Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nat. Rev. Cancer 5, 161–171 (2005).
Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007).
Shi, J., Votruba, A. R., Farokhzad, O. C. & Langer, R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 10, 3223–3230 (2010).
Swartz, M. A., Hirosue, S. & Hubbell, J. A. Engineering approaches to immunotherapy. Sci. Transl Med. 4, 148rv9 (2012).
Kearney, C. J. & Mooney, D. J. Macroscale delivery systems for molecular and cellular payloads. Nat. Mater. 12, 1004–1017 (2013).
Smith, A. D. Big moment for nanotech: oncology therapeutics poised for a leap. OncLive http://www.onclive.com/publications/Oncology-live/2013/June-2013/Big-Moment-for-Nanotech-Oncology-Therapeutics-Poised-for-a-Leap (2013).
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).
This paper described the EPR effect in cancer, which has become the foundational underpinning for the delivery of NPs and macromolecules to solid tumours.
Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305 (1986).
This study demonstrated higher microvascular permeability of macromolecules into tumours than into normal tissues, providing a rational basis for the use of large-size therapeutic agents in cancer treatment.
Bertrand, N., Wu, J., Xu, X., Kamaly, N. & Farokhzad, O. C. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv. Drug Deliv. Rev. 66, 2–25 (2014).
Maeda, H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv. Drug Deliv. Rev. 91, 3–6 (2015).
Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl Med. 4, 128ra39 (2012).
First-in-human testing of a targeted, controlled- release polymeric NP for cancer chemotherapy.
Eliasof, S. et al. Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle. Proc. Natl Acad. Sci. USA 110, 15127–15132 (2013).
Zuckerman, J. E. et al. Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA. Proc. Natl Acad. Sci. USA 111, 11449–11454 (2014).
Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513–520 (2005).
Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat. Rev. Cancer 9, 665–674 (2009).
Barenholz, Y. Doxil®—the first FDA-approved nano-drug: lessons learned. J. Control. Release 160, 117–134 (2012).
Petersen, G. H., Alzghari, S. K., Chee, W., Sankari, S. S. & La-Beck, N. M. Meta-analysis of clinical and preclinical studies comparing the anticancer efficacy of liposomal versus conventional non-liposomal doxorubicin. J. Control. Release 232, 255–264 (2016).
Celator Pharmaceuticals, Inc. Celator announces phase 3 trial for VYXEOS™ (CPX-351) in patients with high-risk acute myeloid leukemia demonstrates statistically significant improvement in overall survival. prnewswire http://www.prnewswire.com/news-releases/celator-announces-phase-3-trial-for-vyxeos-cpx-351-in-patients-with-high-risk-acute-myeloid-leukemia-demonstrates-statistically-significant-improvement-in-overall-survival-300235620.html (2016).
Gradishar, W. J. et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin. Oncol. 23, 7794–7803 (2005).
Rugo, H. S. et al. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J. Clin. Oncol. 33, 2361–2369 (2015).
Ahn, H. K. et al. A phase II trial of Cremorphor EL-free paclitaxel (Genexol-PM) and gemcitabine in patients with advanced non-small cell lung cancer. Cancer Chemother. Pharmacol. 74, 277–282 (2014).
Kato, K. et al. Phase II study of NK105, a paclitaxel-incorporating micellar nanoparticle, for previously treated advanced or recurrent gastric cancer. Invest. New Drugs 30, 1621–1627 (2012).
Clark, A. J. et al. CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing. Proc. Natl Acad. Sci. USA 113, 3850–3854 (2016).
Ashton, S. et al. Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Sci. Transl Med. 8, 325ra17 (2016).
Hirsch, L. R. et al. Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance. Proc. Natl Acad. Sci. USA 100, 13549–13554 (2003).
Maier-Hauff, K. et al. Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J. Neurooncol. 103, 317–324 (2011).
Maggiorella, L. et al. Nanoscale radiotherapy with hafnium oxide nanoparticles. Future Oncol. 8, 1167–1181 (2012).
Dritschilo, A. et al. Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies. Clin. Cancer Res. 12, 1251–1259 (2006).
Elazar, V. et al. Sustained delivery and efficacy of polymeric nanoparticles containing osteopontin and bone sialoprotein antisenses in rats with breast cancer bone metastasis. Int. J. Cancer 126, 1749–1760 (2010).
Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).
This study reported the first therapeutic knockdown in humans by polymeric NP-based systemic siRNA delivery.
Tabernero, J. et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov. 3, 406–417 (2013).
Schultheis, B. et al. First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors. J. Clin. Oncol. 32, 4141–4148 (2014).
Jensen, S. A. et al. Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Sci. Transl Med. 5, 209ra152 (2013).
Islam, M. A. et al. Biomaterials for mRNA delivery. Biomater. Sci. 3, 1519–1533 (2015).
Tolcher, A. W. et al. A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 73, 363–371 (2014).
Yildiz, I., Shukla, S. & Steinmetz, N. F. Applications of viral nanoparticles in medicine. Curr. Opin. Biotechnol. 22, 901–908 (2011).
Yla-Herttuala, S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European Union. Mol. Ther. 20, 1831–1832 (2012).
Naldini, L. Gene therapy returns to centre stage. Nature 526, 351–360 (2015).
Shukla, S., DiFranco, N. A., Wen, A. M., Commandeur, U. & Steinmetz, N. F. To target or not to target: active versus passive tumor homing of filamentous nanoparticles based on potato virus X. Cell. Mol. Bioeng. 8, 433–444 (2015).
Czapar, A. E. et al. Tobacco mosaic virus delivery of phenanthriplatin for cancer therapy. ACS Nano 10, 4119–4126 (2016).
Batrakova, E. V. & Kim, M. S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J. Control. Release 219, 396–405 (2015).
Chow, E. K. et al. Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Sci. Transl Med. 3, 73ra21 (2011).
Mochalin, V. N. et al. Adsorption of drugs on nanodiamond: toward development of a drug delivery platform. Mol. Pharm. 10, 3728–3735 (2013).
Jiang, T. et al. Furin-mediated sequential delivery of anticancer cytokine and small-molecule drug shuttled by graphene. Adv. Mater. 27, 1021–1028 (2015).
Liu, Z., Robinson, J. T., Sun, X. & Dai, H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J. Am. Chem. Soc. 130, 10876–10877 (2008).
Choi, K. Y., Liu, G., Lee, S. & Chen, X. Theranostic nanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives. Nanoscale 4, 330–342 (2012).
Cheng, Z., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338, 903–910 (2012).
Smith, D. M., Simon, J. K. & Baker, J. R. Jr. Applications of nanotechnology for immunology. Nat. Rev. Immunol. 13, 592–605 (2013).
A seminal review of various nanotechnologies and nanomaterials for a broad range of immunological applications, including cancer vaccine development.
Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978–990 (2013).
Rosenthal, J. A., Chen, L., Baker, J. L., Putnam, D. & DeLisa, M. P. Pathogen-like particles: biomimetic vaccine carriers engineered at the nanoscale. Curr. Opin. Biotechnol. 28, 51–58 (2014).
Schellekens, H. The immunogenicity of therapeutic proteins. Discov. Med. 9, 560–564 (2010).
Kishimoto, T. K. et al. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles. Nat. Nanotechnol. http://dx.doi.org/10.1038/nnano.2016.135 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02648269?term (2016).
Garbuzenko, O. B. et al. Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance. Proc. Natl Acad. Sci. USA 107, 10737–10742 (2010).
Liechty, W. B., Caldorera-Moore, M., Phillips, M. A., Schoener, C. & Peppas, N. A. Advanced molecular design of biopolymers for transmucosal and intracellular delivery of chemotherapeutic agents and biological therapeutics. J. Control. Release 155, 119–127 (2011).
Yu, M., Wu, J., Shi, J. & Farokhzad, O. C. Nanotechnology for protein delivery: overview and perspectives. J. Control. Release http://dx.doi.org/10.1016/j.jconrel.2015.10.012 (2015).
Ramanathan, R. K. et al. Pilot study in patients with advanced solid tumors to evaluate feasibility of ferumoxytol (FMX) as tumor imaging agent prior to MM398, a nanoliposomal irinotecan (nalIRI). Cancer Res. 74 (Suppl.), abstr. CT224 (2014).
Koukourakis, M. I. et al. Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer. J. Clin. Oncol. 17, 3512–3521 (1999).
Arrieta, O. et al. High liposomal doxorubicin tumour tissue distribution, as determined by radiopharmaceutical labelling with 99mTc-LD, is associated with the response and survival of patients with unresectable pleural mesothelioma treated with a combination of liposomal doxorubicin and cisplatin. Cancer Chemother. Pharmacol. 74, 211–215 (2014).
Daldrup-Link, H. E. et al. MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin. Cancer Res. 17, 5695–5704 (2011).
Kalra, A. V. et al. Magnetic resonance imaging with an iron oxide nanoparticle demonstrates the preclinical feasibility of predicting intratumoral uptake and activity of MM-398, a nanoliposomal irinotecan (nal-IRI). Cancer Res. 74 (Suppl.), 2065 (2014).
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).
Miller, M. A. et al. Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci. Transl Med. 7, 314ra183 (2015).
This paper reported that imaging nanoprobes can be used to predict the accumulation and efficacy of therapeutic NPs, paving the road for potential patient selection for high EPR and personalized nanomedicine.
Bashir, M. R., Bhatti, L., Marin, D. & Nelson, R. C. Emerging applications for ferumoxytol as a contrast agent in MRI. J. Magn. Reson. Imaging 41, 884–898 (2015).
Farokhzad, O. C. et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl Acad. Sci. USA 103, 6315–6320 (2006).
Gu, F. et al. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc. Natl Acad. Sci. USA 105, 2586–2591 (2008).
This paper described the development of self- assembled targeted NPs, enabling the creation and screening of libraries of targeted nanotherapeutics with optimal biophysicochemical properties.
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01770353?term (2016).
Harrington, K. J. et al. Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin. Cancer Res. 7, 243–254 (2001).
Koukourakis, M. I. et al. High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours. Br. J. Cancer 83, 1281–1286 (2000).
Seymour, L. W. et al. Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. J. Clin. Oncol. 20, 1668–1676 (2002).
Lee, H. et al. A gradient-loadable 64Cu-chelator for quantifying tumor deposition kinetics of nanoliposomal therapeutics by positron emission tomography. Nanomedicine 11, 155–165 (2015).
Hansen, A. E. et al. Positron emission tomography based elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano 9, 6985–6995 (2015).
Yokoi, K. et al. Serum biomarkers for personalization of nanotherapeutics-based therapy in different tumor and organ microenvironments. Cancer Lett. 345, 48–55 (2014).
This study reported serum biomarkers for the EPR effect in tumours, which may aid in selecting patients with a higher likelihood of NP accumulation and thus therapeutic response.
Yokoi, K. et al. Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment. Cancer Res. 74, 4239–4246 (2014).
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).
Sessa, C., Guibal, A., Del Conte, G. & Ruegg, C. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations? Nat. Clin. Pract. Oncol. 5, 378–391 (2008).
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. USA 104, 2050–2055 (2007).
Nel, A. E. et al. Understanding biophysicochemical interactions at the nano–bio interface. Nat. Mater. 8, 543–557 (2009).
Mahmoudi, M. et al. Protein–nanoparticle interactions: opportunities and challenges. Chem. Rev. 111, 5610–5637 (2011).
Monopoli, M. P., Aberg, C., Salvati, A. & Dawson, K. A. Biomolecular coronas provide the biological identity of nanosized materials. Nat. Nanotechnol. 7, 779–786 (2012).
This article reviewed the basic concept of NP corona and its structure and composition, and highlights how the properties of the corona may affect the biological responses of NPs.
Salvador-Morales, C., Zhang, L., Langer, R. & Farokhzad, O. C. Immunocompatibility properties of lipid-polymer hybrid nanoparticles with heterogeneous surface functional groups. Biomaterials 30, 2231–2240 (2009).
Walkey, C. D., Olsen, J. B., Guo, H., Emili, A. & Chan, W. C. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J. Am. Chem. Soc. 134, 2139–2147 (2012).
Ritz, S. et al. Protein corona of nanoparticles: distinct proteins regulate the cellular uptake. Biomacromolecules 16, 1311–1321 (2015).
Ogawara, K. et al. Pre-coating with serum albumin reduces receptor-mediated hepatic disposition of polystyrene nanosphere: implications for rational design of nanoparticles. J. Control. Release 100, 451–455 (2004).
Salvati, A. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat. Nanotechnol. 8, 137–143 (2013).
Dong, Y. et al. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc. Natl Acad. Sci. USA 111, 3955–3960 (2014).
Chanan-Khan, A. et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Ann. Oncol. 14, 1430–1437 (2003).
Walkey, C. D. & Chan, W. C. Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. Chem. Soc. Rev. 41, 2780–2799 (2012).
Walkey, C. D. et al. Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. ACS Nano 8, 2439–2455 (2014).
Bigdeli, A. et al. Exploring cellular interactions of liposomes using protein corona fingerprints and physicochemical properties. ACS Nano 10, 3723–3737 (2016).
Hajipour, M. J., Laurent, S., Aghaie, A., Rezaee, F. & Mahmoudi, M. Personalized protein coronas: a “key” factor at the nanobiointerface. Biomater. Sci. 2, 1210–1221 (2014).
Sakulkhu, U. et al. Ex situ evaluation of the composition of protein corona of intravenously injected superparamagnetic nanoparticles in rats. Nanoscale 6, 11439–11450 (2014).
Gref, R. et al. Biodegradable long-circulating polymeric nanospheres. Science 263, 1600–1603 (1994).
This pioneering work described the development of long-circulating polymeric NPs, which have since been used in several biomedical applications such as drug delivery, medical imaging and RNAi and gene therapy.
Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010).
Gabizon, A., Shmeeda, H. & Barenholz, Y. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin. Pharmacokinet. 42, 419–436 (2003).
Schottler, S. et al. Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat. Nanotechnol. 11, 372–377 (2016).
Key, J. et al. Soft discoidal polymeric nanoconstructs resist macrophage uptake and enhance vascular targeting in tumors. ACS Nano 9, 11628–11641 (2015).
Anselmo, A. C. et al. Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting. ACS Nano 9, 3169–3177 (2015).
Rodriguez, P. L. et al. Minimal “self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339, 971–975 (2013).
This paper described a biologically inspired strategy in developing NPs that can reduce MPS recognition for enhanced drug delivery.
Hu, C. M. et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl Acad. Sci. USA 108, 10980–10985 (2011).
This article reported a unique biomimetic strategy to extend the systemic circulation of NPs by 'tricking' the immune system.
Parodi, A. et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat. Nanotechnol. 8, 61–68 (2013).
Hu, C. M. et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 (2015).
Hu, Q. et al. Anticancer platelet-mimicking nanovehicles. Adv. Mater. 27, 7043–7050 (2015).
Hobson, B. & Denekamp, J. Endothelial proliferation in tumours and normal tissues: continuous labelling studies. Br. J. Cancer 49, 405–413 (1984).
Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).
Ashina, K. et al. Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo. PLoS ONE 10, e0132367 (2015).
Maeda, H., Nakamura, H. & Fang, J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev. 65, 71–79 (2013).
Deli, M. A. Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. Biochim. Biophys. Acta 1788, 892–910 (2009).
Thurber, G. M. & Weissleder, R. A systems approach for tumor pharmacokinetics. PLoS ONE 6, e24696 (2011).
Matsumoto, Y. et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat. Nanotechnol. 11, 533–538 (2016).
Seki, T., Fang, J. & Maeda, H. Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application. Cancer Sci. 100, 2426–2430 (2009).
Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotechnol. 6, 815–823 (2011).
This study highlighted the effect of NP size on accumulation in hypovascular and hypervascular tumours.
Park, J. H. et al. Magnetic iron oxide nanoworms for tumor targeting and imaging. Adv. Mater. 20, 1630–1635 (2008).
Chauhan, V. P. et al. Fluorescent nanorods and nanospheres for real-time in vivo probing of nanoparticle shape-dependent tumor penetration. Angew. Chem. Int. Ed. 50, 11417–11420 (2011).
Gentile, F. et al. The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows. J. Biomech. 41, 2312–2318 (2008).
Kolhar, P. et al. Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proc. Natl Acad. Sci. USA 110, 10753–10758 (2013).
Smith, B. R. et al. Shape matters: intravital microscopy reveals surprising geometrical dependence for nanoparticles in tumor models of extravasation. Nano Lett. 12, 3369–3377 (2012).
A seminal work on the effect of particle geometry on extravasation and accumulation in different tumour models.
Cheng, H. et al. Nanoparticulate cellular patches for cell-mediated tumoritropic delivery. ACS Nano 4, 625–631 (2010).
Roger, M. et al. Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31, 8393–8401 (2010).
Choi, M. R. et al. A cellular trojan horse for delivery of therapeutic nanoparticles into tumors. Nano Lett. 7, 3759–3765 (2007).
Alizadeh, D., Zhang, L., Hwang, J., Schluep, T. & Badie, B. Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. Nanomedicine 6, 382–390 (2010).
von Maltzahn, G. et al. Nanoparticles that communicate in vivo to amplify tumour targeting. Nat. Mater. 10, 545–552 (2011).
Dreher, M. R. et al. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl Cancer Inst. 98, 335–344 (2006).
Rudnick, S. I. et al. Influence of affinity and antigen internalization on the uptake and penetration of anti-HER2 antibodies in solid tumors. Cancer Res. 71, 2250–2259 (2011).
Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).
Jain, R. K. & Baxter, L. T. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 48, 7022–7032 (1988).
Awwad, H. K., el Naggar, M., Mocktar, N. & Barsoum, M. Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri. Int. J. Radiat. Oncol. Biol. Phys. 12, 1329–1333 (1986).
Yoshii, Y. & Sugiyama, K. Intercapillary distance in the proliferating area of human glioma. Cancer Res. 48, 2938–2941 (1988).
West, C. M., Cooper, R. A., Loncaster, J. A., Wilks, D. P. & Bromley, M. Tumor vascularity: a histological measure of angiogenesis and hypoxia. Cancer Res. 61, 2907–2910 (2001).
Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).
This study demonstrated a multistage NP delivery strategy with long circulation for the EPR effect and deep tumour penetration for delivery into the dense collagen matrix of the tumour.
Chauhan, V. P. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7, 383–388 (2012).
Tong, R., Chiang, H. H. & Kohane, D. S. Photoswitchable nanoparticles for in vivo cancer chemotherapy. Proc. Natl Acad. Sci. USA 110, 19048–19053 (2013).
Sugahara, K. N. et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16, 510–520 (2009).
Ren, Y. et al. Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4. Sci. Transl Med. 4, 147ra112 (2012).
Pittet, M. J. & Weissleder, R. Intravital imaging. Cell 147, 983–991 (2011).
Chauhan, V. P. & Jain, R. K. Strategies for advancing cancer nanomedicine. Nat. Mater. 12, 958–962 (2013).
Bilodeau, M. T. et al. Pentarins: improved tumor targeting through nanoparticle encapsulation of miniaturized biologic drug conjugates. Cancer Res. 75 (Suppl), abstr. 3674 (2015).
Vlahov, I. R. & Leamon, C. P. Engineering folate-drug conjugates to target cancer: from chemistry to clinic. Bioconjug. Chem. 23, 1357–1369 (2012).
Firer, M. A. & Gellerman, G. Targeted drug delivery for cancer therapy: the other side of antibodies. J. Hematol. Oncol. 5, 70 (2012).
Tasciotti, E. et al. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nat. Nanotechnol. 3, 151–157 (2008).
Xu, R. et al. An injectable nanoparticle generator enhances delivery of cancer therapeutics. Nat. Biotechnol. 34, 414–418 (2016).
Li, H. J. et al. Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy. Proc. Natl Acad. Sci. USA 113, 4164–4169 (2016).
Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8, 129–138 (2009).
Davis, M. E. The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. Mol. Pharm. 6, 659–668 (2009).
Zhu, X. et al. Long-circulating siRNA nanoparticles for validating prohibitin1-targeted non-small cell lung cancer treatment. Proc. Natl Acad. Sci. USA 112, 7779–7784 (2015).
Shi, J., Xiao, Z., Kamaly, N. & Farokhzad, O. C. Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation. Acc. Chem. Res. 44, 1123–1134 (2011).
Farokhzad, O. C. & Langer, R. Impact of nanotechnology on drug delivery. ACS Nano 3, 16–20 (2009).
Howard, M. et al. Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm. ACS Nano 8, 4100–4132 (2014).
Pridgen, E. M. et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci. Transl Med. 5, 213ra167 (2013).
This paper described the development of a novel NP technology that can successfully traverse across the digestive tract, potentially opening up new opportunities in cancer nanomedicine beyond intravenous administration, including oral delivery of anticancer macromolecules.
Cheng, Y., Morshed, R. A., Auffinger, B., Tobias, A. L. & Lesniak, M. S. Multifunctional nanoparticles for brain tumor imaging and therapy. Adv. Drug Deliv. Rev. 66, 42–57 (2014).
Zhu, X. et al. Polymeric nanoparticles amenable to simultaneous installation of exterior targeting and interior therapeutic proteins. Angew. Chem. Int. Ed. 55, 3309–3312 (2016).
Leserman, L. D., Barbet, J., Kourilsky, F. & Weinstein, J. N. Targeting to cells of fluorescent liposomes covalently coupled with monoclonal antibody or protein A. Nature 288, 602–604 (1980).
Heath, T. D., Fraley, R. T. & Papahdjopoulos, D. Antibody targeting of liposomes: cell specificity obtained by conjugation of F(ab')2 to vesicle surface. Science 210, 539–541 (1980).
Espelin, C. W., Leonard, S. C., Geretti, E., Wickham, T. J. & Hendriks, B. S. Dual HER2 targeting with trastuzumab and liposomal-encapsulated doxorubicin (MM-302) demonstrates synergistic antitumor activity in breast and gastric cancer. Cancer Res. 76, 1517–1527 (2016).
Gratton, S. E. et al. The effect of particle design on cellular internalization pathways. Proc. Natl Acad. Sci. USA 105, 11613–11618 (2008).
Chithrani, B. D., Ghazani, A. A. & Chan, W. C. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 6, 662–668 (2006).
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
Narayanan, V. & Weekes, C. D. Nanoparticle albumin-bound (nab)-paclitaxel for the treatment of pancreas ductal adenocarcinoma. Gastrointest. Cancer 5, 11–19 (2015).
Thurber, G. M. et al. Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat. Commun. 4, 1504 (2013).
Chittajallu, D. R. et al. In vivo cell-cycle profiling in xenograft tumors by quantitative intravital microscopy. Nat. Methods 12, 577–585 (2015).
Laughney, A. M. et al. Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin. Sci. Transl Med. 6, 261ra152 (2014).
Dubach, J. M. et al. In vivo imaging of specific drug-target binding at subcellular resolution. Nat. Commun. 5, 3946 (2014).
Kanasty, R., Dorkin, J. R., Vegas, A. & Anderson, D. Delivery materials for siRNA therapeutics. Nat. Mater. 12, 967–977 (2013).
Ozpolat, B., Sood, A. K. & Lopez-Berestein, G. Liposomal siRNA nanocarriers for cancer therapy. Adv. Drug Deliv. Rev. 66, 110–116 (2014).
Zuckerman, J. E. & Davis, M. E. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat. Rev. Drug Discov. 14, 843–856 (2015).
Chen, Y., Zhu, X., Zhang, X., Liu, B. & Huang, L. Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy. Mol. Ther. 18, 1650–1656 (2010).
Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).
Sahay, G. et al. Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat. Biotechnol. 31, 653–658 (2013).
Xu, Z. P. et al. Subcellular compartment targeting of layered double hydroxide nanoparticles. J. Control. Release 130, 86–94 (2008).
Cheng, F. Y. et al. Stabilizer-free poly(lactide-co-glycolide) nanoparticles for multimodal biomedical probes. Biomaterials 29, 2104–2112 (2008).
Boddapati, S. V. et al. Mitochondriotropic liposomes. J. Liposome Res. 15, 49–58 (2005).
Boddapati, S. V., D'Souza, G. G., Erdogan, S., Torchilin, V. P. & Weissig, V. Organelle-targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 8, 2559–2563 (2008).
Marrache, S. & Dhar, S. Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics. Proc. Natl Acad. Sci. USA 109, 16288–16293 (2012).
Yameen, B. et al. Insight into nanoparticle cellular uptake and intracellular targeting. J. Control. Release 190, 485–499 (2014).
Kalra, A. V. et al. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res. 74, 7003–7013 (2014).
Koizumi, F. et al. Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors. Cancer Res. 66, 10048–10056 (2006).
Nakajima, T. E. et al. Antitumor effect of SN-38-releasing polymeric micelles, NK012, on spontaneous peritoneal metastases from orthotopic gastric cancer in mice compared with irinotecan. Cancer Res. 68, 9318–9322 (2008).
Hamaguchi, T. et al. NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel. Br. J. Cancer 92, 1240–1246 (2005).
Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).
This article reviewed the different types of stimuli-responsive NPs for controlled drug delivery.
Xu, X. et al. Ultra-pH-responsive and tumor-penetrating nanoplatform for targeted siRNA delivery with robust anti-cancer efficacy. Angew. Chem. Int. Ed. 55, 7091–7094 (2016).
Wu, J. et al. Hydrophobic cysteine poly(disulfide)-based redox-hypersensitive nanoparticle platform for cancer theranostics. Angew. Chem. Int. Ed. 54, 9218–9223 (2015).
Wang, Y. et al. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat. Mater. 13, 204–212 (2014).
Paris, J. L., Cabanas, M. V., Manzano, M. & Vallet-Regi, M. Polymer-grafted mesoporous silica nanoparticles as ultrasound-responsive drug carriers. ACS Nano 9, 11023–11033 (2015).
He, Q. et al. NIR-responsive on-demand release of CO from metal carbonyl-caged graphene oxide nanomedicine. Adv. Mater. 27, 6741–6746 (2015).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).
Neri, D. & Bicknell, R. Tumour vascular targeting. Nat. Rev. Cancer 5, 436–446 (2005).
Murphy, E. A. et al. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc. Natl Acad. Sci. USA 105, 9343–9348 (2008).
Hood, J. D. et al. Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404–2407 (2002).
Santel, A. et al. RNA interference in the mouse vascular endothelium by systemic administration of siRNA-lipoplexes for cancer therapy. Gene Ther. 13, 1360–1370 (2006).
Fehring, V. et al. Delivery of therapeutic siRNA to the lung endothelium via novel lipoplex formulation DACC. Mol. Ther. 22, 811–820 (2014).
Dahlman, J. E. et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nat. Nanotechnol. 9, 648–655 (2014).
Murakami, M. et al. Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis. Cancer Res. 73, 4862–4871 (2013).
Mantovani, A. & Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010).
Zhang, X. et al. Hydrazinocurcumin encapsuled nanoparticles “re-educate” tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression. PLoS ONE 8, e65896 (2013).
Zhu, S., Niu, M., O'Mary, H. & Cui, Z. Targeting of tumor-associated macrophages made possible by PEG-sheddable, mannose-modified nanoparticles. Mol. Pharm. 10, 3525–3530 (2013).
Sengupta, S. et al. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436, 568–572 (2005).
Guo, S. et al. Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. ACS Nano 8, 4996–5009 (2014).
Park, J. et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater. 11, 895–905 (2012).
Mueller, M. M. & Fusenig, N. E. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).
Schroeder, A. et al. Treating metastatic cancer with nanotechnology. Nat. Rev. Cancer 12, 39–50 (2012).
This review highlighted the opportunities and challenges in developing nanotechnologies to treat metastatic cancer.
Tsukigawa, K. et al. Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin. Cancer Sci. 106, 270–278 (2015).
Dozono, H. et al. HPMA copolymer-conjugated pirarubicin in multimodal treatment of a patient with stage IV prostate cancer and extensive lung and bone metastases. Target. Oncol. 11, 101–106 (2016).
Swami, A. et al. Engineered nanomedicine for myeloma and bone microenvironment targeting. Proc. Natl Acad. Sci. USA 111, 10287–10292 (2014).
This paper described NPs that target the bone microenvironment as an alternative targeting strategy for cancer.
Alexis, F., Pridgen, E., Molnar, L. K. & Farokhzad, O. C. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 5, 505–515 (2008).
Perrault, S. D., Walkey, C., Jennings, T., Fischer, H. C. & Chan, W. C. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 9, 1909–1915 (2009).
Karnik, R. et al. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett. 8, 2906–2912 (2008).
Valencia, P. M. et al. Single-step assembly of homogenous lipid-polymeric and lipid-quantum dot nanoparticles enabled by microfluidic rapid mixing. ACS Nano 4, 1671–1679 (2010).
Rhee, M. et al. Synthesis of size-tunable polymeric nanoparticles enabled by 3D hydrodynamic flow focusing in single-layer microchannels. Adv. Mater. 23, H79–H83 (2011).
Chen, D. et al. Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. J. Am. Chem. Soc. 134, 6948–6951 (2012).
Kim, Y. et al. Mass production and size control of lipid-polymer hybrid nanoparticles through controlled microvortices. Nano Lett. 12, 3587–3591 (2012).
Rolland, J. P. et al. Direct fabrication and harvesting of monodisperse, shape-specific nanobiomaterials. J. Am. Chem. Soc. 127, 10096–10100 (2005).
Xu, J. et al. Future of the particle replication in nonwetting templates (PRINT) technology. Angew. Chem. Int. Ed. 52, 6580–6589 (2013).
This article reviewed the PRINT technology and its application in the biomedical and material sciences.
Toh, Y. C. et al. A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip 9, 2026–2035 (2009).
Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).
This report described the development of 'organ-on-a-chip' and its potential for use in screening drugs and nanotherapeutics.
Albanese, A., Lam, A. K., Sykes, E. A., Rocheleau, J. V. & Chan, W. C. Tumour-on-a-chip provides an optical window into nanoparticle tissue transport. Nat. Commun. 4, 2718 (2013).
Choi, S. Y. et al. Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv. Drug Deliv. Rev. 79–80, 222–237 (2014).
Sharpless, N. E. & Depinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5, 741–754 (2006).
Lin, D. et al. High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res. 74, 1272–1283 (2014).
Rongvaux, A. et al. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32, 364–372 (2014).
Hubbard, G. K. et al. Combined MYC activation and Pten loss are sufficient to create genomic instability and lethal metastatic prostate cancer. Cancer Res. 76, 283–292 (2016).
Lim, J. M. et al. Ultra-high throughput synthesis of nanoparticles with homogeneous size distribution using a coaxial turbulent jet mixer. ACS Nano 8, 6056–6065 (2014).
Bangham, A. D. & Horne, R. W. Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope. J. Mol. Biol. 8, 660–668 (1964).
Folkman, J. & Long, D. M. The use of silicone rubber as a carrier for prolonged drug therapy. J. Surg. Res. 4, 139–142 (1964).
Langer, R. & Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797–800 (1976).
Samyang Biopharm. History. SamyangBiopharm https://www.samyangbiopharm.com/eng/Aboutus/history (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00689065?term (2013).
MagForce. MagForce Nanotechnologies AG receives European regulatory approval for its Nano Cancer® therapy. magforce.de http://www.magforce.de/en/presse-investoren/news-events/detail/article/magforce-nanotechnologies-ag-erhaelt-europaeische-zulassung-fuer-die-nano-krebsR-therapie.html (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01300533?term (2016).
Inman, S. FDA approves second-line MM-398 regimen for metastatic pancreatic cancer. OncLive http://www.onclive.com/web-exclusives/fda-approves-mm-398-regimen-for-metastatic-pancreatic-cancer (2015).
Stathopoulos, G. P. et al. Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial. Ann. Oncol. 21, 2227–2232 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01644890?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00377936?term (2008).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00542048?term (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01537536?term (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00448305?term (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02494570?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02646319?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01380769?term (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02187302?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01652079?term (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02213744?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01792479?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02283320?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01812746?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00964080?term (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01702129?term (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02112656?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01696084?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00361842?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00848042?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01679470?term (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02379845?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02340156?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02340117?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01733238?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02226965?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01435720?term (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01808638?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01262235?term (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02191878?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02314052?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01829971?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00882180?term (2011).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01158079?term (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01591356?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01505153?term (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00409188?term (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00952692?term (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01095848?term (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01052142?term (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00860522?term (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00356980?term (2012).
Tardi, P. G. et al. Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo. Mol. Cancer Ther. 8, 2266–2275 (2009).
Zhang, Y. F., Wang, J. C., Bian, D. Y., Zhang, X. & Zhang, Q. Targeted delivery of RGD-modified liposomes encapsulating both combretastatin A-4 and doxorubicin for tumor therapy: in vitro and in vivo studies. Eur. J. Pharm. Biopharm. 74, 467–473 (2010).
Shim, G. et al. Trilysinoyl oleylamide-based cationic liposomes for systemic co-delivery of siRNA and an anticancer drug. J. Control. Release 155, 60–66 (2011).
Xu, Z. et al. The characteristics and performance of a multifunctional nanoassembly system for the co-delivery of docetaxel and iSur-pDNA in a mouse hepatocellular carcinoma model. Biomaterials 31, 916–922 (2010).
Yang, Y. et al. Nanoparticle delivery of pooled siRNA for effective treatment of non-small cell lung cancer. Mol. Pharm. 9, 2280–2289 (2012).
Ko, Y. T., Falcao, C. & Torchilin, V. P. Cationic liposomes loaded with proapoptotic peptide D-(KLAKLAK)2 and Bcl-2 antisense oligodeoxynucleotide G3139 for enhanced anticancer therapy. Mol. Pharm. 6, 971–977 (2009).
Lv, S. et al. Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. Biomaterials 35, 6118–6129 (2014).
Duan, X. et al. Smart pH-sensitive and temporal-controlled polymeric micelles for effective combination therapy of doxorubicin and disulfiram. ACS Nano 7, 5858–5869 (2013).
Tang, S. et al. Inhibition of metastasis and growth of breast cancer by pH-sensitive poly (β-amino ester) nanoparticles co-delivering two siRNA and paclitaxel. Biomaterials 48, 1–15 (2015).
Ediriwickrema, A., Zhou, J., Deng, Y. & Saltzman, W. M. Multi-layered nanoparticles for combination gene and drug delivery to tumors. Biomaterials 35, 9343–9354 (2014).
Wang, Y., Gao, S., Ye, W. H., Yoon, H. S. & Yang, Y. Y. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nat. Mater. 5, 791–796 (2006).
Lee, S. J. et al. Co-delivery of VEGF and Bcl-2 dual-targeted siRNA polymer using a single nanoparticle for synergistic anti-cancer effects in vivo. J. Control. Release 220, 631–641 (2015).
Devulapally, R. et al. Polymer nanoparticles mediated codelivery of antimiR-10b and antimiR-21 for achieving triple negative breast cancer therapy. ACS Nano 9, 2290–2302 (2015).
Xu, X. et al. Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug. Proc. Natl Acad. Sci. USA 110, 18638–18643 (2013).
Deng, Z. J. et al. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACS Nano 7, 9571–9584 (2013).
Jiang, T., Mo, R., Bellotti, A., Zhou, J. & Gu, Z. Gel-liposome-mediated co-delivery of anticancer membrane-associated proteins and small-molecule drugs for enhanced therapeutic efficacy. Adv. Funct. Mater. 24, 2295–2304 (2014).
Zheng, M. et al. Single-step assembly of DOX/ICG loaded lipid—polymer nanoparticles for highly effective chemo-photothermal combination therapy. ACS Nano 7, 2056–2067 (2013).
Werner, M. E. et al. Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis. Biomaterials 32, 8548–8554 (2011).
Han, L. et al. Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer. Biomaterials 32, 1242–1252 (2011).
Lee, I. H. et al. Targeted chemoimmunotherapy using drug-loaded aptamer-dendrimer bioconjugates. J. Control. Release 155, 435–441 (2011).
Fang, J. H. et al. Magnetic core-shell nanocapsules with dual-targeting capabilities and co-delivery of multiple drugs to treat brain gliomas. Adv. Healthc. Mater. 3, 1250–1260 (2014).
Wang, L. et al. Synergistic anticancer effect of RNAi and photothermal therapy mediated by functionalized single-walled carbon nanotubes. Biomaterials 34, 262–274 (2013).
Xiao, Z. et al. DNA self-assembly of targeted near-infrared-responsive gold nanoparticles for cancer thermo-chemotherapy. Angew. Chem. Int. Ed. 51, 11853–11857 (2012).
Liu, T. et al. Drug delivery with PEGylated MoS2 nano-sheets for combined photothermal and chemotherapy of cancer. Adv. Mater. 26, 3433–3440 (2014).