Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0041-1736474
Size-Adjustable Nano-Drug Delivery Systems for Enhanced Tumor Retention and Penetration
Funding We are very grateful for the support from the National Natural Science Foundation (Grant No. 81773658), the Program Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System (Grant No. SCCXTD-2020-18), and Sichuan University Postdoctoral Interdisciplinary Innovation Fund.
![](https://www.thieme-connect.de/media/10.1055-s-00043364/202103/lookinside/thumbnails/10-1055-s-0041-1736474_2100029re-1.jpg)
Abstract
Over the past decades, nano-drug delivery systems have shown great potential in improving tumor treatment. And the controllability and design flexibility of nanoparticles endow them a broad development space. The particle size is one of the most important factors affecting the potency of nano-drug delivery systems. Large-size (100–200 nm) nanoparticles are more conducive to long circulation and tumor retention, but have poor tumor penetration; small-size (<50 nm) nanoparticles can deeply penetrate tumor but are easily cleared. Most of the current fixed-size nanoparticles are difficult to balance the retention and penetration, while the proposal of size-adjustable nano-drug delivery systems offers a solution to this paradox. Many endogenous and exogenous stimuli, such as acidic pH, upregulated enzymes, temperature, light, catalysts, redox conditions, and reactive oxygen species, can trigger the in situ transformation of nanoparticles based on protonation, hydrolysis, click reaction, phase transition, photoisomerization, redox reaction, etc. In this review, we summarize the principles and applications of stimuli-responsive size-adjustable strategies, including size-enlargement strategies and size-shrinkage strategies. We also propose the challenges faced by size-adjustable nano-drug delivery systems, hoping to promote the development of this strategy.
Keywords
size-adjustable - nano-drug delivery systems - stimuli-responsive - tumor retention - tumor penetrationPublication History
Received: 25 July 2021
Accepted: 24 August 2021
Article published online:
22 November 2021
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011; 63 (03) 136-151
- 2 Li C, Wang J, Wang Y. et al. Recent progress in drug delivery. Acta Pharm Sin B 2019; 9 (06) 1145-1162
- 3 Yang Z, Chen Q, Chen J. et al. Tumor-pH-responsive dissociable albumin-tamoxifen nanocomplexes enabling efficient tumor penetration and hypoxia relief for enhanced cancer photodynamic therapy. Small 2018; 14 (49) e1803262
- 4 Duan X, Li Y. Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. Small 2013; 9 (9–10): 1521-1532
- 5 Perrault SD, Walkey C, Jennings T, Fischer HC, Chan WC. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett 2009; 9 (05) 1909-1915
- 6 Mei L, Liu Y, Rao J. et al. Enhanced tumor retention effect by click chemistry for improved cancer immunochemotherapy. ACS Appl Mater Interfaces 2018; 10 (21) 17582-17593
- 7 Ruan S, Hu C, Tang X. et al. Increased gold nanoparticle retention in brain tumors by in situ enzyme-induced aggregation. ACS Nano 2016; 10 (11) 10086-10098
- 8 Larsen EK, Nielsen T, Wittenborn T. et al. Size-dependent accumulation of PEGylated silane-coated magnetic iron oxide nanoparticles in murine tumors. ACS Nano 2009; 3 (07) 1947-1951
- 9 Du J, Xu N, Fan J, Sun W, Peng X. Carbon dots for in vivo bioimaging and theranostics. Small 2019; 15 (32) e1805087
- 10 Farzin A, Etesami SA, Quint J, Memic A, Tamayol A. Magnetic nanoparticles in cancer therapy and diagnosis. Adv Healthc Mater 2020; 9 (09) e1901058
- 11 Chaturvedi VK, Singh A, Singh VK, Singh MP. Cancer nanotechnology: a new revolution for cancer diagnosis and therapy. Curr Drug Metab 2019; 20 (06) 416-429
- 12 Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 2010; 7 (11) 653-664
- 13 Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today 2002; 7 (10) 569-579
- 14 Liu X, Chen Y, Li H. et al. Enhanced retention and cellular uptake of nanoparticles in tumors by controlling their aggregation behavior. ACS Nano 2013; 7 (07) 6244-6257
- 15 Wu W, Li S, Lin Z, Li J. pH-sensitive nanocarriers for enhanced tumor retention and rapid intracellular drug release. J Control Release 2015; 213: e111 –e112
- 16 Krebs MR, Domike KR, Donald AM. Protein aggregation: more than just fibrils. Biochem Soc Trans 2009; 37 (Pt 4): 682-686
- 17 Li H, Chen Y, Li Z, Li X, Jin Q, Ji J. Hemoglobin as a smart pH-sensitive nanocarrier to achieve aggregation enhanced tumor retention. Biomacromolecules 2018; 19 (06) 2007-2013
- 18 Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. J Control Release 2008; 126 (03) 187-204
- 19 Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev 2001; 53 (03) 321-339
- 20 Zhang W, Lin Y. The mechanism of asparagine endopeptidase in the progression of malignant tumors: a review. Cells 2021; 10 (05) 1153
- 21 Spinelli FM, Vitale DL, Sevic I, Alaniz L. Hyaluronan in the tumor microenvironment. Adv Exp Med Biol 2020; 1245: 67-83
- 22 Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141 (01) 52-67
- 23 Mijanović O, Branković A, Panin AN. et al. Cathepsin B: a sellsword of cancer progression. Cancer Lett 2019; 449: 207-214
- 24 Jaaks P, Bernasconi M. The proprotein convertase furin in tumour progression. Int J Cancer 2017; 141 (04) 654-663
- 25 Peng Z, Chang Y, Fan J, Ji W, Su C. Phospholipase A2 superfamily in cancer. Cancer Lett 2021; 497: 165-177
- 26 Chen JM, Dando PM, Rawlings ND. et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem 1997; 272 (12) 8090-8098
- 27 Liu C, Sun C, Huang H, Janda K, Edgington T. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res 2003; 63 (11) 2957-2964
- 28 Liu Z, Xiong M, Gong J. et al. Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment. Nat Commun 2014; 5: 4280
- 29 Zhou H, Sun H, Lv S. et al. Legumain-cleavable 4-arm poly(ethylene glycol)-doxorubicin conjugate for tumor specific delivery and release. Acta Biomater 2017; 54: 227-238
- 30 He X, Cao H, Wang H. et al. Inflammatory monocytes loading protease-sensitive nanoparticles enable lung metastasis targeting and intelligent drug release for anti-metastasis therapy. Nano Lett 2017; 17 (09) 5546-5554
- 31 Toole BP. Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol 1990; 2 (05) 839-844
- 32 Stern R. Hyaluronan catabolism: a new metabolic pathway. Eur J Cell Biol 2004; 83 (07) 317-325
- 33 Stern R. Hyaluronidases in cancer biology. Semin Cancer Biol 2008; 18 (04) 275-280
- 34 Hu Q, Sun W, Lu Y. et al. Tumor microenvironment-mediated construction and deconstruction of extracellular drug-delivery depots. Nano Lett 2016; 16 (02) 1118-1126
- 35 Jochum FD, Theato P. Temperature- and light-responsive smart polymer materials. Chem Soc Rev 2013; 42 (17) 7468-7483
- 36 Schild HG. Poly(N-isopropylacrylamide): experiment. Theory and Application Prog. Polym Sci 1992; 17 (02) 163-249
- 37 Idziak I, Avoce D, Lessard D, Gravel D, Zhu XX. Thermosensitivity of aqueous solutions of poly(N,N-diethylacrylamide). Macromolecules 1999; 32: 1260-1263
- 38 Lutz JF, Hoth A. Preparation of ideal PEG analogues with a tunable thermosensitivity by controlled radical copolymerization of 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene glycol) methacrylate. Macromolecules 2006; 39: 893-896
- 39 Qiao SL, Ma Y, Wang Y. et al. General approach of stimuli-induced aggregation for monitoring tumor therapy. ACS Nano 2017; 11 (07) 7301-7311
- 40 Liu FH, Cong Y, Qi GB, Ji L, Qiao ZY, Wang H. Near-infrared laser-driven in situ self-assembly as a general strategy for deep tumor therapy. Nano Lett 2018; 18 (10) 6577-6584
- 41 Melancon MP, Zhou M, Li C. Cancer theranostics with near-infrared light-activatable multimodal nanoparticles. Acc Chem Res 2011; 44 (10) 947-956
- 42 Hajebi S, Rabiee N, Bagherzadeh M. et al. Stimulus-responsive polymeric nanogels as smart drug delivery systems. Acta Biomater 2019; 92: 1-18
- 43 Liu G, Liu W, Dong CM. UV- and NIR-responsive polymeric nanomedicines for on-demand drug delivery. Polym Chem-UK 2013; 4 (12) 3431-3443
- 44 Lu Y, Lin Y, Chen Z. et al. Enhanced endosomal escape by light-fueled liquid-metal transformer. Nano Lett 2017; 17 (04) 2138-2145
- 45 Shiraishi Y, Shirakawa E, Tanaka K, Sakamoto H, Ichikawa S, Hirai T. Spiropyran-modified gold nanoparticles: reversible size control of aggregates by UV and visible light irradiations. ACS Appl Mater Interfaces 2014; 6 (10) 7554-7562
- 46 Manna A, Chen PL, Akiyama H, Wei TX, Tamada K, Knoll W. Optimized photoisomerization on gold nanoparticles capped by unsymmetrical azobenzene disulfides. Chem Mater 2003; 15 (01) 20-28
- 47 Cheng X, Sun R, Yin L, Chai Z, Shi H, Gao M. Light-triggered assembly of gold nanoparticles for photothermal therapy and photoacoustic imaging of tumors in vivo. Adv Mater 2017; 29 (06) 201604894
- 48 Kuk S, Lee BI, Lee JS, Park CB. Rattle-structured upconversion nanoparticles for near-IR-induced suppression of Alzheimer's β-amyloid aggregation. Small 2017; 13 (11) 1603139
- 49 Nyk M, Kumar R, Ohulchanskyy TY, Bergey EJ, Prasad PN. High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in Tm3+ and Yb3+ doped fluoride nanophosphors. Nano Lett 2008; 8 (11) 3834-3838
- 50 Zhao T, Wang P, Li Q. et al. Near-infrared triggered decomposition of nanocapsules with high tumor accumulation and stimuli responsive fast elimination. Angew Chem Int Ed Engl 2018; 57 (10) 2611-2615
- 51 Alonso F, Moglie Y, Radivoy G. Copper nanoparticles in click chemistry. Acc Chem Res 2015; 48 (09) 2516-2528
- 52 Liang L, Astruc D. The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) “click” reaction and its applications. An overview. Coord Chem Rev 2011; 255 (23–24): 2933-2945
- 53 Ning X, Guo J, Wolfert MA, Boons GJ. Visualizing metabolically labeled glycoconjugates of living cells by copper-free and fast huisgen cycloadditions. Angew Chem Int Ed Engl 2008; 47 (12) 2253-2255
- 54 Dommerholt J, Schmidt S, Temming R. et al. Readily accessible bicyclononynes for bioorthogonal labeling and three-dimensional imaging of living cells. Angew Chem Int Ed Engl 2010; 49 (49) 9422-9425
- 55 Lee S, Koo H, Na JH. et al. Chemical tumor-targeting of nanoparticles based on metabolic glycoengineering and click chemistry. ACS Nano 2014; 8 (03) 2048-2063
- 56 Rondon A, Degoul F. Antibody pretargeting based on bioorthogonal click chemistry for cancer imaging and targeted radionuclide therapy. Bioconjug Chem 2020; 31 (02) 159-173
- 57 Deng M, Guo R, Zang S. et al. pH-Triggered copper-free click reaction-mediated micelle aggregation for enhanced tumor retention and elevated immuno-chemotherapy against melanoma. ACS Appl Mater Interfaces 2021; 13 (15) 18033-18046
- 58 Panté N, Kann M. Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell 2002; 13 (02) 425-434
- 59 Chen B, Dai W, He B. et al. Current multistage drug delivery systems based on the tumor microenvironment. Theranostics 2017; 7 (03) 538-558
- 60 Liu J, Huang Y, Kumar A. et al. pH-sensitive nano-systems for drug delivery in cancer therapy. Biotechnol Adv 2014; 32 (04) 693-710
- 61 Thambi T, Deepagan VG, Chang KY, Chang KY, Park JH. Synthesis and physicochemical characterization of amphiphilic block copolymers bearing acid-sensitive orthoester linkage as the drug carrier. Polymer (Guildf) 2011; 52 (21) 4753-4759
- 62 Ding M, Song N, He X. et al. Toward the next-generation nanomedicines: design of multifunctional multiblock polyurethanes for effective cancer treatment. ACS Nano 2013; 7 (03) 1918-1928
- 63 Gurski LA, Jha AK, Zhang C, Jia X, Farach-Carson MC. Hyaluronic acid-based hydrogels as 3D matrices for in vitro evaluation of chemotherapeutic drugs using poorly adherent prostate cancer cells. Biomaterials 2009; 30 (30) 6076-6085
- 64 Jin Y, Song L, Su Y. et al. Oxime linkage: a robust tool for the design of pH-sensitive polymeric drug carriers. Biomacromolecules 2011; 12 (10) 3460-3468
- 65 Hu FQ, Zhang YY, You J, Yuan H, Du YZ. pH triggered doxorubicin delivery of PEGylated glycolipid conjugate micelles for tumor targeting therapy. Mol Pharm 2012; 9 (09) 2469-2478
- 66 Li HJ, Du JZ, Du XJ. et al. Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy. Proc Natl Acad Sci U S A 2016; 113 (15) 4164-4169
- 67 Li L, Sun W, Zhong J. et al. Multistage nanovehicle delivery system based on stepwise size reduction and charge reversal for programmed nuclear targeting of systemically administered anticancer drugs. Adv Funct Mater 2015; 25: 4101-4113
- 68 Koren E, Apte A, Jani A, Torchilin VP. Multifunctional PEGylated 2C5-immunoliposomes containing pH-sensitive bonds and TAT peptide for enhanced tumor cell internalization and cytotoxicity. J Control Release 2012; 160 (02) 264-273
- 69 Min SK, Su JH, Han JK. et al. pH-Responsive PEG-Poly(β-amino ester) block copolymer micelles with a sharp transition. Macromol Rapid Commun 2006; 27 (06) 447-451
- 70 Lee ES, Shin HJ, Na K, Bae YH. Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization. J Control Release 2003; 90 (03) 363-374
- 71 Wan D, Yang Y, Liu Y. et al. Sequential depletion of myeloid-derived suppressor cells and tumor cells with a dual-pH-sensitive conjugated micelle system for cancer chemoimmunotherapy. J Control Release 2020; 317: 43-56
- 72 Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2 (03) 161-174
- 73 Wong C, Stylianopoulos T, Cui J. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci U S A 2011; 108 (06) 2426-2431
- 74 Miao L, Lin CM, Huang L. Stromal barriers and strategies for the delivery of nanomedicine to desmoplastic tumors. J Control Release 2015; 219: 192-204
- 75 Cun X, Chen J, Li M. et al. Tumor-associated fibroblast-targeted regulation and deep tumor delivery of chemotherapeutic drugs with a multifunctional size-switchable nanoparticle. ACS Appl Mater Interfaces 2019; 11 (43) 39545-39559
- 76 Yu Q, Qiu Y, Li J. et al. Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy. J Control Release 2020; 321: 564-575
- 77 Menzel EJ, Farr C. Hyaluronidase and its substrate hyaluronan: biochemistry, biological activities and therapeutic uses. Cancer Lett 1998; 131 (01) 3-11
- 78 Wang Y, Yin S, Mei L. et al. A dual receptors-targeting and size-switchable “cluster bomb” co-loading chemotherapeutic and transient receptor potential ankyrin 1 (TRPA-1) inhibitor for treatment of triple negative breast cancer. J Control Release 2020; 321: 71-83
- 79 Wang L, Huo M, Chen Y, Shi J. Tumor microenvironment-enabled nanotherapy. Adv Healthc Mater 2018; 7 (08) e1701156
- 80 Yang D, Chen W, Hu J. Design of controlled drug delivery system based on disulfide cleavage trigger. J Phys Chem B 2014; 118 (43) 12311-12317
- 81 Wang H, Li Y, Bai H. et al. A cooperative dimensional strategy for enhanced nucleus-targeted delivery of anticancer drugs. Adv Funct Mater 2017; 27: 1700339
- 82 Guo X, Wei X, Jing Y, Zhou S. Size changeable nanocarriers with nuclear targeting for effectively overcoming multidrug resistance in cancer therapy. Adv Mater 2015; 27 (41) 6450-6456
- 83 Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 2006; 5: 14
- 84 Sun C, Liang Y, Hao N. et al. A ROS-responsive polymeric micelle with a π-conjugated thioketal moiety for enhanced drug loading and efficient drug delivery. Org Biomol Chem 2017; 15 (43) 9176-9185
- 85 Luo CQ, Zhou YX, Zhou TJ. et al. Reactive oxygen species-responsive nanoprodrug with quinone methides-mediated GSH depletion for improved chlorambucil breast cancers therapy. J Control Release 2018; 274: 56-68
- 86 Gupta MK, Meyer TA, Nelson CE, Duvall CL. Poly(PS-b-DMA) micelles for reactive oxygen species triggered drug release. J Control Release 2012; 162 (03) 591-598
- 87 Staff RH, Gallei M, Mazurowski M. et al. Patchy nanocapsules of poly(vinylferrocene)-based block copolymers for redox-responsive release. ACS Nano 2012; 6 (10) 9042-9049
- 88 Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nat Rev Cancer 2003; 3 (05) 380-387
- 89 He C, Duan X, Guo N. et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun 2016; 7: 12499
- 90 Cao Z, Ma Y, Sun C. et al. ROS-sensitive polymeric nanocarriers with red light-activated size shrinkage for remotely controlled drug release. Chem Mater 2018; 30 (02) 517-525
- 91 Park J, Choi Y, Chang H, Um W, Ryu JH, Kwon IC. Alliance with EPR effect: combined strategies to improve the epr effect in the tumor microenvironment. Theranostics 2019; 9 (26) 8073-8090
- 92 Danhier F. To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine. J Control Release 2016; 244: 108-121