardo,, D. G., Egeblad,, M., Evans,, R. M., Fearon,, D., Greten,, F. R., Hingorani,, S. R., Hunter,, T., Hynes,, R. O., Jain,, R. K., Janowitz,, T., Jorgensen,, C., Kimmelman,, A. C., Kolonin,, M. G., Maki,, R. G., Powers,, R. S., Puré,, E., Ramirez,, D. C., … Werb,, Z. (2020). A framework for advancing our understanding of cancer‐associated fibroblasts. Nature Reviews Cancer, 20(3), 174–186. https://doi.org/10.1038/s41568-019-0238-1
Scafer,, F. Q., & Buettner,, G. R. (2001). Redox environment of the cells as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology %26 Medicine, 30(11), 1191–1212. https://doi.org/10.1016/s0891-5849(01)00480-4
Schumacker,, P. T. (2006). Reactive oxygen species in cancer cells: Live by the sword, die by the sword. Cancer Cell, 10(3), 175–176. https://doi.org/10.1016/j.ccr.2006.08.015
Seelige,, R., Searles,, S., & Bui,, J. D. (2018). Mechanisms regulating immune surveillance of cellular stress in cancer. Cellular and Molecular Life Sciences, 75(2), 225–240. https://doi.org/10.1007/s00018-017-2597-7
Shen,, Z., Xia,, J., Ma,, Q., Zhu,, W., Gao,, Z., Han,, S., Liang,, Y., Cao,, J., & Sun,, Y. (2020). Tumor microenvironment‐triggered nanosystems as dual‐relief tumor hypoxia immunomodulators for enhanced phototherapy. Theranostics, 10(20), 9132–9152. https://doi.org/10.7150/thno.46076
Shi,, X., & Shiao,, S. L. (2018). The role of macrophage phenotype in regulating the response to radiation therapy. Translational Research, 191, 64–80. https://doi.org/10.1016/j.trsl.2017.11.002
Shi,, Y., van der Meel,, R., Chen,, X., & Lammers,, T. (2020). The EPR effect and beyond: Strategies to improve tumor targeting and cancer nanomedicine treatment efficacy. Theranostics, 10(17), 7921–7924. https://doi.org/10.7150/thno.49577
Soerensen,, M. M., Ros,, W., Rodriguez‐Ruiz,, M. E., Robbrecht,, D., Rohrberg,, K. S., Martin‐Liberal,, J., Lassen,, U. N., Bermejo,, I. M., Lolkema,, M. P., Tabernero,, J., Boetsch,, C., Piper‐Lepoutre,, H., Waldhauer,, I., Charo,, J., Evers,, S., Teichgräber,, V., & Schellens,, J. H. M. (2018). Safety, PK/PD, and anti‐tumor activity of RO6874281, an engineered variant of interleukin‐2 (IL‐2v) targeted to tumor‐associated fibroblasts via binding to fibroblast activation protein (FAP). Developmental Therapeutics—Immunotherapy, 36(15_suppl), e15155. https://doi.org/10.1200/JCO.2018.36.15_suppl.e15155
Sormendi,, S., & Wielockx,, B. (2018). Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Frontiers in Immunology, 9, 40. https://doi.org/10.3389/fimmu.2018.00040
Sugarbaker,, P. H. (2019). Intraperitoneal delivery of chemotherapeutic agents for the treatment of peritoneal metastases: Current challenges and how to overcome them. Expert Opinion on Drug Delivery, 16(12), 1393–1401. https://doi.org/10.1080/17425247.2019.1693997
Tadeo,, I., Álvaro,, T., Navarro,, S., & Noguera,, R. (2016). Tumor microenvironment heterogeneity: A review of the biology masterpiece, evaluation systems, and therapeutic implications, IntechOpen. https://doi.org/10.5772/62479
Tak,, W. Y., Lin,, S.‐M., Wang,, Y., Zheng,, J., Vecchione,, A., Park,, S. Y., Chen,, M. H., Wong,, S., Xu,, R., Peng,, C. Y., Chiou,, Y. Y., Huang,, G. T., Cai,, J., Abdullah,, B. J. J., Lee,, J. S., Lee,, J. Y., Choi,, J. Y., Gopez‐Cervantes,, J., Sherman,, M., Finn,, R. S., … Lencioni,, R. (2018). Phase III heat study adding lyso‐thermosensitive liposomal doxorubicin to radiofrequency ablation inpatients with unresectable hepatocellular carcinoma lesions. Clinical Cancer Research, 24(1), 73. https://doi.org/10.1158/1078-0432.CCR-16-2433
Tanziela,, T., Shaikh,, S., Jiang,, H., Lu,, Z., & Wang,, X. (2020). Efficient encapsulation of biocompatible nanoparticles in exosomes for cancer theranostics. Nano Today, 35, 100964. https://doi.org/10.1016/j.nantod.2020.100964
Traverso,, N., Ricciarelli,, R., Nitti,, M., Marengo,, B., Furfaro,, A. L., Pronzato,, M. A., Marinari,, U. M., & Domenicotti,, C. (2013). Role of glutathione in cancer progression and chemoresistance. Oxidative Medicine and Cellular Longevity, 2013, 972913. https://doi.org/10.1155/2013/972913
van der Meel,, R., Sulheim,, E., Shi,, Y., Kiessling,, F., Mulder,, W. J. M., & Lammers,, T. (2019). Smart cancer nanomedicine. Nature Nanotechnology, 14(11), 1007–1017. https://doi.org/10.1038/s41565-019-0567-y
Wang,, M., Zhao,, J., Zhang,, L., Wei,, F., Lian,, Y., Wu,, Y., Gong,, Z., Zhang,, S., Zhou,, J., Cao,, K., Li,, X., Xiong,, W., Li,, G., Zeng,, Z., & Guo,, C. (2017). Role of tumor microenvironment in tumorigenesis. J Cancer, 8(5), 761–773. https://doi.org/10.7150/jca.17648
Wang,, Y., Zhang,, Y., Cai,, G., & Li,, Q. (2020). Exosomes as actively targeted nanocarriers for cancer therapy. International Journal of Nanomedicine, 15, 4257–4273. https://doi.org/10.2147/IJN.S239548
WHO. (2020). Cancer—Overview. https://www.who.int/health-topics/cancer#tab=tab_1
Wu,, F., Qiu,, F., Wai‐Keong,, S. A., & Diao,, Y. (2020). The smart dual‐stimuli responsive nanoparticles for controlled antitumor drug release and cancer therapy. Anti‐Cancer Agents in Medicinal Chemistry, 20. https://doi.org/10.2174/1871520620666200924110418
Wu,, X., Zhang,, Y., Wang,, Z., Wu,, J., Yan,, R., Guo,, C., & Jin,, Y. (2020). Near‐infrared light‐initiated upconversion nanoplatform with tumor microenvironment responsiveness for improved photodynamic therapy. ACS Applied Bio Materials, 3(9), 5813–5823. https://doi.org/10.1021/acsabm.0c00545
Xiao,, J., Zhang,, G., Xu,, R., Chen,, H., Wang,, H., Tian,, G., Wang,, B., Yang,, C., Bai,, G., Zhang,, Z., Yang,, H., Zhong,, K., Zou,, D., & Wu,, Z. (2019). A pH‐responsive platform combining chemodynamic therapy with limotherapy for simultaneous bioimaging and synergistic cancer therapy. Biomaterials, 216, 119254. https://doi.org/10.1016/j.biomaterials.2019.119254
Xiao,, Y., & Yu,, D. (2020). Tumor microenvironment as a therapeutic target in cancer. Pharmacology %26 Therapeutics, 107753. https://doi.org/10.1016/j.pharmthera.2020.107753
Xiao,, Z., Locasale,, J. W., & Dai,, Z. (2020). Metabolism in the tumor microenvironment: Insights from single‐cell analysis. Oncoimmunology, 9(1), 1726556. https://doi.org/10.1080/2162402X.2020.1726556
Xu,, H., Hu,, M., Liu,, M., An,, S., Guan,, K., Wang,, M., Li,, L., Zhang,, J., Li,, J., & Huang,, L. (2020). Nano‐puerarin regulates tumor microenvironment and facilitates chemo‐and immunotherapy in murine triple negative breast cancer model. Biomaterials, 235, 119769. https://doi.org/10.1016/j.biomaterials.2020.119769
Yang,, B., Zhou,, S., Zeng,, J., Zhang,, L. P., Zhang,, R. H., Liang,, K., Xie,, L., Shao,, B., Song,, S., Huang,, G., Zhao,, D., Chen,, P., & Kong,, B. (2020). Super‐assembled core‐shell mesoporous silica‐metal‐phenolic network nanoparticles for combinatorial photothermal therapy and chemotherapy. Nano Research, 13(4), 1013–1019. https://doi.org/10.1007/s12274-020-2736-6
Yang,, G., Tian,, J., Chen,, C., Jiang,, D., Xue,, Y., Wang,, C., Gao,, Y., & Zhang,, W. (2019). An oxygen self‐sufficient NIR‐responsive nanosystem for enhanced PDT and chemotherapy against hypoxic tumors. Chemical Science, 10(22), 5766–5772. https://doi.org/10.1039/c9sc00985j
Yang,, L. V. (2017). Tumor microenvironment and metabolism. International Journal of Molecular Sciences, 18(12), 2729. https://doi.org/10.3390/ijms18122729
Yang,, W., Lee,, J. C., Chen,, M. H., Zhang,, Z. Y., Bai,, X. M., Yin,, S. S., Cao,, K., Wang,, S., Wu,, W., & Yan,, K. (2019). Thermosensitive liposomal doxorubicin plus radiofrequency ablation increased tumor destruction and improved survival in patients with medium and large hepatocellular carcinoma: A randomized, double‐blinded, dummy‐controlled clinical trial in a single center. Journal of Cancer Research and Therapeutics, 15(4), 773–783. https://doi.org/10.4103/jcrt.JCRT_801_18
Ying,, W., Zhang,, Y., Gao,, W., Cai,, X., Wang,, G., Wu,, X., Chen,, L., Meng,, Z., Zheng,, Y., Hu,, B., & Lin,, X. (2020). Hollow magnetic nanocatalysts drive starvation‐chemodynamic‐hyperthermia synergistic therapy for tumor. ACS Nano, 14(8), 9662–9674. https://doi.org/10.1021/acsnano.0c00910
Yuan,, Y. (2016). Spatial heterogeneity in the tumor microenvironment. Cold Spring Harbor Perspectives in Medicine, 6(8), a026583. https://doi.org/10.1101/cshperspect.a026583
Zeng,, X., Liu,, C., Yao,, J., Wan,, H., Wan,, G., Li,, Y., & Chen,, N. (2020). Breast cancer stem cells, heterogeneity, targeting therapies and therapeutic implications. Pharmacological Research, 163, 105320. https://doi.org/10.1016/j.phrs.2020.105320
Zhang,, M., Guo,, X., Wang,, M., & Liu,, K. (2020). Tumor microenvironment‐induced structure changing drug/gene delivery system for overcoming delivery‐associated challenges. Journal of Controlled Release, 323, 203–224. https://doi.org/10.1016/j.jconrel.2020.04.026
Zhang,, W., Wang,, F., Hu,, C., Zhou,, Y., Gao,, H., & Hu,, J. (2020). The progress and perspective of nanoparticle‐enabled tumor metastasis treatment. Acta Pharmaceutica Sinica B, 10(11), 2037–2053. https://doi.org/10.1016/j.apsb.2020.07.013
Zhang,, Y., Wang,, B., Zhao,, R., Zhang,, Q., & Kong,, X. (2020). Multifunctional nanoparticles as photosensitizer delivery carriers for enhanced photodynamic cancer therapy. Materials Science %26 Engineering. C, Materials for Biological Applications, 115, 111099. https://doi.org/10.1016/j.msec.2020.111099. Epub 2020 May 16 32600703.
Zhang,, Y., & Weinberg,, R. A. (2018). Epithelial‐to‐mesenchymal transition in cancer: Complexity and opportunities. Frontiers in Medicine, 12(4), 361–373. https://doi.org/10.1007/s11684-018-0656-6
Zhang,, Z., Dombroski,, J. A., & King,, M. R. (2019). Engineering of exosomes to target cancer metastasis. Cellular and Molecular Bioengineering, 13(1), 1–16. https://doi.org/10.1007/s12195-019-00607-x
Zhou,, J., Geng,, S., Wang,, Q., Yin,, Q., Lou,, R., Wei,, L., Wu,, Y., Du,, B., & Yao,, H. (2020). Ovalbumin‐modified nanoparticles increase the tumor accumulation by a tumor microenvironment‐mediated “giant”. Journal of Materials Chemistry B, 8(33), 7528–7538. https://doi.org/10.1039/d0tb00542h
Zhou,, Q., Dong,, C., Fan,, W., Jiang,, H., Xiang,, J., Qiu,, N., Piao,, Y., Xie,, T., Luo,, Y., Li,, Z., Liu,, F., & Shen,, Y. (2020). Tumor extravasation and infiltration as barriers of nanomedicine for high efficacy: The current status and transcytosis strategy. Biomaterials, 240, 119902. https://doi.org/10.1016/j.biomaterials.2020.119902
Zhou,, Y., Chen,, X., Cao,, J., & Gao,, H. (2020). Overcoming the biological barriers in the tumor microenvironment for improving drug delivery and efficacy. Journal of Materials Chemistry B, 8(31), 6765–6781. https://doi.org/10.1039/d0tb00649a
Ziello,, J. E., Jovin,, I. S., & Huang,, Y. (2007). Hypoxia‐inducible factor (HIF)‐1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. The Yale Journal of Biology and Medicine, 80(2), 51–60. PMID: 18160990.

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