[1] Mohammad Chehelgerdi, c.a. (2023). Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation. BMC.
[2] Luan N.M. Nguyen, Wayne Ngo, Zachary P. Lin, Shrey Sindhwani, Presley MacMillan, Stefan M. Mladjenovic & Warren C.W. Chan, The mechanisms of nanoparticle delivery to solid tumours, Springer Nature (2024).
[3] Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).
[4] Papahadjopoulos, D. & Miller, N. Phospholipid model membranes. I. Biochim. Biophys. Acta Biomembr. 135, 624–638 (1967).
[5] Sessa, G. & Weissmann, G. Phospholipid spherules (liposomes) as a model for biological membranes. J. Lipid Res. 9, 310–318 (1968).
[6] Dong, J. et al. EGFR aptamer-conjugated liposome-polycation-DNA complex for targeted delivery of SATB1 siRNA to choriocarcinoma cells. Biomed. Pharmacother. 107, 849–859 (2018).
[7] Kim, D., Jeong, Y.Y. & Jon, S. A drug-loaded aptamer–gold nanoparticle bioconjugate for combined CT imaging and therapy of prostate cancer. ACS Nano 4, 3689–3696 (2010).
[8] Corsi, F. et al. HER2 expression in breast cancer cells is downregulated upon active targeting by antibody-engineered multifunctional nanoparticles in mice. ACS Nano 5, 6383–6393 (2011).
[9] Cohen, H. et al. Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Ther. 7, 1896–1905 (2000).
[10] Perez, C. et al. Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA. J. Control. Release 75, 211–224 (2001).
[11] Levine, R.M., Pearce, T.R., Adil, M. & Kokkoli, E. Preparation and characterization of liposome-encapsulated plasmid DNA for gene delivery. Langmuir 29, 9208–9215 (2013).
[12] Mai, Y. et al. Intranasal delivery of cationic liposome-protamine complex mRNA vaccine elicits effective anti-tumor immunity. Cell Immunol. 354, 104143 (2020).
[13] McKay, P.F. et al. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat. Commun. 11, 3523 (2020).
[14] Ashley, C.E. et al. Delivery of siRNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers. ACS Nano 6, 2174–2188 (2012).
[15] Zinger, A. et al. Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano 13, 11008–11021 (2019).
[16] Feczk, T., Tóth, J., Dsa, G. & Gyenis, J. Optimization of protein encapsulation in PLGA nanoparticles. Chem. Eng. Process. 50, 757–765 (2011).
[17] Cao, A. et al. A facile method to encapsulate proteins in silica nanoparticles: encapsulated green fluorescent protein as a robust fluorescence probe. Angew. Chem. 12, 3086–3089 (2010).
[18] George, T.A. et al. Liposome-encapsulated anthraquinone improves efficacy and safety in triple negative breast cancer. J. Control. Release 342, 31–43 (2022).
[19] Ngo, W. et al. DNA-controlled encapsulation of small molecules in protein nanoparticles. J. Am. Chem. Soc. 142, 17938–17944 (2020).
[20] Yoo, H.S., Lee, K.H., Oh, J.E. & Park, T.G. In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin-PLGA conjugates. J. Control. Release 68, 419–431 (2000).
[21] Rayamajhi, S. et al. pH-responsive cationic liposome for endosomal escape mediated drug delivery. Colloids Surf. B Biointerfaces 188, 110804 (2020).
[22] Palanikumar, L. et al. pH-responsive high stability polymeric nanoparticles for targeted delivery of anticancer therapeutics. Commun. Biol. 3, 95 (2020).
[23] Tai, L.-A. et al. Thermosensitive liposomes entrapping iron oxide nanoparticles for controllable drug release. Nanotechnology 20, 135101 (2009).
[24] Sun, J., Yu, Z., Hong, C. & Pan, C. Biocompatible zwitterionic sulfobetaine copolymer-coated mesoporous silica nanoparticles for temperature-responsive drug release. Macromol. Rapid Commun. 33, 811–818 (2012).
[25] Vlasova, K.Y. et al. Magnetic liposome design for drug release systems responsive to super-low frequency alternating current magnetic field (AC MF). J. Colloid Interf. Sci. 552, 689–700 (2019).
[26] Ge, J., Neofytou, E., Cahill, T.J., Beygui, R.E. & Zare, R.N. Drug release from electric-field-responsive nanoparticles. ACS Nano 6, 227–233 (2012).
[27] Nadia Esfandiari, S. (2022). CO2 utilization as gas antisolvent for the pharmaceutical micro and nanoparticle production: A review. Arabian Journal of Chemistry.
[28] Sun, D., Zhou, S. & Gao, W. What went wrong with anticancer nanomedicine design and how to make it right. ACS Nano 14, 12281–12290 (2020).
[29] Mahshid Askarizadeh, N.E. (2023). Kinetic Modeling to Explain the Release of Medicine from Drug Delivery Systems. ChemBioEng Rev.
[30] Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).
[31] Nakamura, H., Fang, J., Jun, F. & Maeda, H. Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls. Expert Opin. Drug Deliv. 12, 53–64 (2014).
[32] Lammers, T., Kiessling, F., Hennink, W.E. & Storm, G. Drug targeting to tumors: principles, pitfalls and (pre-)clinical progress. J. Control. Release 161, 175–187 (2012).
[33] Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).
[34] He, H., Liu, L., Morin, E.E., Liu, M. & Schwendeman, A. Survey of clinical translation of cancer nanomedicines — lessons learned from successes and failures. Acc. Chem. Res. 52, 2445–2461 (2019).
[35] Nichols, J.W. & Bae, Y.H. EPR: evidence and fallacy. J. Control. Release 190, 451–464 (2014).
[36] Danhier, F. To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine? J. Control. Release 244, 108–121 (2016).
[37] Nakamura, Y., Mochida, A., Choyke, P.L. & Kobayashi, H. Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjug. Chem. 27, 2225–2238 (2016).
[38] Park, K. The drug delivery field at the inflection point: time to fight its way out of the egg. J. Control. Release 267, 2–14 (2017).
[39] Weil, R. Chemotherapeutic experiments on rat tumors. J. Cancer Res. https://doi.org/
10.1158/jcr.1916.95 (1916).
[40] Duran-Reynals, F. Studies on the localization of dyes and foreign proteins in normal and malignant tissues. Am. J. Cancer 3, 98–107 (1939).
[41] Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305 (1986).
[42] Kreuter, J. Nanoparticle-based dmg delivery systems. J. Control. Release 16, 169–176 (1991).
[43] Oppenheim, R. C. Solid colloidal drug delivery systems: nanoparticles. Int. J. Pharm. 8, 217–234 (1981).
[44] Tabata, Y., Murakami, Y. & Ikada, Y. Photodynamic effect of polyethylene glycol-modified fullerene on tumor. Jpn. J. Cancer Res. 88, 1108–1116 (1997).
[45] Allemann, E. et al. PEG‐coated poly(lactic acid) nanoparticles for the delivery of
hexadecafluoro zinc phthalocyanine to EMT‐6 mouse mammary tumours. J. Pharm.
Pharmacol. 47, 382–387 (1995).
[46] Hodoshima, N. et al. Lipid nanoparticles for delivering antitumor drugs. Int. J. Pharm. 146, 81–92 (1997).
[47] Rui Sun a 1, J,Y. S.Z. (2022). The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives. Advanced Drug Delivery Reviews.
[48] Iwai, K., Maeda, H. & Konno, T. Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Res. 44, 2115–2121
(1984).
[49] Padera, T. P. et al. Lymphatic metastasis in the absence of functional intratumor
lymphatics. Science 296, 1883–1886 (2002).
This article presents evidence that tumour lymphatics are dysfunctional and collapsed, suggesting a mechanism of poor lymphatic drainage of the EPR effect.
[50] Prabhakar, U. et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 73, 2412–2417 (2013).
[51] MacMillan, P. et al. Toward predicting nanoparticle distribution in heterogeneous tumor tissues. Nano Lett. 23, 7197–7205 (2023).
[52] Cheng, Y.-H., He, C., Riviere, J. E., Monteiro-Riviere, N. A. & Lin, Z. Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic
modeling and simulation approach. ACS Nano 14, 3075–3095 (2020).
[53] Dai, Q. et al. Quantifying the ligand-coated nanoparticle delivery to cancer cells in solid tumors. ACS Nano 12, 8423–8435 (2018).
This article established that only 0.0014% of injected nanoparticles are delivered to cancer cells.
[54] Nguyen, L. N. M. et al. The exit of nanoparticles from solid tumours.Nat. Mater. 22, 1261–1272 (2023). This article reports that nanoparticles exit the tumour through the lymphatics in and around the tumour, and proposes the ATR principle as an alternative mechanism of nanoparticle delivery.
[55] Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 9, 615–627 (2010).
[56] Sindhwani, S. et al. The entry of nanoparticles into solid tumours. Nat. Mater. 19, 566–575 (2020). This article reports that active transport processes of nanoparticle entry are dominant over passive transport.
[57] Duncan, R. Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharm. Sci. Technol. Today 2, 441–449 (1999).
[58] Duncan, R. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2, 347–360 (2003).
[59] Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nat. Rev. Cancer 5, 161–171 (2005).
[60] Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6,
688–701 (2006).
[61] Greish, K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J. Drug Target. 15, 457–464 (2008).
[62] Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
[63] Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
[64] Yuan, F. et al. Microvascular permeability and interstitial penetration of sterically
stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 54, 3352–3356 (1994).
[65] Yuan, F. et al. Vascular permeability in a human tumor xenograft: molecular size
dependence and cutoff size. Cancer Res. 55, 3752–3756 (1995).
[66] Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type
and microenvironment. Proc. Natl Acad. Sci. 95, 4607–4612 (1998). This article presents electron microscopy images of nanoparticles entering the tumour via interendothelial gaps, suggesting a mechanism of enhanced permeability of the EPR effect.
[67] Zhang, Y. et al. Strategies to improve tumor penetration of nanomedicines through
nanoparticle design. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1519 (2019).
[68] Bazak, R., Houri, M., Achy, S. E., Hussein, W. & Refaat, T. Passive targeting of nanoparticles to cancer: a comprehensive review of the literature. Mol. Clin. Oncol. 2, 904–908 (2014).
[69] Wang, M. & Thanou, M. Targeting nanoparticles to cancer. Pharmacol. Res. 62, 90–99 (2010).
[70] Kalyane, D. et al. Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater. Sci. Eng. C 98, 1252–1276 (2019).
[71] Sharifi, b. M. (2022). An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment. MDPI.
[72] Maeda, H., Wu, J., Sawa, T., Matsumura, Y. & Hori, K. Tumor vascular permeability and
the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65, 271–284
(2000).
[73] Krešimir Pavelić 1, *. K. (2023). Nanoparticles in Medicine: Current Status in Cancer Treatment. MDPI.
[74] Xianzhou Huang, T. H. (2024). Advances and applications of nanoparticles in cancer therapy.
[75] Kingston, B. R. et al. Specific endothelial cells govern nanoparticle entry into solid
tumors. ACS Nano 15, 14080–14094 (2021).
[76] Thurston, G. et al. Cationic liposomes target angiogenic endothelial cells in tumors
and chronic inflammation in mice. J. Clin. Invest. 101, 1401–1413 (1998).
[77] Feng, D., Nagy, J. A., Dvorak, H. F. & Dvorak, A. M. Ultrastructural studies define
soluble macromolecular, particulate, and cellular transendothelial cell pathways in
venules, lymphatic vessels, and tumor‐associated microvessels in man and animals. Microsc. Res. Tech. 57, 289–326 (2002).
[78] Kohn, S., Nagy, J. A., Dvorak, H. F. & Dvorak, A. M. Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab. Invest. 67, 596–607 (1992).
[79] Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).
[80] Liang, C. et al. Tumor metastasis inhibition by imaging‐guided photothermal therapy with single‐walled carbon nanotubes. Adv. Mater. 26, 5646–5652 (2014).
[81] Kwong, B., Gai, S. A., Elkhader, J., Wittrup, K. D. & Irvine, D. J. Localized immunotherapy via liposome-anchored anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity. Cancer Res. 73, 1547–1558 (2013).
[82] Naumenko, V. A. et al. Extravasating neutrophils open vascular barrier and improve
liposomes delivery to tumors. ACS Nano 13, 12599–12612 (2019).
[83] Ballou, B. et al. Sentinel lymph node imaging using quantum dots in mouse tumor
models. Bioconjug. Chem. 18, 389–396 (2007).
[84] Valdés-Olmos, R. A. et al. Evaluation of mammary lymphoscintigraphy by a single
intratumoral injection for sentinel node identification. J. Nucl. Med. 41, 1500–1506 (2000).
[85] Liu, J. et al. Enhanced primary tumor penetration facilitates nanoparticle draining into
lymph nodes after systemic injection for tumor metastasis inhibition. ACS Nano 13, 8648–8658 (2019).
[86] Qin, L. et al. A tumor-to-lymph procedure navigated versatile gel system for combinatorial therapy against tumor recurrence and metastasis. Sci. Adv. 6, eabb3116 (2020).
[87] Jiang, X. et al. Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy. J. Immunother. Cancer 10, e003960 (2022).
[88] Ludford, R. J. The vital staining of normal and malignant cells.-II. The staining of
malignant tumours with trypan blue. Proc. R. Soc. Lond. B 104, 493–512 (1929).
[89] Lin, Z. P. et al. Macrophages actively transport nanoparticles in tumors after extravasation. ACS Nano 16, 6080–6092 (2022). This article reports that nanoparticle transport through the tumour occurs via
cellular-based mechanisms, showing that perivascular macrophages sequester
extravasated nanoparticles and transport them throughout the tumour.
[90] Miller, M. A. et al. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. Nat. Commun. 6, 8692 (2015).
[91] Cedervall, T. et al. Understanding the nanoparticle–protein corona using methods to
quantify exchange rates and affinities of proteins for nanoparticles. Proc. Natl Acad. Sci.
104, 2050–2055 (2007).
[92] Tenzer, S. et al. Rapid formation of plasma protein corona critically affects nanoparticle
pathophysiology. Nat. Nanotechnol. 8, 772–781 (2013).
[93] Goncalves, A. et al. Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops. J. Lipid Res. 56, 1123–1133 (2015).
[94] Schnitzer, J. E. gp60 is an albumin-binding glycoprotein expressed by continuous
endothelium involved in albumin transcytosis. Am. J. Physiol. Heart C. 262, H246–H254
(1992).
[95] Gormley, A. J. et al. Guided delivery of polymer therapeutics using plasmonic
photothermal therapy. Nano Today 7, 158–167 (2012).
[96] Zhen, Z. et al. Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles. ACS Nano 8, 6004–6013 (2014).
[97] Sano, K., Nakajima, T., Choyke, P. L. & Kobayashi, H. Markedly enhanced permeability and retention effects induced by photo-immunotherapy of tumors. ACS Nano 7, 717–724 (2013).
[98] Liang, C. et al. Nanoparticle-mediated internal radioisotope therapy to locally increase
the tumor vasculature permeability for synergistically improved cancer therapies.
Biomaterials 197, 368–379 (2019).
[99] Ashton, J. R. et al. Dual-energy CT imaging of tumor liposome delivery after gold
nanoparticle-augmented radiation therapy. Theranostics 8, 1782–1797 (2018).
[100] Haber, T. et al. Specific targeting of ovarian tumor-associated macrophages by large, anionic nanoparticles. Proc. Natl Acad. Sci. 117, 19737–19745 (2020).
[101] Walkey, C. D., Olsen, J. B., Guo, H., Emili, A. & Chan, W. C. W. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J. Am. Chem. Soc. 134, 2139–2147 (2012).
[102] Menard, J. A., Cerezo-Magaaٌ, M. &
Belting, M. Functional role of extracellular vesicles and lipoproteins in the tumour microenvironment. Philos. Trans. R. Soc. B Biol. Sci. 373, 20160480 (2018).
[103] Frankel, W. L. & Jin, M. Serosal surfaces, mucin pools, and deposits, Oh my: challenges in staging colorectal carcinoma. Mod. Pathol. 28, S95–S108 (2015).
[104] Ouyang, B. et al. The dose threshold for nanoparticle tumour delivery. Nat. Mater. 19,
1362–1371 (2020).
[105] Poon, W. et al. Elimination pathways of nanoparticles. ACS Nano 13, 5785–5798 (2019).
[106] Tsoi, K. M. et al. Mechanism of hard-nanomaterial clearance by the liver. Nat. Mater. 15, 1212–1221 (2016).
[107] Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).
[108] Zhang, Y.-N. et al. Nanoparticle size influences antigen retention and presentation
in lymph node follicles for humoral immunity. Nano Lett. 19, 7226–7235 (2019).
[109] Zhang, Y.-N., Poon, W., Sefton, E. & Chan, W. C. W. Suppressing subcapsular sinus macrophages enhances transport of nanovaccines to lymph node follicles for robust humoral immunity. ACS Nano 14, 9478–9490 (2020).
[110] Nakamura, T. et al. The effect of size and charge of lipid nanoparticles prepared by microfluidic mixing on their lymph node transitivity and distribution. Mol. Pharm. 17, 944–953 (2020)
