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Tumor Microenvironment-Responsive Nanoplatforms for Triggering Drug Delivery

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Handbook of Cancer and Immunology

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Abstract

Cancer is the second leading cause of mortality among nontransmissible diseases globally. Despite the advances in chemotherapy, the insufficient drug selectivity against cancer cells poses multiple challenges to this treatment modality, such as severe adverse effects and multidrug resistance. The pharmacokinetic properties of many chemotherapy agents (e.g., limited solubility) also restrict modes of administration options. Clearly, newer therapeutic strategies are required. Nanomedicine, particularly, is an innovative approach: drug encapsulation within nanoparticles (NPs) has the potential to enhance tumor selectivity, reduce systemic adverse effects, combine multiple drugs within the same nanoplatform, and enhance drug pharmacokinetics/biocompatibility. However, nano-therapies targeting directly the tumor cells exhibit certain constraints due to the heterogeneous expression of the target molecule between individuals or within the same tumor, expression of the target moiety on healthy tissues, and limited tumor penetration. The tumor microenvironment (TME) represents an optimal target due to its intrinsic physicochemical conditions (e.g., hypoxia, low pH, high oxidative stress, enzyme overexpression), which differ from the ones present in healthy tissues. Therefore, NPs can be sensitized to the TME stimuli for selective drug delivery. This chapter will discuss the TME stimuli in the context of nanoplatform-based drug delivery. In addition, novel TME-responsive, nanoplatform-based therapies to overcome conventional chemotherapy challenges will be discussed.

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References

  • Amith SR, Wilkinson JM, Fliegel L (2016) Na+/H+ exchanger NHE1 regulation modulates metastatic potential and epithelial-mesenchymal transition of triple-negative breast cancer cells. Oncotarget 7(16):21091–21113

    Article  PubMed  PubMed Central  Google Scholar 

  • Anastasiou D (2017) Tumour microenvironment factors shaping the cancer metabolism landscape. Br J Cancer 116(3):277–286

    Article  CAS  PubMed  Google Scholar 

  • Armstrong GT et al (2014) Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 32(12):1218–1227

    Article  PubMed  PubMed Central  Google Scholar 

  • Ashton TM et al (2018) Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res 24(11):2482–2490

    Article  CAS  PubMed  Google Scholar 

  • Aykin-Burns N et al (2009) Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 418(1):29–37

    Article  CAS  PubMed  Google Scholar 

  • Baghban R et al (2020) Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal 18(1):59

    Article  PubMed  PubMed Central  Google Scholar 

  • Bailly A-L et al (2019) In vivo evaluation of safety, biodistribution and pharmacokinetics of laser-synthesized gold nanoparticles. Sci Rep 9(1):12890

    Article  PubMed  PubMed Central  Google Scholar 

  • Becelli R et al (2007) Intracellular and extracellular tumor pH measurement in a series of patients with oral cancer. J Craniofac Surg 18(5):1051

    Article  PubMed  Google Scholar 

  • Berra E, Pagès G, Pouysségur J (2000) MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev 19(1):139–145

    Article  CAS  PubMed  Google Scholar 

  • Bradshaw PT et al (2016) Cardiovascular disease mortality among breast cancer survivors. Epidemiology 27(1):6–13

    Article  PubMed  PubMed Central  Google Scholar 

  • Burtenshaw D et al (2017) Nox, reactive oxygen species and regulation of vascular cell fate. Antioxidants 6(4):90

    Article  PubMed  PubMed Central  Google Scholar 

  • Burton RF (1978) Intracellular buffering. Respir Physiol 33(1):51–58

    Article  CAS  PubMed  Google Scholar 

  • Calvayrac O et al (2017) The RAS-related GTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism. EMBO Mol Med 9(2):238–250

    Article  CAS  PubMed  Google Scholar 

  • Cancer Research UK (n.d.) Cancer statistics for the UK. https://www.cancerresearchuk.org/health-professional/cancer-statistics-for-the-uk#heading-Two

  • Carter KA et al (2019) Blood interactions, pharmacokinetics, and depth-dependent ablation of rat mammary tumors with photoactivatable, liposomal doxorubicin. Mol Cancer Ther 18(3):592–601

    Article  CAS  PubMed  Google Scholar 

  • Chen L et al (2018) The toxicity of silica nanoparticles to the immune system. Nanomedicine 13(15):1939–1962

    Article  PubMed  Google Scholar 

  • Chen F et al (2022) The V-ATPases in cancer and cell death. Cancer Gene Ther 29(11):1529–1541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheul-Seong KIM et al (2010) Effects of Silybinin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen in rats. Anticancer Res 30(1):79

    Google Scholar 

  • Clemons TD et al (2018) Distinction between active and passive targeting of nanoparticles dictate their overall therapeutic efficacy. Langmuir 34(50):15343–15349

    Article  CAS  PubMed  Google Scholar 

  • Colby AH et al (2021) Pilot-scale production of expansile nanoparticles: practical methods for clinical scale-up. J Control Release 337:144–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Confeld MI et al (2020) Targeting the tumor core: hypoxia-responsive nanoparticles for the delivery of chemotherapy to pancreatic tumors. Mol Pharm 17(8):2849–2863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couto-Vieira J et al (2020) Multi-cancer V-ATPase molecular signatures: a distinctive balance of subunit C isoforms in esophageal carcinoma. EBioMedicine 51:102581

    Article  PubMed  PubMed Central  Google Scholar 

  • Cun X et al (2016) A dual strategy to improve the penetration and treatment of breast cancer by combining shrinking nanoparticles with collagen depletion by losartan. Acta Biomater 31:186–196

    Article  CAS  PubMed  Google Scholar 

  • Das K, Roychoudhury A (2014) Reactive oxygen species (ROS) and response of antioxidants as ROS-scavengers during environmental stress in plants. Front Environ Sci 2:53

    Article  Google Scholar 

  • Datta J et al (2017) Akt activation mediates acquired resistance to fibroblast growth factor receptor inhibitor BGJ398. Mol Cancer Ther 16(4):614–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Gracia Lux C et al (2012) Biocompatible polymeric nanoparticles degrade and release cargo in response to biologically relevant levels of hydrogen peroxide. J Am Chem Soc 134(38):15758–15764

    Article  PubMed  PubMed Central  Google Scholar 

  • de la Cruz-López KG et al (2019) Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol 9:1143

    Article  PubMed  PubMed Central  Google Scholar 

  • De S et al (2005) VEGF–integrin interplay controls tumor growth and vascularization. Proc Natl Acad Sci 102(21):7589–7594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deacon JC, Engelman DM, Barrera FN (2015) Targeting acidity in diseased tissues: mechanism and applications of the membrane-inserting peptide, pHLIP. Arch Biochem Biophys 565:40–48

    Article  CAS  PubMed  Google Scholar 

  • Dewhirst MW et al (1999) Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer 79(11–12):1717–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Einzig AI et al (1991) A phase II study of taxol in patients with malignant melanoma. Investig New Drugs 9(1):59–64

    Article  CAS  Google Scholar 

  • Escalona RM et al (2022) Expression of TIMPs and MMPs in ovarian tumors, ascites, ascites-derived cells, and cancer cell lines: characteristic modulatory response before and after chemotherapy treatment. Front Oncol 11:796588

    Article  PubMed  PubMed Central  Google Scholar 

  • Fajgenbaum DC, June CH (2020) Cytokine storm. N Engl J Med 383(23):2255–2273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan F, Jin L, Yang L (2021) pH-sensitive nanoparticles composed solely of membrane-disruptive macromolecules for treating pancreatic cancer. ACS Appl Mater Interfaces 13(11):12824–12835

    Article  CAS  PubMed  Google Scholar 

  • Fan D et al (2023) Nanomedicine in cancer therapy. Signal Transduct Target Ther 8(1):293

    Article  PubMed  PubMed Central  Google Scholar 

  • Farhana A, Lappin SL (2020) Biochemistry, lactate dehydrogenase. StatPearls Publishing, Treasure Island

    Google Scholar 

  • Feng W et al (2020) pH/redox sequentially responsive nanoparticles with size shrinkage properties achieve deep tumor penetration and reversal of multidrug resistance. Biomater Sci 8(17):4767–4778

    Article  CAS  PubMed  Google Scholar 

  • Filho OM et al (2021) Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab. Cancer Discov 11(10):2474–2487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Filipczak N et al (2022) Hypoxia-sensitive drug delivery to tumors. J Control Release 341:431–442

    Article  CAS  PubMed  Google Scholar 

  • Folkman J et al (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339(6219):58–61

    Article  CAS  PubMed  Google Scholar 

  • Frohna P et al (2006) Evaluation of the absolute oral bioavailability and bioequivalence of Erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects. J Clin Pharmacol 46(3):282–290

    Article  CAS  PubMed  Google Scholar 

  • Gambardella V et al (2020) Personalized medicine: recent progress in cancer therapy. Cancers (Basel) 12(4):1009

    Article  CAS  PubMed  Google Scholar 

  • Gavas S, Quazi S, Karpiński TM (2021) Nanoparticles for cancer therapy: current progress and challenges. Nanoscale Res Lett 16(1):173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ge R, Wang Z, Cheng L (2022) Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance. NPJ Precis Oncol 6(1):31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerlowski LE, Jain RK (1986) Microvascular permeability of normal and neoplastic tissues. Microvasc Res 31(3):288–305

    Article  CAS  PubMed  Google Scholar 

  • Goddard ZR et al (2020) Active targeting of gold nanoparticles as cancer therapeutics. Chem Soc Rev 49(23):8774–8789

    Article  CAS  PubMed  Google Scholar 

  • Gong Y et al (2013) TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression. PLoS One 8(10):e77366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Avila G et al (2022) Nanotechnology and matrix metalloproteinases in cancer diagnosis and treatment. Front Mol Biosci 9:918789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griguolo G et al (2021) Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer. NPJ Precis Oncol 5(1):23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo B et al (2023) Cuproptosis induced by ROS responsive nanoparticles with Elesclomol and copper combined with αPD-L1 for enhanced cancer immunotherapy. Adv Mater 35(22):2212267

    Article  CAS  Google Scholar 

  • Haklar G et al (2001) Different kinds of reactive oxygen and nitrogen species were detected in colon and breast tumors. Cancer Lett 165(2):219–224

    Article  CAS  PubMed  Google Scholar 

  • Han Y, Liu D, Li L (2020) PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res 10(3):727–742

    CAS  PubMed  PubMed Central  Google Scholar 

  • Han J et al (2021) Comprehensive analysis of expression, prognosis and immune infiltration for TIMPs in glioblastoma. BMC Neurol 21(1):447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto T et al (2023) A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer. Br J Cancer 129(7):1176–1183

    Article  CAS  PubMed  Google Scholar 

  • Hashizume H et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He L et al (2022) The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer. Front Immunol 13:1093990

    Article  CAS  PubMed  Google Scholar 

  • Henrotin YE, Bruckner P, Pujol JPL (2003) The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr Cartil 11(10):747–755

    Article  CAS  Google Scholar 

  • Hernández-Reséndiz I et al (2019) Mutant p53R248Q downregulates oxidative phosphorylation and upregulates glycolysis under normoxia and hypoxia in human cervix cancer cells. J Cell Physiol 234(5):5524–5536

    Article  PubMed  Google Scholar 

  • Hobbs SK et al (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci 95(8):4607–4612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hompland T, Fjeldbo CS, Lyng H (2021) Tumor hypoxia as a barrier in cancer therapy: why levels matter. Cancers (Basel) 13(3):499

    Article  CAS  PubMed  Google Scholar 

  • Hsu C-C, Tseng L-M, Lee H-C (2016) Role of mitochondrial dysfunction in cancer progression. Exp Biol Med 241(12):1281–1295

    Article  CAS  Google Scholar 

  • Hu C et al (2018) Enzyme-triggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy. Biomaterials 168:64–75

    Article  CAS  PubMed  Google Scholar 

  • Iotti S et al (2005) Quantitative mathematical expressions for accurate in vivo assessment of cytosolic [ADP] and ΔG of ATP hydrolysis in the human brain and skeletal muscle. Biochim Biophys Acta Bioenerg 1708(2):164–177

    Article  CAS  Google Scholar 

  • Isaka N et al (2004) Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res 64(13):4400–4404

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa K et al (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320(5876):661–664

    Article  CAS  PubMed  Google Scholar 

  • Jackson HW et al (2017) TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 17(1):38–53

    Article  CAS  PubMed  Google Scholar 

  • Jäger E et al (2016) Fluorescent boronate-based polymer nanoparticles with reactive oxygen species (ROS)-triggered cargo release for drug-delivery applications. Nanoscale 8(13):6958–6963

    Article  PubMed  Google Scholar 

  • James JS (1995) DOXIL approved for KS. AIDS Treat News 236:6

    Google Scholar 

  • Jessani N et al (2004) Carcinoma and stromal enzyme activity profiles associated with breast tumor growth in vivo. Proc Natl Acad Sci 101(38):13756–13761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji H et al (2021) Recent advances in ROS-sensitive Nano-formulations for atherosclerosis applications. Pharmaceutics 13(9):1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin M-Z, Jin W-L (2020) The updated landscape of tumor microenvironment and drug repurposing. Signal transduction and targeted. Therapy 5(1):166

    Google Scholar 

  • Johnson RP, John JV, Kim I (2014) Poly(L-histidine)-containing polymer bioconjugate hybrid materials as stimuli-responsive theranostic systems. J Appl Polym Sci 131(18):796

    Article  Google Scholar 

  • Joshi U et al (2020) Hypoxia-sensitive micellar nanoparticles for co-delivery of siRNA and chemotherapeutics to overcome multi-drug resistance in tumor cells. Int J Pharm 590:119915

    Article  CAS  PubMed  Google Scholar 

  • Kang SI, Bae YH (2002) pH-induced solubility transition of sulfonamide-based polymers. J Control Release 80(1):145–155

    Article  CAS  PubMed  Google Scholar 

  • Kang H et al (2020) Size-dependent EPR effect of polymeric nanoparticles on tumor targeting. Adv Healthc Mater 9(1):1901223

    Article  CAS  Google Scholar 

  • Karan S et al (2021) Near-infrared fluorescent probe activated by nitroreductase for in vitro and in vivo hypoxic tumor detection. J Med Chem 64(6):2971–2981

    Article  CAS  PubMed  Google Scholar 

  • Kennel KB, Greten FR (2021) Immune cell – produced ROS and their impact on tumor growth and metastasis. Redox Biol 42:101891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan I, Saeed K, Khan I (2019) Nanoparticles: properties, applications and toxicities. Arab J Chem 12(7):908–931

    Article  CAS  Google Scholar 

  • Kindler HL et al (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23(31):8033–8040

    Article  CAS  PubMed  Google Scholar 

  • Kirschke H et al (2000) Antisense RNA inhibition of cathepsin L expression reduces tumorigenicity of malignant cells. Eur J Cancer 36(6):787–795

    Article  CAS  PubMed  Google Scholar 

  • Kiyose K et al (2010) Hypoxia-sensitive fluorescent probes for in vivo real-time fluorescence imaging of acute ischemia. J Am Chem Soc 132(45):15846–15848

    Article  CAS  PubMed  Google Scholar 

  • Kizaka-Kondoh S, Konse-Nagasawa H (2009) Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia. Cancer Sci 100(8):1366–1373

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi Y, Oguro A, Imaoka S (2021) Feedback of hypoxia-inducible factor-1alpha (HIF-1alpha) transcriptional activity via redox factor-1 (Ref-1) induction by reactive oxygen species (ROS). Free Radic Res 55(2):154–164

    Article  CAS  PubMed  Google Scholar 

  • Kohane DS, Langer R (2010) Biocompatibility and drug delivery systems. Chem Sci 1(4):441–446

    Article  CAS  Google Scholar 

  • Kong J, Park SS, Ha C-S (2022) pH-sensitive polyacrylic acid-gated mesoporous silica nanocarrier incorporated with calcium ions for controlled drug release. Materials 15(17):5926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kotsafti A et al (2020) Reactive oxygen species and antitumor immunity – from surveillance to evasion. Cancers 12(7):1748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumari R, Sunil D, Ningthoujam RS (2020) Hypoxia-responsive nanoparticle based drug delivery systems in cancer therapy: an up-to-date review. J Control Release 319:135–156

    Article  CAS  PubMed  Google Scholar 

  • Lai Y et al (2018) Serum VEGF levels in the early diagnosis and severity assessment of non-small cell lung cancer. J Cancer 9(9):1538–1547

    Article  PubMed  PubMed Central  Google Scholar 

  • Layer RW (1963) The chemistry of imines. Chem Rev 63(5):489–510

    Article  CAS  Google Scholar 

  • Lee Y et al (2021) Rhamnolipid-coated W/O/W double emulsion nanoparticles for efficient delivery of doxorubicin/erlotinib and combination chemotherapy. J Nanobiotechnol 19(1):411

    Article  CAS  Google Scholar 

  • Leu AJ et al (2000) Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 60(16):4324–4327

    CAS  PubMed  Google Scholar 

  • Lewis DM et al (2016) Intratumoral oxygen gradients mediate sarcoma cell invasion. Proc Natl Acad Sci 113(33):9292–9297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X-F et al (2007) Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res 67(16):7646–7653

    Article  CAS  PubMed  Google Scholar 

  • Li S et al (2009) Inhibition of proliferation and apoptosis induced by a Na+/H+ exchanger-1 (NHE-1) antisense gene on drug-resistant human small cell lung cancer cells. Oncol Rep 21(5):1243–1249

    PubMed  Google Scholar 

  • Li C et al (2019) Low perfusion compartments in glioblastoma quantified by advanced magnetic resonance imaging and correlated with patient survival. Radiother Oncol 134:17–24

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Q, Li X, Zhao C (2020a) Strategies to obtain encapsulation and controlled release of small hydrophilic molecules. Front Bioeng Biotechnol 8:437

    Article  PubMed  PubMed Central  Google Scholar 

  • Li X et al (2020b) Hypoxia/pH dual-responsive nitroimidazole-modified chitosan/rose bengal derivative nanoparticles for enhanced photodynamic anticancer therapy. Dyes Pigments 179:108395

    Article  CAS  Google Scholar 

  • Li M et al (2020c) Enzyme-responsive nanoparticles for anti-tumor drug delivery. Front Chem 8:647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Zhu Y, Matson JB (2022) pH-responsive self-assembling peptide-based biomaterials: designs and applications. ACS Appl Bio Mater 5(10):4635–4651

    Article  CAS  Google Scholar 

  • Lin X-L et al (2017) Overexpression of NOX4 predicts poor prognosis and promotes tumor progression in human colorectal cancer. Oncotarget 8(20):33586–33600

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu B, Thayumanavan S (2020) Mechanistic investigation on oxidative degradation of ROS-responsive Thioacetal/Thioketal moieties and their implications. Cell Reports Physical Science 1(12):100271

    Article  CAS  Google Scholar 

  • Liu F et al (2017a) Increased expression of monoamine oxidase A is associated with epithelial to mesenchymal transition and clinicopathological features in non-small cell lung cancer. Oncol Lett 15:3245

    PubMed  PubMed Central  Google Scholar 

  • Liu Y et al (2017b) Effects of engineered nanoparticles on the innate immune system. Semin Immunol 34:25–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu X et al (2019) Long-term pulmonary exposure to multi-walled carbon nanotubes promotes breast cancer metastatic cascades. Nat Nanotechnol 14(7):719–727

    Article  CAS  PubMed  Google Scholar 

  • Majidinia M et al (2020) Overcoming multidrug resistance in cancer: recent progress in nanotechnology and new horizons. IUBMB Life 72(5):855–871

    Article  CAS  PubMed  Google Scholar 

  • Mansoori B et al (2017) The different mechanisms of cancer drug resistance: a brief review. Adv Pharm Bull 7(3):339–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12_Part_1):6387–6392

    CAS  PubMed  Google Scholar 

  • Matteson DS (1989) Boronic esters in stereodirected synthesis. Tetrahedron 45(7):1859–1885

    Article  CAS  Google Scholar 

  • McKeown SR (2014) Defining normoxia, physoxia and hypoxia in tumours – implications for treatment response. Br J Radiol 87(1035):20130676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medical Subject Headings (1993) Reactive oxygen species. https://www.ncbi.nlm.nih.gov/mesh/68017382

  • Medical Subject Headings (2006) Nanomedicine. https://www.ncbi.nlm.nih.gov/mesh/68050997

  • Medical Subject Headings (2011) Tumour microenvironment. https://www.ncbi.nlm.nih.gov/mesh/?term=tumour+microenvironment

  • Melincovici CS et al (2018) Vascular endothelial growth factor (VEGF) – key factor in normal and pathological angiogenesis. Roman J Morphol Embryol 59(2):455–467

    Google Scholar 

  • Meulewaeter S et al (2023) Continuous freeze-drying of messenger RNA lipid nanoparticles enables storage at higher temperatures. J Control Release 357:149–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Missirlis D et al (2006) Doxorubicin encapsulation and diffusional release from stable, polymeric, hydrogel nanoparticles. Eur J Pharm Sci 29(2):120–129

    Article  CAS  PubMed  Google Scholar 

  • Möller MN et al (2019) Diffusion and transport of reactive species across cell membranes. In: Trostchansky A, Rubbo H (eds) Bioactive lipids in health and disease. Springer International Publishing, Cham, pp 3–19

    Chapter  Google Scholar 

  • Mondal L et al (2019) CD-340 functionalized doxorubicin-loaded nanoparticle induces apoptosis and reduces tumor volume along with drug-related cardiotoxicity in mice. Int J Nanomedicine 14:8073–8094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Movellan KT et al (2020) Imidazole–imidazole hydrogen bonding in the pH-sensing histidine side chains of influenza A M2. J Am Chem Soc 142(6):2704–2708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Movsas B et al (2000) Increasing levels of hypoxia in prostate carcinoma correlate significantly with increasing clinical stage and patient age. Cancer 89(9):2018–2024

    Article  CAS  PubMed  Google Scholar 

  • Mu Y et al (2021) Advances in pH-responsive drug delivery systems. OpenNano 5:100031

    Article  Google Scholar 

  • Mundekkad D, Cho WC (2022) Nanoparticles in clinical translation for cancer therapy. Int J Mol Sci 23(3):1685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Narum SM et al (2020) Chapter 4 – Passive targeting in nanomedicine: fundamental concepts, body interactions, and clinical potential. In: Chung EJ, Leon L, Rinaldi C (eds) Nanoparticles for biomedical applications. Elsevier, Amsterdam, pp 37–53

    Chapter  Google Scholar 

  • Nathanson SD, Nelson L (1994) Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma. Ann Surg Oncol 1(4):333–338

    Article  CAS  PubMed  Google Scholar 

  • Nelson DL, Cox MM, Lehninger AL (2017) Lehninger principles of biochemistry. In: Principles of biochemistry, 7th edn. WH Freeman, New York

    Google Scholar 

  • Newell K et al (1993) Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proc Natl Acad Sci U S A 90(3):1127–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishida N et al (2006) Angiogenesis in cancer. Vasc Health Risk Manag 2(3):213–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nygren P (2001) What is cancer chemotherapy? Acta Oncol 40(2–3):166–174

    Article  CAS  PubMed  Google Scholar 

  • Ofridam F et al (2021) pH-sensitive polymers: classification and some fine potential applications. Polym Adv Technol 32(4):1455–1484

    Article  CAS  Google Scholar 

  • Onodera T et al (2020) Human pancreatic cancer cells under nutrient deprivation are vulnerable to redox system inhibition. J Biol Chem 295(49):16678–16690

    Article  CAS  PubMed  Google Scholar 

  • Ortiz-Prado E et al (2019) Partial pressure of oxygen in the human body: a general review. Am J Blood Res 9(1):1–14

    CAS  PubMed  PubMed Central  Google Scholar 

  • Osei-Owusu J et al (2022) Molecular determinants of pH sensing in the proton-activated chloride channel. Proc Natl Acad Sci 119(31):e2200727119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pacheco A, Martins A, Guilhermino L (2018) Toxicological interactions induced by chronic exposure to gold nanoparticles and microplastics mixtures in Daphnia magna. Sci Total Environ 628–629:474–483

    Article  PubMed  Google Scholar 

  • Padera TP et al (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296(5574):1883–1886

    Article  CAS  PubMed  Google Scholar 

  • Palanikumar L et al (2020) pH-responsive high stability polymeric nanoparticles for targeted delivery of anticancer therapeutics. Commun Biol 3(1):95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pandya AD et al (2019) Paclitaxel-loaded biodegradable ROS-sensitive nanoparticles for cancer therapy. Int J Nanomedicine 14:6269–6285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pattison S et al (2017) Early relapses after adjuvant chemotherapy suggests primary chemoresistance in diffuse gastric cancer. PLoS One 12(9):e0183891

    Article  PubMed  PubMed Central  Google Scholar 

  • Payen VL et al (2020) Monocarboxylate transporters in cancer. Mol Metab 33:48–66

    Article  CAS  PubMed  Google Scholar 

  • Poland CA et al (2008) Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nat Nanotechnol 3(7):423–428

    Article  CAS  PubMed  Google Scholar 

  • Prabhu PP et al (2021) Development of lapatinib nanosponges for enhancing bioavailability. J Drug Deliv Sci Technol 65:102684

    Article  CAS  Google Scholar 

  • Pu Y-S et al (2009) Characterization of membranous and cytoplasmic EGFR expression in human normal renal cortex and renal cell carcinoma. J Biomed Sci 16(1):82

    Article  PubMed  PubMed Central  Google Scholar 

  • Pusztai L et al (2005) Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 104(4):682–691

    Article  CAS  PubMed  Google Scholar 

  • Quintero-Fabián S et al (2019) Role of matrix metalloproteinases in angiogenesis and Cancer. Frontiers. Oncology 9:1370

    Google Scholar 

  • Ren F et al (2015) Overexpression of MMP family members functions as prognostic biomarker for breast cancer patients: a systematic review and meta-analysis. PLoS One 10(8):e0135544

    Article  PubMed  PubMed Central  Google Scholar 

  • Reunanen N, Kähäri V (2013) Matrix metalloproteinases in cancer cell invasion. In: Madame Curie bioscience database [Internet]. Landes Bioscience, Austin

    Google Scholar 

  • Rinaldi A et al (2022) Applications of the ROS-responsive thioketal linker for the production of smart nanomedicines. Polymers (Basel) 14(4):687

    Article  CAS  PubMed  Google Scholar 

  • Robergs RA, Ghiasvand F, Parker D (2004) Biochemistry of exercise-induced metabolic acidosis. Am J Phys Regul Integr Comp Phys 287(3):R502–R516

    CAS  Google Scholar 

  • Ruan S et al (2015) Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release. Biomaterials 60:100–110

    Article  CAS  PubMed  Google Scholar 

  • Rudzińska M et al (2019) The role of cysteine cathepsins in cancer progression and drug resistance. Int J Mol Sci 20(14):3602

    Article  PubMed  PubMed Central  Google Scholar 

  • San-Millán I, Brooks GA (2017) Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis 38(2):119–133

    PubMed  Google Scholar 

  • Sarin H (2010) Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J Angiogenes Res 2(1):14

    Article  PubMed  PubMed Central  Google Scholar 

  • Semenza GL (2001) HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 13(2):167–171

    Article  CAS  PubMed  Google Scholar 

  • Shin S-C, Choi J-S, Li X (2006) Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm 313(1):144–149

    Article  CAS  PubMed  Google Scholar 

  • Shinn J et al (2022) Smart pH-responsive nanomedicines for disease therapy. J Pharm Investig 52(4):427–441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shirinifard A et al (2009) 3D multi-cell simulation of tumor growth and angiogenesis. PLoS One 4(10):e7190

    Article  PubMed  PubMed Central  Google Scholar 

  • Sloane BF, Dunn JR, Honn KV (1981) Lysosomal cathepsin B: correlation with metastatic potential. Science 212(4499):1151–1153

    Article  CAS  PubMed  Google Scholar 

  • Song SJ, Choi JS (2022) Enzyme-responsive amphiphilic peptide nanoparticles for biocompatible and efficient drug delivery. Pharmaceutics 14:143. https://doi.org/10.3390/pharmaceutics14010143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song C-C et al (2013) Oxidation-accelerated hydrolysis of the ortho ester-containing acid-labile polymers. ACS Macro Lett 2(3):273–277

    Article  CAS  PubMed  Google Scholar 

  • Song C-C, Du F-S, Li Z-C (2014) Oxidation-responsive polymers for biomedical applications. J Mater Chem B 2(22):3413–3426

    Article  CAS  PubMed  Google Scholar 

  • Srinivas US et al (2019) ROS and the DNA damage response in cancer. Redox Biol 25:101084

    Article  CAS  PubMed  Google Scholar 

  • Steckiewicz KP et al (2019) Impact of gold nanoparticles shape on their cytotoxicity against human osteoblast and osteosarcoma in in vitro model. Evaluation of the safety of use and anti-cancer potential. J Mater Sci Mater Med 30(2):22

    Article  PubMed  PubMed Central  Google Scholar 

  • Subhan MA et al (2021) Recent advances in tumor targeting via EPR effect for cancer treatment. J Personal Med 11(6):571

    Article  Google Scholar 

  • Sun T et al (2016) Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients. Oncol Lett 11(1):575–583

    Article  CAS  PubMed  Google Scholar 

  • Sun Y et al (2020) The pH dependent mechanisms of non-enzymatic peptide bond cleavage reactions. Phys Chem Chem Phys 22(1):107–113

    Article  CAS  Google Scholar 

  • Sung H et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  • Sutter CH, Laughner E, Semenza GL (2000) Hypoxia-inducible factor 1α protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations. Proc Natl Acad Sci 97(9):4748–4753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swift T et al (2016) The pH-responsive behaviour of poly(acrylic acid) in aqueous solution is dependent on molar mass. Soft Matter 12(9):2542–2549

    Article  CAS  PubMed  Google Scholar 

  • Tabish TA et al (2019) Graphene oxide-based targeting of extracellular cathepsin D and cathepsin L as a novel anti-metastatic enzyme cancer therapy. Cancers (Basel) 11(3):319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan GJ et al (2013) Cathepsins mediate tumor metastasis. World J Biol Chem 4(4):91–101

    Article  PubMed  PubMed Central  Google Scholar 

  • Tang L et al (2013) Size-dependent tumor penetration and in vivo efficacy of monodisperse drug–silica nanoconjugates. Mol Pharm 10(3):883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thambi T et al (2014) Hypoxia-responsive polymeric nanoparticles for tumor-targeted drug delivery. Biomaterials 35(5):1735–1743

    Article  CAS  PubMed  Google Scholar 

  • The National Institutes of Health – National Library of Medicine (1974) Nitroimidazoles. https://www.ncbi.nlm.nih.gov/mesh/?term=nitroimidazoles

  • The National Institutes of Health – National Library of Medicine (2023a) Tamoxifen. https://pubchem.ncbi.nlm.nih.gov/compound/2733526

  • The National Institutes of Health – National Library of Medicine (2023b) Erlotinib. https://pubchem.ncbi.nlm.nih.gov/compound/176870

  • The National Institutes of Health – National Library of Medicine (n.d.) Azo compounds. https://www.ncbi.nlm.nih.gov/mesh/?term=azo+compounds

  • Thomas C, Tampé R (2020) Structural and mechanistic principles of ABC transporters. Annu Rev Biochem 89(1):605–636

    Article  CAS  PubMed  Google Scholar 

  • Tiwari AK et al (2009) Nilotinib (AMN107, Tasigna®) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol 78(2):153–161

    Article  CAS  PubMed  Google Scholar 

  • Tiwari A, Trivedi R, Lin S-Y (2022) Tumor microenvironment: barrier or opportunity towards effective cancer therapy. J Biomed Sci 29(1):83

    Article  PubMed  PubMed Central  Google Scholar 

  • Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552(2):335–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uddin MN, Roni MA (2021) Challenges of storage and stability of mRNA-based COVID-19 vaccines. Vaccines 9(9):1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venditti I (2019) Morphologies and functionalities of polymeric nanocarriers as chemical tools for drug delivery: a review. J King Saud Univ Sci 31(3):398–411

    Article  Google Scholar 

  • Walker J, Martin C, Callaghan R (2004) Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy. Eur J Cancer 40(4):594–605

    Article  CAS  PubMed  Google Scholar 

  • Wan W-J et al (2019) Doxorubicin and siRNA-PD-L1 co-delivery with T7 modified ROS-sensitive nanoparticles for tumor chemoimmunotherapy. Int J Pharm 566:731–744

    Article  CAS  PubMed  Google Scholar 

  • Wan W-J et al (2021) Coadministration of iRGD peptide with ROS-sensitive nanoparticles co-delivering siFGL1 and siPD-L1 enhanced tumor immunotherapy. Acta Biomater 136:473–484

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Khalil RA (2018) Matrix metalloproteinases, vascular remodeling, and vascular disease. Adv Pharmacol 81:241–330

    Article  CAS  PubMed  Google Scholar 

  • Wang Y et al (2019) Hypoxia-active nanoparticles used in tumor theranostic. Int J Nanomedicine 14:3705–3722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ward C et al (2020) The impact of tumour pH on cancer progression: strategies for clinical intervention. Explor Target Antitumor Ther 1(2):71–100

    Article  PubMed  PubMed Central  Google Scholar 

  • Werle B et al (1999) Immunochemical analysis of cathepsin B in lung tumours: an independent prognostic factor for squamous cell carcinoma patients. Br J Cancer 81(3):510–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • WHO (2019) Global health estimates: leading causes of death. https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death

  • Wu C-P et al (2022) P-glycoprotein mediates resistance to the anaplastic lymphoma kinase inhibitor Ensartinib in cancer cells. Cancers 14(9):2341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia H et al (2022) A pH−/enzyme-responsive nanoparticle selectively targets endosomal toll-like receptors to potentiate robust cancer vaccination. Nano Lett 22(7):2978–2987

    Article  CAS  PubMed  Google Scholar 

  • Xu H, Li S, Liu Y-S (2022) Nanoparticles in the diagnosis and treatment of vascular aging and related diseases. Signal Transduct Target Ther 7(1):231

    Article  PubMed  PubMed Central  Google Scholar 

  • Yadati T et al (2020) The ins and outs of cathepsins: physiological function and role in disease management. Cell 9(7):1679

    Article  CAS  Google Scholar 

  • Yang L et al (2009) Single chain epidermal growth factor receptor antibody conjugated nanoparticles for in vivo tumor targeting and imaging. Small 5(2):235–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi H et al (2021) ROS-responsive liposomes with NIR light-triggered doxorubicin release for combinatorial therapy of breast cancer. J Nanobiotechnol 19(1):134

    Article  CAS  Google Scholar 

  • Yilmaz G et al (2023) Exosomes released from cisplatin-resistant ovarian cancer cells modulate the reprogramming of cells in tumor microenvironments toward the cancerous cells. Biomed Pharmacother 157:113973

    Article  CAS  PubMed  Google Scholar 

  • Yung WKA et al (1999) Multicenter phase II trial of Temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17(9):2762–2762

    Article  CAS  PubMed  Google Scholar 

  • Zang LY, Misra HP (1993) Generation of reactive oxygen species during the monoamine oxidase-catalyzed oxidation of the neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Biol Chem 268(22):16504–16512

    Article  CAS  PubMed  Google Scholar 

  • Zeillinger R et al (1992) Expression of cathepsin D in head and neck cancer. Eur J Cancer 28(8):1413–1415

    Article  Google Scholar 

  • Zhang XD et al (2010) Toxicologic effects of gold nanoparticles in vivo by different administration routes. Int J Nanomedicine 5:771–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y et al (2016) Co-delivery of doxorubicin and curcumin by pH-sensitive prodrug nanoparticle for combination therapy of cancer. Sci Rep 6:21225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao B-X et al (2012) The efficiency of tumor-specific pH-responsive peptide-modified polymeric micelles containing paclitaxel. Biomaterials 33(8):2508–2520

    Article  CAS  PubMed  Google Scholar 

  • Zhao H et al (2016) Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. elife 5:e10250

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou K et al (2020) Redox- and MMP-2-sensitive drug delivery nanoparticles based on gelatin and albumin for tumor targeted delivery of paclitaxel. Mater Sci Eng C 114:111006

    Article  CAS  Google Scholar 

  • Zhu L et al (2013) Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety. Proc Natl Acad Sci 110(42):17047–17052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhuo S et al (2020) pH-sensitive biomaterials for drug delivery. Molecules 25(23):5649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, School of Life Sciences, University of Sussex, Brighton, UK

    Francesco Melia, Robin Rogoyski & Md Zahidul Islam Pranjol

  2. Department of Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK

    Palita Udomjarumanee

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  1. Francesco Melia
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  2. Palita Udomjarumanee
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  3. Robin Rogoyski
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  4. Md Zahidul Islam Pranjol
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Correspondence to Md Zahidul Islam Pranjol .

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  1. Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Sweden

    Nima Rezaei

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Melia, F., Udomjarumanee, P., Rogoyski, R., Pranjol, M.Z.I. (2024). Tumor Microenvironment-Responsive Nanoplatforms for Triggering Drug Delivery. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_412-1

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