Tumor Biology; Usefulness of Thermosensitive and pH Sensitive Polymeric Nanoparticles for Tumor Targeting: A Review
Abstract
Polymeric nanoparticles (PNPs) have attracted the interest of many scientists and have been utilized in an increasing number of fields during the last two decades. The conventional chemotherapeutic agents have poor pharmacokinetic parameters such as non-specific distribution of drugs, the lack of drug specific affinity towards a pathological site, and thus necessitating large dose of a drug to achieve high local concentration in the body leading to systemic toxicity associated with serious side effects. A thorough and precise understanding of tumor microenvironment such as angiogenesis, tumor pH, enhanced permeation and retention (EPR) effect, abnormal lymphatics, multidrug resistance (MDR) and high interstitial fluid pressure, allows designing drug delivery systems that specifically target anti-cancer drugs to tumors. An attempt has been made in this article to highlight the temperature and pH sensitive PNPs, and PNPs with dual and double response to both temperature and pH that have a distinct capacity to target tumors with limited effect on healthy tissues. The stimuli responsive nanoparticles are classified based on their mechanism of response to temperature and pH. Structure of the polymer, methods of drug loading, and characterization of PNPs are elucidated.
Keywords: Polymeric nanoparticles; pH sensitive polymers; Thermosensitive polymers; Tumor microenvironment; Multidrug resistance; Drug loading.
Keywords:
Polymeric nanoparticles, pH sensitive polymers, Thermosensitive polymers, Tumor microenvironment, Multidrug resistance, Drug loadingDOI
https://doi.org/10.22270/jddt.v12i4.5420References
Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Sig Transduct Target Ther. 2020; 5(1): 28. DOI: https://doi.org/10.1038/s41392-020-0134-x.
Kindt TJ, Goldsby RA, Osborne BA, Kuby J. Kuby Immunology. 6th ed. New York: W.H. Freeman and Co; 2007: 525-538.
Agarwal MB. Is cancer chemotherapy dying? Asian J Transfus Sci. 2016; 10(3): 1–7. DOI: https://doi.org/10.4103/0973-6247.182735.
Begines B, Ortiz T, Pérez-Aranda M, Martínez G, Merinero M, Argüelles-Arias F, Alcudia A. Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects. Nanomaterials. 2020; 10(7): 1403. DOI: https://doi.org/10.3390/nano10071403.
Bregoli L, Movia D, Gavigan-Imedio JD, Lysaght J, Reynolds J, Prina-Mello A. Nanomedicine applied to translational oncology: A future perspective on cancer treatment. Nanomedicine: Nanotechnology, Biology and Medicine. 2016; 12(1): 81–103. DOI: https://doi.org/10.1016/j.nano.2015.08.006.
Danquah MK, Zhang XA, Mahato RI. Extravasation of polymeric nanomedicines across tumor vasculature. Advanced Drug Delivery Reviews. 2011; 63(8): 623–639. DOI: https://doi.org/10.1016/j.addr.2010.11.005.
Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of Controlled Release. 2010; 148(2): 135–146. DOI: https://doi.org/10.1016/j.jconrel.2010.08.027.
Arneth B. Tumor Microenvironment. Medicina. 2020; 56(1): 15. DOI: https://doi.org/10.3390/medicina56010015.
Donnem T, Reynolds AR, Kuczynski EA, Gatter K, Vermeulen PB, Kerbel RS, Harris AL, Pezzella F. Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer. 2018; 18: 323–336. DOI: https://doi.org/10.1038/nrc.2018.14.
Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008; 8: 604–617. DOI: https://doi.org/10.1038/nrc2353.
Stollman TH, Ruers TJM, Oyen WJG, Boerman OC. New targeted probes for radioimaging of angiogenesis. Methods. 2009; 48(2): 188–192. DOI: https://doi.org/10.1016/j.ymeth.2009.03.006.
Tannock IF, Rotin D. Acid pH in Tumors and Its Potential for Therapeutic Exploitation. Cancer Res. 1989; 49 (16): 4373-4384.
Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proceedings of the National Academy of Sciences. 1998; 95(8): 4607–4612. DOI: https://doi.org/10.1073/pnas.95.8.4607.
Asgharzadeh MR, Barar J, Pourseif MM, Eskandani M, Jafari Niya M, Mashayekhi MR, Omidi Y. Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy. Bioimpacts. 2017; 7(2): 115–133. DOI: https://doi.org/10.15171/bi.2017.15.
Kim J, Dang CV. Cancer’s Molecular Sweet Tooth and the Warburg Effect: Figure 1., Cancer Res. 2006; 66(18): 8927–8930. DOI: https://doi.org/10.1158/0008-5472.CAN-06-1501.
Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452: 230–233. DOI: https://doi.org/10.1038/nature06734.
Wykoff CC, Beasley NJP, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. Hypoxia-inducible Expression of Tumor-associated Carbonic Anhydrases. Cancer Res. 2000; 60 (24): 7075-7083.
Gerweck LE, Seetharaman K. Cellular pH Gradient in Tumor versus Normal Tissue: Potential Exploitation for the Treatment of Cancer. Cancer Res. 1996; 56(6): 1194-1198.
Hockel M, Vaupel P. Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects. JNCI Journal of the National Cancer Institute. 2001; 93(4): 266–276. DOI: https://doi.org/10.1093/jnci/93.4.266.
Giaccia AJ. Hypoxic stress proteins: Survival of the fittest, Seminars in Radiation Oncology. 1996; 6(1): 46–58. DOI: https://doi.org/10.1016/S1053-4296(96)80035-X.
Graeber TG, Osmanian C, Jackstt T, Housmant HG, Koch CJ, Lowetll SW, Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. 1996; 379 (6560): 88-91. DOI: 10.1038/379088a0.
Denny WA. Prodrug strategies in cancer therapy. European Journal of Medicinal Chemistry. 2001; 36: 577–595. DOI: https://doi.org/10.1016/S0223-5234(01)01253-3.
Kaneta T, Takai Y, Iwata R, Hakamatsuka T, Yasuda H, Nakayama K, Ishikawa Y, Watanuki S, Furumoto S, Funaki Y, Nakata E, Jingu K, Tsujitani M, Itoh M, Fukuda H, Takahashi S, Yamada S. Initial evaluation of dynamic human imaging using18F-FRP170 as a new PET tracer for imaging hypoxia. Annals of Nuclear Medicine. 2007; 21: 101–7. DOI: https://doi.org/10.1007/BF03033987.
Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible Factor-1-dependent Regulation of the Multidrug Resistance (MDR1) gene. Cancer Res. 2002; 62(12): 3887-94.
Comerford KM, Cummins EP, Taylor CT. c-Jun. NH2-Terminal Kinase Activation Contributes to Hypoxia-Inducible Factor 1α–Dependent P-Glycoprotein Expression in Hypoxia. 2004; 64 (24): 9057-9061.
Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1., Journal of Biological Chemistry. 1994; 269: 23757–23763. DOI: https://doi.org/10.1016/S0021-9258(17)31580-6.
Kalyane D, Raval N, Maheshwari R, Tambe V, Kalia K, Tekade RK. Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Materials Science and Engineering: C. 2019; 98: 1252–1276. DOI: https://doi.org/10.1016/j.msec.2019.01.066.
Huynh E, Zheng G. Cancer nanomedicine: addressing the dark side of the enhanced permeability and retention effect. Nanomedicine. 2015; 10: 1993–1995. DOI: http://dx.doi.org.umiss.idm.oclc.org/10.2217/nnm.15.86.
Yhee JY, Son S, Joo MK, Kwon IC. The EPR Effect in Cancer Therapy. Cancer Targeted Drug Delivery. 2013; 621–632. DOI: https://doi.org/10.1007/978-1-4614-7876-8_23.
Padera TP, Meijer EFG, Munn LL. The Lymphatic System in Disease Processes and Cancer Progression, Annual Review of Biomedical Engineering. 2016; 18: 125–158. DOI: https://doi.org/10.1146/annurev-bioeng-112315-031200.
Padera TP, Stoll BR, Tooredman JB, Capen D, Di Tomaso E, Jain RK. Cancer cells compress intratumour vessels. Nature. 2004; 427: 695–695. DOI: https://doi.org/10.1038/427695a.
Padera TP, Kadambi A, Di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn JJ, Jain RK. Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics. Science. 2002; 296: 1883–1886.
Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK. Absence of Functional Lymphatics within a Murine Sarcoma: A Molecular and Functional Evaluation. Cancer Res. 2000; 60(16): 4324-4327.
Fukumura D, Jain RK. Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize. Journal of Cellular Biochemistry. 2007; 101: 937–949. DOI: https://doi.org/10.1002/jcb.21187.
Isaka N, Padera TP, Hagendoorn J, Fukumura D, Jain RK. Peritumor Lymphatics Induced by Vascular Endothelial Growth Factor-C Exhibit Abnormal Function. Cancer Research. 2004; 64(13): 4400-4.
Munson JM, Shieh AC. Interstitial fluid flow in cancer: implications for disease progression and treatment. Cancer Manag Res. 2014; 6: 317–328. DOI: https://doi.org/10.2147/CMAR.S65444.
Stine CA, Munson JM. Convection-Enhanced Delivery: Connection to and Impact of Interstitial Fluid Flow, Frontiers in Oncology. 2019; 9: 966. DOI: https://doi.org/10.3389/fonc.2019.00966.
Friedman R. Drug resistance in cancer: molecular evolution and compensatory proliferation. Oncotarget. 2016; 7: 11746–11755. DOI: https://doi.org/10.18632/oncotarget.7459.
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. Advanced Drug Delivery Reviews. 2011; 63: 136–151. DOI: https://doi.org/10.1016/j.addr.2010.04.009.
Robinson K, Tiriveedhi V. Perplexing Role of P-Glycoprotein in Tumor Microenvironment. Frontiers in Oncology. 2020;10. DOI: https://doi.org/10.3389/fonc.2020.00265.
Matsumoto NM, Buchman GW, Rome LH, Maynard HD. Dual pH- and Temperature-Responsive Protein Nanoparticles. Eur Polym J. 2015; 69: 532–539. DOI: https://doi.org/10.1016/j.eurpolymj.2015.01.043.
Patra JK, Das G, Fraceto LF, Campos EVR, Del P. Rodriguez-Torres M, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, Habtemariam S, Shin HS. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnol. 2018;16: 71. DOI: https://doi.org/10.1186/s12951-018-0392-8.
Torchilin VP. Drug targeting. European Journal of Pharmaceutical Sciences. 2000; 11(2): S81–S91. DOI: https://doi.org/10.1016/S0928-0987(00)00166-4.
Singh R, Lillard JW. Nanoparticle-based targeted drug delivery. Experimental and Molecular Pathology. 2009; 86: 215–223. DOI: https://doi.org/10.1016/j.yexmp.2008.12.004.
Rosenblum D, Joshi N, Tao W, Karp JM, Peer D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun. 2018; 9: 1410. DOI: https://doi.org/10.1038/s41467-018-03705-y.
Bazak R, Houri M, Achy SE, Hussein W, Refaat T. Passive targeting of nanoparticles to cancer: A comprehensive review of the literature. Molecular and Clinical Oncology. 2014; 2: 904. DOI: http://dx.doi.org.umiss.idm.oclc.org/10.3892/mco.2014.356.
Haley B, Frenkel E. Nanoparticles for drug delivery in cancer treatment. Urologic Oncology: Seminars and Original Investigations. 2008; 26: 57–64. DOI: https://doi.org/10.1016/j.urolonc.2007.03.015.
El-Sawy HS, Al-Abd AM, Ahmed TA, El-Say KM, Torchilin VP. Stimuli-Responsive Nano-Architecture Drug-Delivery Systems to Solid Tumor Micromilieu: Past, Present, and Future Perspectives. ACS Nano. 2018; 12: 10636–10664. DOI: https://doi.org/10.1021/acsnano.8b06104.
Bader H, Ringsdorf H, Schmidt B. Watersoluble polymers in medicine. Die Angewandte Makromolekulare Chemie. 1984;123: 457–485. DOI: https://doi.org/10.1002/apmc.1984.051230121.
Yokoyama M, Kwon GS, Okano T, Sakurai Y, Seto T, Kataoka K. Preparation of micelle-forming polymer-drug conjugates. Bioconjugate Chem. 1992; 3: 295–301. DOI: https://doi.org/10.1021/bc00016a007.
Rijcken CJF, Soga O, Hennink WE, Van Nostrum CF. Triggered destabilisation of polymeric micelles and vesicles by changing polymers polarity: An attractive tool for drug delivery, Journal of Controlled Release. 2007; 120: 131–148. DOI: https://doi.org/10.1016/j.jconrel.2007.03.023.
Woodle MC, Lasic DD. Sterically stabilized liposomes. Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes. 1992; 1113: 171–199. DOI: https://doi.org/10.1016/0304-4157(92)90038-C.
Molineux G. Pegylation: Engineering improved pharmaceuticals for enhanced therapy, Cancer Treatment Reviews. 2002; 28: 13–16. DOI: https://doi.org/10.1016/S0305-7372(02)80004-4.
Lee JH, Lee HB, Andrade JD. Blood compatibility of polyethylene oxide surfaces, Progress in Polymer Science. 1995; 20: 1043–1079. DOI: https://doi.org/10.1016/0079-6700(95)00011-4.
Benahmed A, Ranger M, Leroux JC. Novel Polymeric Micelles Based on the Amphiphilic Diblock Copolymer Poly(N-vinyl-2-pyrrolidone)-block-poly(D,L-lactide). Pharmaceutical Research. 2001; 18(3): 323-328.
Inoue T, Chen G, Nakamae K, Hoffman AS. An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs. Journal of Controlled Release. 1998; 51: 221–229. DOI: https://doi.org/10.1016/S0168-3659(97)00172-7.
Kabanov AV, Batrakova EV, Alakhov VY. Pluronic® block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release. 2002; 82: 189–212. DOI: https://doi.org/10.1016/S0168-3659(02)00009-3.
Yokoyama M, Fukushima S, Uehara R, Okamoto K, Kataoka K*, Sakurai Y, Okano T. Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. Journal of Controlled Release. 1998; 50: 79–92. DOI: https://doi.org/10.1016/S0168-3659(97)00115-6.
Kwon GS, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Physical Entrapment of Adriamycin in AB Block Copolymer Micelles. Pharm Res. 1995;12: 192–195. DOI: https://doi.org/10.1023/A:1016266523505.
Hagan SA, Coombes AGA, Garnett MC, Dunn SE, Davies MC, Illum L, Davis SS, Harding SE, Purkiss S, Gellert PR. Polylactide−Poly(ethylene glycol) Copolymers as Drug Delivery Systems. 1. Characterization of Water Dispersible Micelle-Forming Systems, Langmuir. 1996; 12: 2153–2161. DOI: https://doi.org/10.1021/la950649v.
Liggins RT, Burt HM. Polyether–polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations. Advanced Drug Delivery Reviews. 2002; 54: 191–202. DOI: https://doi.org/10.1016/S0169-409X(02)00016-9.
Allen C. Polycaprolactone–b-poly(ethylene oxide) copolymer micelles as a delivery vehicle for dihydrotestosterone. Journal of Controlled Release. 2000; 63: 275–286. DOI: https://doi.org/10.1016/S0168-3659(99)00200-X.
Letchford K, Zastre J, Liggins R, Burt H. Synthesis and micellar characterization of short block length methoxy poly(ethylene glycol)-block-poly(caprolactone) diblock copolymers. Colloids and Surfaces B: Biointerfaces. 2004; 35: 81–91. DOI: https://doi.org/10.1016/j.colsurfb.2004.02.012.
Zhang Z, Grijpma DW, Feijen J. Thermo-sensitive transition of monomethoxy poly(ethylene glycol)-block-poly(trimethylene carbonate) films to micellar-like nanoparticles. Journal of Controlled Release. 2006; 112: 57–63. DOI: https://doi.org/10.1016/j.jconrel.2006.01.010.
Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copolymers for drug delivery. Journal of Pharmaceutical Sciences. 2003; 92: 1343–1355. DOI: https://doi.org/10.1002/jps.10397.
Gil E, Hudson S. Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science. 2004; 29: 1173–1222. DOI: https://doi.org/10.1016/j.progpolymsci.2004.08.003.
Schild HG, Poly(N-isopropylacrylamide): Experiment, theory and application, Progress in Polymer Science. 1992; 17: 163–249. DOI: https://doi.org/10.1016/0079-6700(92)90023-R.
Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Advanced Drug Delivery Reviews. 2001; 53(3): 322-39.
Aoyagi T, Ebara M, Sakai K, Sakurai Y, Okano T. Novel bifunctional polymer with reactivity and temperature sensitivity. Journal of Biomaterials Science -- Polymer Edition. 2000; 11: 101–110. DOI: https://doi.org/10.1163/156856200743526.
Malmsten M, Lindman B. Self-assembly in aqueous block copolymer solutions. Macromolecules. 1992; 25: 5440–5445. DOI: https://doi.org/10.1021/ma00046a049.
Kuijpers AJ, Engbers GHM, Feijen J, De Smedt SC, Meyvis TKL, Demeester J, Krijgsveld J, Zaat SAJ, Dankert J. Characterization of the Network Structure of Carbodiimide Cross-Linked Gelatin Gels. Macromolecules. 1999; 32: 3325–3333. DOI: https://doi.org/10.1021/ma981929v.
Ramzi M, Rochas C, Guenet JM. Structure−Properties Relation for Agarose Thermoreversible Gels in Binary Solvents. Macromolecules. 1998; 31: 6106–6111. DOI: https://doi.org/10.1021/ma9801220.
Philippova OE, Hourdet D, Audebert R, Khokhlov AR. pH-Responsive Gels of Hydrophobically Modified Poly(acrylic acid). Macromolecules. 1997; 30: 8278–8285. DOI: https://doi.org/10.1021/ma970957v .
Benns JM, Choi JS, Mahato RI, Park JS, Kim SW. pH-Sensitive Cationic Polymer Gene Delivery Vehicle: N -Ac-poly( L -histidine)-graft-poly( L -lysine) Comb Shaped Polymer. Bioconjugate Chem. 2000; 11: 637–645. DOI: https://doi.org/10.1021/bc0000177.
Lee ES, Gao Z, Bae YH. Recent progress in tumor pH targeting nanotechnology. Journal of Controlled Release. 2008; 132: 164–170. DOI: https://doi.org/10.1016/j.jconrel.2008.05.003.
Liu Y, Cao X, Luo M, Le Z, Xu W. Self-assembled micellar nanoparticles of a novel star copolymer for thermo and pH dual-responsive drug release. Journal of Colloid and Interface Science. 2009; 329: 244–252. DOI: https://doi.org/10.1016/j.jcis.2008.10.007 .
Li L, Yang WW, Xu DG. Stimuli-responsive nanoscale drug delivery systems for cancer therapy. Journal of Drug Targeting. 2019; 27: 423–433. DOI: https://doi.org/10.1080/1061186X.2018.1519029 .
Soon Y, Sun C, Sang L, Jung S, Jin L. pH/Temperature-Sensitive Polymers for Controlled Drug Delivery. Polymeric Drugs and Delivery Systems. 2019; 39-56.
Yokoyama M. Polymeric micelles as drug carriers: their lights and shadows. Journal of Drug Targeting. 2014; 22: 576–583. DOI: https://doi.org/10.3109/1061186X.2014.934688 .
Wei H et al., Self-assembled thermo- and pH responsive micelles of poly(10-undecenoic acid-b-N-isopropylacrylamide) for drug delivery. J Control Release. 2006 ;116(3):266-74. DOI: https://doi.org/10.1016/j.jconrel.2006.08.018 .
Banda S, Tiwari PB, Darici Y, YC Tse-Dinh. Investigating direct interaction between Escherichia coli topoisomerase I and RecA. Gene. 2016; 585(1): 65-70. DOI: https://doi.org/10.1016/j.gene.2016.03.013
Banda S, Cao N, Tse-Dinh YC. Distinct mechanism evolved for Mycobacterial RNA polymerase and topoisomerase I protein-protein interaction. Journal of molecular biology. 2017; 429 (19): 2931-2942. DOI: https://doi.org/10.1016/j.jmb.2017.08.011
Yang J, Annamalai T, Cheng B, Banda S, Tyagi R, Tse-Dinh YC. Antimicrobial susceptibility and SOS-dependent increase in mutation frequency are impacted by Escherichia coli topoisomerase I C-terminal point mutation. Antimicrobial agents and chemotherapy. 2015; 59 (10): 6195-6202. DOI: https://doi.org/10.1128/AAC.00855-15
Published
Abstract Display: 515 
PDF Downloads: 523 PDF Downloads: 31 How to Cite
Issue
Section
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.