Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Nanotherapy Targeting the Tumor Microenvironment

Author(s): Bo-Shen Gong, Rui Wang, Hong-Xia Xu, Ming-Yong Miao* and Zhen-Zhen Yao*

Volume 19, Issue 7, 2019

Page: [525 - 533] Pages: 9

DOI: 10.2174/1568009619666181220103714

Price: $65

Abstract

Cancer is characterized by high mortality and low curability. Recent studies have shown that the mechanism of tumor resistance involves not only endogenous changes to tumor cells, but also to the tumor microenvironment (TME), which provides the necessary conditions for the growth, invasion, and metastasis of cancer cells, akin to Stephen Paget’s hypothesis of “seed and soil.” Hence, the TME is a significant target for cancer therapy via nanoparticles, which can carry different kinds of drugs targeting different types or stages of tumors. The key step of nanotherapy is the achievement of accurate active or passive targeting to trigger drugs precisely at tumor cells, with less toxicity and fewer side effects. With deepened understanding of the tumor microenvironment and rapid development of the nanomaterial industry, the mechanisms of nanotherapy could be individualized according to the specific TME characteristics, including low pH, cancer-associated fibroblasts (CAFs), and increased expression of metalloproteinase. However, some abnormal features of the TME limit drugs from reaching all tumor cells in lethal concentrations, and the characteristics of tumors vary in numerous ways, resulting in great challenges for the clinical application of nanotherapy. In this review, we discuss the essential role of the tumor microenvironment in the genesis and development of tumors, as well as the measures required to improve the therapeutic effects of tumor microenvironment-targeting nanoparticles and ways to reduce damage to normal tissue.

Keywords: Tumor microenvironment, nanotherapy, nanoparticles, targeted therapy, nanomedicine, nanotechnology.

Graphical Abstract
[1]
Bhatt, A.P.; Redinbo, M.R.; Bultman, S.J. The role of the microbiome in cancer development and therapy. CA Cancer J. Clin., 2017, 67(4), 326-344.
[2]
Wang, L.; Huo, M.; Chen, Y.; Shi, J. Tumor microenvironment-enabled nanotherapy; Adv. Health Mater, 2017.
[http://dx.doi.org/10.1002/adhm.201701156.]
[3]
Tian, J.; Min, Y.; Rodgers, Z.; Au, K.M.; Hagan, C.T.; Zhang, M.; Roche, K.; Yang, F.; Wagner, K.; Wang, A.Z. Co-delivery of paclitaxel and cisplatin with biocompatible PLGA-PEG nanoparticles enhances chemoradiotherapy in non-small cell lung cancer models. J. Mater. Chem. B Mater. Biol. Med., 2017, 5, 6049-6057.
[4]
Guo, G.; Tortorella, M.; Zhang, B.; Wang, Y. Disassembly of micelle-like polyethylenimine nanocomplexes for siRNA delivery: High transfection efficiency and reduced toxicity achieved by simple reducible lipid modification. J. Colloid Interface Sci., 2017, 504, 633-644.
[5]
Tian, L.; Bae, Y.H. Cancer nanomedicines targeting tumor extracellular pH. Colloids Surf. B Biointerfaces, 2012, 99, 116-126.
[6]
Gao, Z.; Zhang, L.; Sun, Y. Nanotechnology applied to overcome tumor drug resistance. J. Control. Release, 2012, 162, 45-55.
[7]
Al-Yasiri, A.Y.; Khoobchandani, M.; Cutler, C.S.; Watkinson, L.; Carmack, T.; Smith, C.J.; Kuchuk, M.; Loyalka, S.K.; Lugão, A.B.; Katti, K.V. Mangiferin functionalized radioactive gold nanoparticles (MGF-(198)AuNPs) in prostate tumor therapy: Green nanotechnology for production, in vivo tumor retention and evaluation of therapeutic efficacy. Dalton Trans., 2017, 46(42), 1456-1471.
[8]
Roy, A.; Li, S.D. Modifying the tumor microenvironment using nanoparticle therapeutics. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2016, 8(6), 891-908.
[9]
Witz, I.P. The tumor microenvironment: the making of a paradigm. Cancer Microenviron., 2009, 2(Suppl. 1), 9-17.
[10]
Muntimadugu, E.; Kommineni, N.; Khan, W. Exploring the potential of nanotherapeutics in targeting tumor microenvironment for cancer therapy. Pharmacol. Res., 2017, (126), 109-122.
[11]
Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J.J.; Lötvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol., 2007, 9, 654-659.
[12]
Zou, W.; Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol., 2008, 8, 467-477.
[13]
Yu, H.; Kortylewski, M.; Pardoll, D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol., 2007, 7, 41-51.
[14]
Pahl, J.; Cerwenka, A. Tricking the balance: NK cells in anti-cancer immunity. Immunobiology, 2017, 222, 11-20.
[15]
Spaks, A. Role of CXC group chemokines in lung cancer development and progression. J. Thorac. Dis., 2017, 9, S164-S171.
[16]
Persano, L.; Rampazzo, E.; Basso, G.; Viola, G. Glioblastoma cancer stem cells: role of the microenvironment and therapeutic targeting. Biochem. Pharmacol., 2013, 85, 612-622.
[17]
Xin, Y.; Huang, M.; Guo, W.W.; Huang, Q.; Zhang, L.Z.; Jiang, G. Nano-based delivery of RNAi in cancer therapy. Mol. Cancer, 2017, 16, 134.
[18]
Kang, B.; Kukreja, A.; Song, D.; Huh, Y.M.; Haam, S. Strategies for using nanoprobes to perceive and treat cancer activity: A review. J. Biol. Eng., 2017, 11, 13.
[19]
Ji, T.; Zhao, Y.; Ding, Y.; Nie, G. Using functional nanomaterials to target and regulate the tumor microenvironment: diagnostic and therapeutic applications. Adv. Mater.Weinheim, 2013, 25, 3508-3525.
[20]
Upreti, M.; Jyoti, A.; Sethi, P. Tumor microenvironment and nanotherapeutics. Transl. Cancer Res., 2013, 2, 309-319.
[21]
Huang, S.; Shao, K.; Liu, Y.; Kuang, Y.; Li, J.; An, S.; Guo, Y.; Ma, H.; Jiang, C. Tumor-targeting and microenvironment-responsive smart nanoparticles for combination therapy of antiangiogenesis and apoptosis. ACS Nano, 2013, 7, 2860-2871.
[22]
Luciano, R.; Battafarano, G.; Saracino, R.; Rossi, M.; Perrotta, A.; Manco, M.; Muraca, M.; Del Fattore, A. New perspectives in glioblastoma: nanoparticles-based approaches. Curr. Cancer Drug Targets, 2017, 17, 203-220.
[23]
Park, J.; Wrzesinski, S.H.; Stern, E.; Look, M.; Criscione, J.; Ragheb, R.; Jay, S.M.; Demento, S.L.; Agawu, A.; Licona, L.P.; Ferrandino, A.F.; Gonzalez, D.; Habermann, A.; Flavell, R.A.; Fahmy, T.M. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater., 2012, 11, 895-905.
[24]
Feczkó, T.; Fodor-Kardos, A.; Sivakumaran, M.; Haque, S.Q.T. In vitro IFN-α release from IFN-α- and pegylated IFN-α-loaded poly(lactic-co-glycolic acid) and pegylated poly(lactic-co-glycolic acid) nanoparticles. Nanomedicine (Lond), 2016, 11, 2029-2034.
[25]
Shvedova, A.A.; Tkach, A.V.; Kisin, E.R.; Khaliullin, T.; Stanley, S.; Gutkin, D.W.; Star, A.; Chen, Y.; Shurin, G.V.; Kagan, V.E.; Shurin, M.R. Carbon nanotubes enhance metastatic growth of lung carcinoma via up-regulation of myeloid-derived suppressor cells. Small, 2013, 9, 1691-1695.
[26]
Nakamura, Y.; Mochida, A.; Choyke, P.L.; Kobayashi, H. Nanodrug delivery: Is the enhanced permeability and retention effect sufficient for curing cancer. Bioconjug. Chem., 2016, 27, 2225-2238.
[27]
Adiseshaiah, P.P.; Hall, J.B.; McNeil, S.E. Nanomaterial standards for efficacy and toxicity assessment. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2010, 2, 99-112.
[28]
Lee, K.Y.; Lee, G.Y.; Lane, L.A.; Li, B.; Wang, J.; Lu, Q.; Wang, Y.; Nie, S. Functionalized, long-circulating, and ultrasmall gold nanocarriers for overcoming the barriers of low nanoparticle delivery efficiency and poor tumor penetration. Bioconjug. Chem., 2017, 28, 244-252.
[29]
Stylianopoulos, T.; Jain, R.K. Design considerations for nanotherapeutics in oncology. Nanomedicine , 2015, 11, 1893-1907.
[30]
Wong, C.; Stylianopoulos, T.; Cui, J.; Martin, J.; Chauhan, V.P.; Jiang, W.; Popovic, Z.; Jain, R.K.; Bawendi, M.G.; Fukumura, D. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl. Acad. Sci. USA, 2011, 108, 2426-2431.
[31]
Carter, T.; Mulholland, P.; Chester, K. Antibody-targeted nanoparticles for cancer treatment. Immunotherapy, 2016, 8, 941-958.
[32]
Akhtar, M.J.; Ahamed, M.; Alhadlaq, H.A.; Alrokayan, S.A.; Kumar, S. Targeted anticancer therapy: Overexpressed receptors and nanotechnology. Clin. Chim. Acta, 2014, 436, 78-92.
[33]
Kaur, S.; Prasad, C.; Balakrishnan, B.; Banerjee, R. Trigger responsive polymeric nanocarriers for cancer therapy. Biomater. Sci., 2015, 3, 955-987.
[34]
Du, J.Z.; Mao, C.Q.; Yuan, Y.Y.; Yang, X.Z.; Wang, J. Tumor extracellular acidity-activated nanoparticles as drug delivery systems for enhanced cancer therapy. Biotechnol. Adv., 2014, 32, 789-803.
[35]
Zhu, J.; Liao, L.; Bian, X.; Kong, J.; Yang, P.; Liu, B. pH-controlled delivery of doxorubicin to cancer cells, based on small mesoporous carbon nanospheres. Small, 2012, 8, 2715-2720.
[36]
Qian, W.Y.; Sun, D.M.; Zhu, R.R.; Du, X.L.; Liu, H.; Wang, S.L. pH-sensitive strontium carbonate nanoparticles as new anticancer vehicles for controlled etoposide release. Int. J. Nanomedicine, 2012, 7, 5781-5792.
[37]
Kanamala, M.; Wilson, W.R.; Yang, M.; Palmer, B.D.; Wu, Z. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review. Biomaterials, 2016, 85, 152-167.
[38]
Corbet, C.; Feron, O. Tumour acidosis: From the passenger to the driver’s seat. Nat. Rev. Cancer, 2017, 17(10), 577-593.
[39]
Nakazawa, M.S.; Keith, B.; Simon, M.C. Oxygen availability and metabolic adaptations. Nat. Rev. Cancer, 2016, 16(10), 663-673.
[40]
Scheuermann, T.H.; Li, Q.; Ma, H.W.; Key, J.; Zhang, L.; Chen, R.; Garcia, J.A.; Naidoo, J.; Longgood, J.; Frantz, D.E.; Tambar, U.K.; Gardner, K.H.; Bruick, R.K. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol., 2013, 9(4), 271-276.
[41]
Pourmorteza, M.; Rahman, Z.U.; Young, M. Evofosfamide, a new horizon in the treatment of pancreatic cancer. Anticancer Drugs, 2016, 27(8), 723-725.
[42]
Lohse, I.; Rasowski, J.; Cao, P.; Pintilie, M.; Do, T.; Tsao, M.S.; Hill, R.P.; Hedley, D.W. Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302. Oncotarget, 2016, 7(23), 33571-33580.
[43]
Torosean, S.; Flynn, B.; Axelsson, J.; Gunn, J.; Samkoe, K.S.; Hasan, T.; Doyley, M.M.; Pogue, B.W. Nanoparticle uptake in tumors is mediated by the interplay of vascular and collagen density with interstitial pressure. Nanomedicine , 2013, 9, 151-158.
[44]
Singh, Y.; Pawar, V.K.; Meher, J.G.; Raval, K.; Kumar, A.; Shrivastava, R.; Bhadauria, S.; Chourasia, M.K. Targeting tumor associated macrophages (TAMs) via nanocarriers. J. Control. Release, 2017, 254, 92-106.
[45]
Wang, Y.; Lin, Y.X.; Qiao, S.L.; An, H.W.; Ma, Y.; Qiao, Z.Y.; Rajapaksha, R.P.; Wang, H. Polymeric nanoparticles promote macrophage reversal from M2 to M1 phenotypes in the tumor microenvironment. Biomaterials, 2017, 112, 153-163.
[46]
Wang, T.; Shigdar, S.; Shamaileh, H.A.; Gantier, M.P.; Yin, W.; Xiang, D.; Wang, L.; Zhou, S.F.; Hou, Y.; Wang, P.; Zhang, W.; Pu, C.; Duan, W. Challenges and opportunities for siRNA-based cancer treatment. Cancer Lett., 2017, 387, 77-83.
[47]
Danhier, F.; Feron, O.; Préat, V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Release, 2010, 148, 135-146.
[48]
Ruan, S.; He, Q.; Gao, H. Matrix metalloproteinase triggered size-shrinkable gelatin-gold fabricated nanoparticles for tumor microenvironment sensitive penetration and diagnosis of glioma. Nanoscale, 2015, 7, 9487-9496.
[49]
Pastorino, L.; Erokhina, S.; Caneva-Soumetz, F.; Ruggiero, C. Paclitaxel-containing nano-engineered polymeric capsules towards cancer therapy. J. Nanosci. Nanotechnol., 2009, 9, 6753-6759.
[50]
Yim, H.; Park, S.J.; Bae, Y.H.; Na, K. Biodegradable cationic nanoparticles loaded with an anticancer drug for deep penetration of heterogeneous tumours. Biomaterials, 2013, 34, 7674-7682.
[51]
Lee, Y.; Thompson, D.H. Stimuli-responsive liposomes for drug delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2017, 9(5), e1450.
[52]
Sassaroli, E.; Li, K.C.; O’Neill, B.E. Numerical investigation of heating of a gold nanoparticle and the surrounding microenvironment by nanosecond laser pulses for nanomedicine applications. Phys. Med. Biol., 2009, 54, 5541-5560.
[53]
Cheng, R.; Meng, F.; Deng, C.; Klok, H.A.; Zhong, Z. Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials, 2013, 34, 3647-3657.
[54]
Shao, Y.; Fu, J. Integrated micro/nanoengineered functional biomaterials for cell mechanics and mechanobiology: a materials perspective. Adv. Mater.Weinheim, 2014, 26, 1494-1533.
[55]
Zhu, L.; Torchilin, V.P. Stimulus-responsive nanopreparations for tumor targeting. Integr. Biol., 2013, 5, 96-107.
[56]
Spencer, D.S.; Puranik, A.S.; Peppas, N.A. Intelligent nanoparticles for advanced drug delivery in cancer treatment. Curr. Opin. Chem. Eng., 2015, 7, 84-92.
[57]
Liu, Y.; Ding, X.; Li, J.; Luo, Z.; Hu, Y.; Liu, J.; Dai, L.; Zhou, J.; Hou, C.; Cai, K. Enzyme responsive drug delivery system based on mesoporous silica nanoparticles for tumor therapy in vivo. Nanotechnology, 2015, 26, 145102.
[58]
Chen, W.H.; Luo, G.F.; Lei, Q.; Cao, F.Y.; Fan, J.X.; Qiu, W.X.; Jia, H.Z.; Hong, S.; Fang, F.; Zeng, X.; Zhuo, R.X.; Zhang, X.Z. Rational design of multifunctional magnetic mesoporous silica nanoparticle for tumor-targeted magnetic resonance imaging and precise therapy. Biomaterials, 2016, 76, 87-101.
[59]
Chen, Y.; Ye, D.; Wu, M.; Chen, H.; Zhang, L.; Shi, J.; Wang, L. Break-up of two-dimensional MnO2 nanosheets promotes ultrasensitive pH-triggered theranostics of cancer. Adv. Mater.Weinheim, 2014, 26, 7019-7026.
[60]
Krishnamurthy, S.; Vaiyapuri, R.; Zhang, L.; Chan, J.M. Lipid-coated polymeric nanoparticles for cancer drug delivery. Biomater. Sci., 2015, 3, 923-936.
[61]
Suarato, G.; Li, W.; Meng, Y. Role of pH-responsiveness in the design of chitosan-based cancer nanotherapeutics: A review.Biointerphases, 2016. 11, 04B201.
[62]
Curtis, L.T.; Frieboes, H.B. The Tumor Microenvironment as a Barrier to Cancer Nanotherapy. Adv. Exp. Med. Biol., 2016, 936, 165-190.
[63]
Jhaveri, A.; Deshpande, P.; Torchilin, V. Stimuli-sensitive nanopreparations for combination cancer therapy. J. Control. Release, 2014, 190, 352-370.
[64]
van de Ven, A.L.; Wu, M.; Lowengrub, J.; McDougall, S.R.; Chaplain, M.A.; Cristini, V.; Ferrari, M.; Frieboes, H.B. Integrated intravital microscopy and mathematical modeling to optimize nanotherapeutics delivery to tumors. AIP Adv., 2012, 2, 11208.
[65]
Jahangirian, H.; Lemraski, E.G.; Webster, T.J.; Rafiee-Moghaddam, R.; Abdollahi, Y. A review of drug delivery systems based on nanotechnology and green chemistry: green nanomedicine. Int. J. Nanomedicine, 2017, 12, 2957-2978.
[66]
Fonseca, N.A.; Gregório, A.C.; Valério-Fernandes, A.; Simões, S.; Moreira, J.N. Bridging cancer biology and the patients’ needs with nanotechnology-based approaches. Cancer Treat. Rev., 2014, 40, 626-635.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy