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Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Key Points

  • Nanoparticulate pharmaceutical drug delivery systems (NDDSs) are used in research and clinical settings to overcome several issues associated with traditional drugs, such as poor aqueous solubility, low bioavailability and nonspecific distribution in the body, and to enhance drug efficiency.

  • Multifunctional NDDSs are able to simultaneously bear a sufficient load of a drug, have increased circulation times and target the drug to the intended site of action. Moreover, they can respond to various stimuli that are characteristic of the pathological site and can even be supplemented with a contrast moiety to enable monitoring of their biodistribution, target accumulation or the efficacy of the therapy.

  • One of the most common properties of NDDSs is the combination of prolonged circulation times with targetabilty. Active targeting of NDDSs can be achieved by surface modification of the NDDS with targeting ligands.

  • Diseases that could benefit from NDDS-based therapy include cancer, cardiovascular diseases and infectious diseases.

  • NDDSs that respond to different types of stimuli are an important and continuously growing area of research. This responsiveness can be used to control the properties and behaviour of NDDSs. The stimuli can be internal and intrinsic for the target site (such as changes in pH, temperature, redox condition or the activity of certain enzymes) or ones that are external and artificially applied (such as a magnetic field, ultrasound and various types of irradiation).

  • After reaching the target, NDDSs may still need to cross the barrier of the cell membrane to deliver their drug load into the cell cytoplasm or specific organelles inside the cell; strategies to facilitate this process have been developed or are under investigation.

  • Multifunctional NDDSs have been constructed for multimodal imaging, which could overcome several problems associated with individual imaging modalities, such as insufficient sensitivity or resolution.

Abstract

The use of nanoparticulate pharmaceutical drug delivery systems (NDDSs) to enhance the in vivo effectiveness of drugs is now well established. The development of multifunctional and stimulus-sensitive NDDSs is an active area of current research. Such NDDSs can have long circulation times, target the site of the disease and enhance the intracellular delivery of a drug. This type of NDDS can also respond to local stimuli that are characteristic of the pathological site by, for example, releasing an entrapped drug or shedding a protective coating, thus facilitating the interaction between drug-loaded nanocarriers and target cells or tissues. In addition, imaging contrast moieties can be attached to these carriers to track their real-time biodistribution and accumulation in target cells or tissues. Here, I highlight recent developments with multifunctional and stimuli-sensitive NDDSs and their therapeutic potential for diseases including cancer, cardiovascular diseases and infectious diseases.

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Figure 1: Schematic of a drug-loaded, multifunctional, stimuli-sensitive NDDS.
Figure 2: Multifunctional and stimuli-sensitive NDDSs in cardiovascular pathologies and infectious diseases.
Figure 3: Penetration of NDDSs into pathological tissue and interaction with target cells.
Figure 4: Methods for targeted drug release.

References

  1. Torchilin, V. P. (ed.) Nanoparticulates as Drug Carriers (Imperial College Press, 2006).

    Book  Google Scholar 

  2. Thassu, D., Deleers, M. & Pathak, Y. (eds) Nanoparticulate Drug Delivery Systems (Informa Healthcare USA, 2007).

    Book  Google Scholar 

  3. Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nature Rev. Cancer 5, 161–171 (2005).

    Article  CAS  Google Scholar 

  4. van Vlerken, L. E. & Amiji, M. M. Multi-functional polymeric nanoparticles for tumour-targeted drug delivery. Expert Opin. Drug Deliv. 3, 205–216 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Torchilin, V. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur. J. Pharm. Biopharm. 71, 431–444 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jain, R. K. Transport of molecules, particles, and cells in solid tumors. Annu. Rev. Biomed. Eng. 1, 241–263 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Maeda, H. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjugate Chem. 21, 797–802 (2010).

    Article  CAS  Google Scholar 

  9. Nagamitsu, A., Greish, K. & Maeda, H. Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors. Jpn J. Clin. Oncol. 39, 756–766 (2009).

    Article  PubMed  Google Scholar 

  10. Monsky, W. L. et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 59, 4129–4135 (1999).

    CAS  PubMed  Google Scholar 

  11. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nature Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  Google Scholar 

  12. Klibanov, A. L., Maruyama, K., Torchilin, V. P. & Huang, L. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 268, 235–237 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Ishida, T. et al. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J. Control Release 112, 15–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Ishida, T., Atobe, K., Wang, X. & Kiwada, H. Accelerated blood clearance of PEGylated liposomes upon repeated injections: effect of doxorubicin-encapsulation and high-dose first injection. J. Control Release 115, 251–258 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Whiteman, K. R., Subr, V., Ulbrich, K. & Torchilin, V. P. Poly(HPMA)-coated liposomes demonstrate prolonged circulation in mice. J. Liposome Res. 11, 153–164 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Torchilin, V. P. et al. Amphiphilic poly-N-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials 22, 3035–3044 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Takeuchi, H., Kojima, H., Yamamoto, H. & Kawashima, Y. Evaluation of circulation profiles of liposomes coated with hydrophilic polymers having different molecular weights in rats. J. Control Release 75, 83–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Geng, Y. et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnol. 2, 249–255 (2007).

    Article  CAS  Google Scholar 

  19. Maksimenko, A. et al. A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity. Proc. Natl Acad. Sci. USA 111, E217–E226 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Niidome, T. et al. PEG-modified gold nanorods with a stealth character for in vivo applications. J. Control. Release 114, 343–347 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. von Maltzahn, G. et al. Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas. Cancer Res. 69, 3892–3900 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Kaminskas, L. M. et al. Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-L-lysine dendrimers. Mol. Pharm. 6, 1190–1204 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Wang, W. et al. The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress. Nanotechnology 20, 105103 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Schipper, M. L. et al. Particle size, surface coating, and PEGylation influence the biodistribution of quantum dots in living mice. Small 5, 126–134 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sawant, R. R. & Torchilin, V. P. Challenges in development of targeted liposomal therapeutics. AAPS J. 14, 303–315 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Trapani, G., Denora, N., Trapani, A. & Laquintana, V. Recent advances in ligand targeted therapy. J. Drug Target 20, 1–22 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Torchilin, V. P. et al. p-nitrophenylcarbonyl-PEG-PE-liposomes: fast and simple attachment of specific ligands, including monoclonal antibodies, to distal ends of PEG chains via p-nitrophenylcarbonyl groups. Biochim. Biophys. Acta 1511, 397–411 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Gao, J. et al. Tumor-targeted PE38KDEL delivery via PEGylated anti-HER2 immunoliposomes. Int. J. Pharm. 374, 145–152 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Elbayoumi, T. A. & Torchilin, V. P. Tumor-specific anti-nucleosome antibody improves therapeutic efficacy of doxorubicin-loaded long-circulating liposomes against primary and metastatic tumor in mice. Mol. Pharm. 6, 246–254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gupta, B. & Torchilin, V. P. Monoclonal antibody 2C5-modified doxorubicin-loaded liposomes with significantly enhanced therapeutic activity against intracranial human brain U-87 MG tumor xenografts in nude mice. Cancer Immunol. Immunother. 56, 1215–1223 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Eck, W. et al. PEGylated gold nanoparticles conjugated to monoclonal F19 antibodies as targeted labeling agents for human pancreatic carcinoma tissue. ACS Nano. 2, 2263–2272 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Hu, K. et al. Lactoferrin-conjugated PEG-PLA nanoparticles with improved brain delivery: in vitro and in vivo evaluations. J. Control. Release 134, 55–61 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Le Droumaguet, B. et al. Versatile and efficient targeting using a single nanoparticulate platform: application to cancer and Alzheimer's disease. ACS Nano. 6, 5866–5879 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Kang, H., O'Donoghue, M. B., Liu, H. & Tan, W. A liposome-based nanostructure for aptamer directed delivery. Chem. Commun. 46, 249–251 (2010).

    Article  CAS  Google Scholar 

  35. Kim, I. Y. et al. Antitumor activity of EGFR targeted pH-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice. J. Control. Release 140, 55–60 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Yang, X., Grailer, J. J., Pilla, S., Steeber, D. A. & Gong, S. Tumor-targeting, pH-responsive, and stable unimolecular micelles as drug nanocarriers for targeted cancer therapy. Bioconjug. Chem. 21, 296–504 (2010).

    Article  CAS  Google Scholar 

  37. Shen, M. et al. Multifunctional drug delivery system for targeting tumor and its acidic microenvironment. J. Control. Release 161, 884–892 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Binsalamah, Z. M., Paul, A., Prakash, S. & Shum-Tim, D. Nanomedicine in cardiovascular therapy: recent advancements. Expert Rev. Cardiovasc. Ther. 10, 805–815 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Psarros, C., Lee, R., Margaritis, M. & Antoniades, C. Nanomedicine for the prevention, treatment and imaging of atherosclerosis. Nanomedicine 8 (Suppl. 1), 59–68 (2012).

    Article  CAS  Google Scholar 

  40. Peters, D. et al. Targeting atherosclerosis by using modular, multifunctional micelles. Proc. Natl Acad. Sci. USA 106, 9815–9819 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Iverson, N. M., Sparks, S. M., Demirdirek, B., Uhrich, K. E. & Moghe, P. V. Controllable inhibition of cellular uptake of oxidized low-density lipoprotein: structure-function relationships for nanoscale amphiphilic polymers. Acta Biomater. 6, 3081–3091 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Broz, P. et al. Inhibition of macrophage phagocytotic activity by a receptor-targeted polymer vesicle-based drug delivery formulation of pravastatin. J. Cardiovasc. Pharmacol. 51, 246–252 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Mulder, W. J. et al. Molecular imaging of macrophages in atherosclerotic plaques using bimodal PEG-micelles. Magn. Reson. Med. 58, 1164–1170 (2007).

    Article  PubMed  Google Scholar 

  44. Sy, J. C. & Davis, M. E. Delivering regenerative cues to the heart: cardiac drug delivery by microspheres and peptide nanofibers. J. Cardiovasc. Transl. Res. 3, 461–468 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bowey, K., Tanguay, J. F. & Tabrizian, M. Liposome technology for cardiovascular disease treatment and diagnosis. Expert Opin. Drug Deliv. 9, 249–265 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Levchenko, T. S., Hartner, W. C., Verma, D. D., Bernstein, E. A. & Torchilin, V. P. ATP-loaded liposomes for targeted treatment in models of myocardial ischemia. Methods Mol. Biol. 605, 361–375 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Verma, D. D., Hartner, W. C., Thakkar, V., Levchenko, T. S. & Torchilin, V. P. Protective effect of coenzyme Q10-loaded liposomes on the myocardium in rabbits with an acute experimental myocardial infarction. Pharm. Res. 24, 2131–2137 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Guo, Y. et al. Simultaneous diagnosis and gene therapy of immuno-rejection in rat allogeneic heart transplantation model using a T-cell-targeted theranostic nanosystem. ACS Nano. 6, 10646–10657 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. McCarthy, J. R. et al. Multifunctional nanoagent for thrombus-targeted fibrinolytic therapy. Nanomed. 7, 1017–1028 (2012).

    Article  CAS  Google Scholar 

  50. Mehendale, R., Joshi, M. & Patravale, V. B. Nanomedicines for treatment of viral diseases. Crit. Rev. Ther. Drug Carrier Syst. 30, 1–49 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Banerjee, M., Mallick, S., Paul, A., Chattopadhyay, A. & Ghosh, S. S. Heightened reactive oxygen species generation in the antimicrobial activity of a three component iodinated chitosan-silver nanoparticle composite. Langmuir 26, 5901–5908 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Mihu, M. R. et al. The use of nitric oxide releasing nanoparticles as a treatment against Acinetobacter baumannii in wound infections. Virulence 1, 62–67 (2010).

    Article  PubMed  Google Scholar 

  53. Seleem, M. N. et al. Silica-antibiotic hybrid nanoparticles for targeting intracellular pathogens. Antimicrob. Agents Chemother. 53, 4270–4274 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xiong, M. H. et al. Bacteria-responsive multifunctional nanogel for targeted antibiotic delivery. Adv. Mater. 24, 6175–6180 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Low, P. S., Henne, W. A. & Doorneweerd, D. D. Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases. Acc. Chem. Res. 41, 120–129 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Lu, Y. & Low, P. S. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv. Drug Deliv. Rev. 54, 675–693 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Gabizon, A., Shmeeda, H., Horowitz, A. T. & Zalipsky, S. Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates. Adv. Drug Deliv. Rev. 56, 1177–1192 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Lee, R. J. & Low, P. S. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim. Biophys. Acta 1233, 134–144 (1995).

    Article  PubMed  Google Scholar 

  59. Liu, Y. et al. Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand. Anticancer Res. 31, 1521–1525 (2011).

    CAS  PubMed  Google Scholar 

  60. Niu, R. et al. Preparation, characterization, and antitumor activity of paclitaxel-loaded folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes. J. Drug Target 19, 373–381 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Chaudhury, A., Das, S., Bunte, R. M. & Chiu, G. N. Potent therapeutic activity of folate receptor-targeted liposomal carboplatin in the localized treatment of intraperitoneally grown human ovarian tumor xenograft. Int. J. Nanomed. 7, 739–751 (2012).

    CAS  Google Scholar 

  62. Duarte, S., Faneca, H. & Lima, M. C. Folate-associated lipoplexes mediate efficient gene delivery and potent antitumoral activity in vitro and in vivo. Int. J. Pharm. 423, 365–377 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Li, X., Ding, L., Xu, Y., Wang, Y. & Ping, Q. Targeted delivery of doxorubicin using stealth liposomes modified with transferrin. Int. J. Pharm. 373, 116–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Cheng, K. T., Wang, P. C. & Shan, L. Alexa Fluor 680-labeled transferrin-cationic (NBD-labeled DOPE-DOTAP) liposome-encapsulated gadopentetate dimeglumine complex. MICAD [online], (2007).

  65. Ito, Y. et al. Disposition of TF-PEG-Liposome-BSH in tumor-bearing mice. Appl. Radiat. Isot. 67, S109–110 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Koshkaryev, A., Piroyan, A. & Torchilin, V. P. Increased apoptosis in cancer cells in vitro and in vivo by ceramides in transferrin-modified liposomes. Cancer Biol. Ther. 13, 50–60 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim, S. K. & Huang, L. Nanoparticle delivery of a peptide targeting EGFR signaling. J. Control. Release 157, 279–286 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Danhier, F., Feron, O. & Preat, V. To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Release 148, 135–146 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Chiu, G. N. C. et al. Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs. Mol. Cancer Ther. 6, 844–855 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Gabizon, A. et al. Improved therapeutic activity of folate-targeted liposomal doxorubicin in folate receptor-expressing tumor models. Cancer Chemother. Pharmacol. 66, 43–52 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Byrne, J. D., Betancourt, T. & Brannon-Peppas, L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv. Drug Deliv. Rev. 60, 1615–1626 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Wicki, A. et al. Targeting tumor-associated endothelial cells: anti-VEGFR2 immunoliposomes mediate tumor vessel disruption and inhibit tumor growth. Clin. Cancer Res. 18, 454–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Li, S. D., Chono, S. & Huang, L. Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA. Mol. Ther. 16, 942–946 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Chang, D. K. et al. Antiangiogenic targeting liposomes increase therapeutic efficacy for solid tumors. J. Biol. Chem. 284, 12905–12916 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gosk, S., Moos, T., Gottstein, C. & Bendas, G. VCAM-1 directed immunoliposomes selectively target tumor vasculature in vivo. Biochim. Biophys. Acta 1778, 854–863 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Hatakeyama, H. et al. Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes. Int. J. Pharm. 342, 194–200 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nature Mater. 12, 991–1003 (2013).

    Article  CAS  Google Scholar 

  78. Helmlinger, G., Sckell, A., Dellian, M., Forbes, N. S. & Jain, R. K. Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin. Cancer Res. 8, 1284–1291 (2002).

    CAS  PubMed  Google Scholar 

  79. Wojtkowiak, J. W., Verduzco, D., Schramm, K. J. & Gillies, R. J. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol. Pharm. 8, 2032–2038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee, E. S., Shin, H. J., Na, K. & Bae, Y. H. Poly(L-histidine)-PEG block copolymer micelles and pH-induced destabilization. J. Control. Release 90, 363–374 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Kim, D., Lee, E. S., Oh, K. T., Gao, Z. G. & Bae, Y. H. Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH. Small 4, 2043–2050 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kim, D., Gao, Z. G., Lee, E. S. & Bae, Y. H. In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer. Mol. Pharm. 6, 1353–1362 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Farhood, H., Serbina, N. & Huang, L. The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim. Biophys. Acta 1235, 289–295 (1995).

    Article  PubMed  Google Scholar 

  84. Sawant, R. R. et al. Polyethyleneimine-lipid conjugate-based pH-sensitive micellar carrier for gene delivery. Biomaterials 33, 3942–3951 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Navarro, G. et al. P-glycoprotein silencing with siRNA delivered by DOPE-modified PEI overcomes doxorubicin resistance in breast cancer cells. Nanomed. 7, 65–78 (2012).

    Article  CAS  Google Scholar 

  86. Sawant, R. M. et al. “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers. Bioconjug Chem. 17, 943–949 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Needham, D., Park, J. Y., Wright, A. M. & Tong, J. Materials characterization of the low temperature sensitive liposome (LTSL): effects of the lipid composition (lysolipid and DSPE-PEG2000) on the thermal transition and release of doxorubicin. Faraday Discuss. 161, 515–534; discussion 563–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Chen, K. J. et al. Hyperthermia-mediated local drug delivery by a bubble-generating liposomal system for tumor-specific chemotherapy. ACS Nano. 8, 5105–5115 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Schwerdt, A. et al. Hyperthermia-induced targeting of thermosensitive gene carriers to tumors. Hum. Gene Ther. 19, 1283–1292 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. Goldenbogen, B. et al. Reduction-sensitive liposomes from a multifunctional lipid conjugate and natural phospholipids: reduction and release kinetics and cellular uptake. Langmuir 27, 10820–10829 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Meers, P. Enzyme-activated targeting of liposomes. Adv. Drug Deliv. Rev. 53, 265–272 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Gialeli, C., Theocharis, A. D. & Karamanos, N. K. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278, 16–27 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Basel, M. T., Shrestha, T. B., Troyer, D. L. & Bossmann, S. H. Protease-sensitive, polymer-caged liposomes: a method for making highly targeted liposomes using triggered release. ACS Nano. 5, 2162–2175 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Zhu, L. et al. Targeted delivery of methotrexate to skeletal muscular tissue by thermosensitive magnetoliposomes. Int. J. Pharm. 370, 136–143 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Wang, F. H. et al. Diffusion and clearance of superparamagnetic iron oxide nanoparticles infused into the rat striatum studied by MRI and histochemical techniques. Nanotechnology 22, 015103 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Sawant, R. M. et al. Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles. J. Nanoparticle Res. 11, 1777–1785 (2009).

    Article  CAS  Google Scholar 

  97. Liao, C., Sun, Q., Liang, B., Shen, J. & Shuai, X. Targeting EGFR-overexpressing tumor cells using cetuximab-immunomicelles loaded with doxorubicin and superparamagnetic iron oxide. Eur. J. Radiol. 80, 699–705 (2011).

    PubMed  Google Scholar 

  98. Lee, J. H. et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nature Nanotechnol. 6, 418–422 (2011).

    Article  CAS  Google Scholar 

  99. Xie, J., Liu, G., Eden, H. S., Ai, H. & Chen, X. Surface-engineered magnetic nanoparticle platforms for cancer imaging and therapy. Acc. Chem. Res. 44, 883–892 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhu, L., Ye, Z., Cheng, K., Miller, D. D. & Mahato, R. I. Site-specific delivery of oligonucleotides to hepatocytes after systemic administration. Bioconjug. Chem. 19, 290–298 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Zhu, L. & Mahato, R. I. Targeted delivery of siRNA to hepatocytes and hepatic stellate cells by bioconjugation. Bioconjug Chem. 21, 2119–2127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yudina, A. et al. Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes. J. Control. Release 155, 442–448 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Kang, H. et al. Near-infrared light-responsive core-shell nanogels for targeted drug delivery. ACS Nano. 5, 5094–5099 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chen, J. et al. pH and reduction dual-sensitive copolymeric micelles for intracellular doxorubicin delivery. Biomacromolecules 12, 3601–3611 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Zhu, L., Kate, P. & Torchilin, V. P. Matrix metalloprotease 2-responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. ACS Nano 6, 3491–3498 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, T., Upponi, J. R. & Torchilin, V. P. Design of multifunctional non-viral gene vectors to overcome physiological barriers: dilemmas and strategies. Int. J. Pharm. 427, 3–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Sasaki, K. et al. An artificial virus-like nano carrier system: enhanced endosomal escape of nanoparticles via synergistic action of pH-sensitive fusogenic peptide derivatives. Anal. Bioanal Chem. 391, 2717–2727 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Josephson, L., Tung, C. H., Moore, A. & Weissleder, R. High-efficiency intracellular magnetic labeling with novel superparamagnetic-Tat peptide conjugates. Bioconjug. Chem. 10, 186–191 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Torchilin, V. P., Rammohan, R., Weissig, V. & Levchenko, T. S. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc. Natl Acad. Sci. USA 98, 8786–8791 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tseng, Y. L., Liu, J. J. & Hong, R. L. Translocation of liposomes into cancer cells by cell-penetrating peptides penetratin and tat: a kinetic and efficacy study. Mol. Pharmacol. 62, 864–872 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Torchilin, V. P. et al. Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes. Proc. Natl Acad. Sci. USA 100, 1972–1977 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Koshkaryev, A., Piroyan, A. & Torchilin, V. P. Bleomycin in octaarginine-modified fusogenic liposomes results in improved tumor growth inhibition. Cancer Lett. 334, 293–301 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Biswas, S., Dodwadkar, N. S., Deshpande, P. P., Parab, S. & Torchilin, V. P. Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity. Eur. J. Pharm. Biopharm. 84, 517–525 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kale, A. A. & Torchilin, V. P. Design, synthesis, and characterization of pH-sensitive PEG-PE conjugates for stimuli-sensitive pharmaceutical nanocarriers: the effect of substitutes at the hydrazone linkage on the ph stability of PEG-PE conjugates. Bioconjug. Chem. 18, 363–370 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kale, A. A. & Torchilin, V. P. Enhanced transfection of tumor cells in vivo using “smart” pH-sensitive TAT-modified pegylated liposomes. J. Drug Target 15, 538–545 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Koren, E., Apte, A., Jani, A. & Torchilin, V. P. Multifunctional PEGylated 2C5-immunoliposomes containing pH-sensitive bonds and TAT peptide for enhanced tumor cell internalization and cytotoxicity. J. Control. Release 160, 264–273 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Apte, A., Koren, E., Koshkaryev, A. & Torchilin, V. P. Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models. Cancer Biol. Ther. 15, 69–80 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Xiong, X. B. & Lavasanifar, A. Traceable multifunctional micellar nanocarriers for cancer-targeted co-delivery of MDR-1 siRNA and doxorubicin. ACS Nano. 5, 5202–5213 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Galluzzi, L. et al. Mitochondrial gateways to cancer. Mol. Aspects Med. 31, 1–20 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Biswas, S., Dodwadkar, N. S., Sawant, R. R., Koshkaryev, A. & Torchilin, V. P. Surface modification of liposomes with rhodamine-123-conjugated polymer results in enhanced mitochondrial targeting. J. Drug Target 19, 552–561 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Koshkaryev, A., Thekkedath, R., Pagano, C., Meerovich, I. & Torchilin, V. P. Targeting of lysosomes by liposomes modified with octadecyl-rhodamine B. J. Drug Target 19, 606–614 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Thekkedath, R., Koshkaryev, A. & Torchilin, V. P. Lysosome-targeted octadecyl-rhodamine B-liposomes enhance lysosomal accumulation of glucocerebrosidase in Gaucher's cells in vitro. Nanomed. 8, 1055–1065 (2013).

    Article  CAS  Google Scholar 

  123. Willmann, J. K., van Bruggen, N., Dinkelborg, L. M. & Gambhir, S. S. Molecular imaging in drug development. Nature Rev. Drug Discov. 7, 591–607 (2008).

    Article  CAS  Google Scholar 

  124. Liu, J. et al. Bifunctional nanoparticles with fluorescence and magnetism via surface-initiated AGET ATRP mediated by an iron catalyst. Langmuir 27, 12684–12692 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Zheng, J., Liu, J., Dunne, M., Jaffray, D. A. & Allen, C. In vivo performance of a liposomal vascular contrast agent for CT and MR-based image guidance applications. Pharm. Res. 24, 1193–1201 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Wen, S. et al. Multifunctional dendrimer-entrapped gold nanoparticles for dual mode CT/MR imaging applications. Biomaterials 34, 1570–1580 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Li, S., Goins, B., Zhang, L. & Bao, A. Novel multifunctional theranostic liposome drug delivery system: construction, characterization and multimodality MR, near-infrared fluorescent and nuclear imaging. Bioconj. Chem. 23, 1322–1332 (2012).

    Article  CAS  Google Scholar 

  128. Mitchell, N. et al. Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imaging. Biomaterials 34, 1179–1192 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mitra, A., Nan, A., Line, B. R. & Ghandehari, H. Nanocarriers for nuclear imaging and radiotherapy of cancer. Curr. Pharm. Des. 12, 4729–4749 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Trubetskoy, V. S., Cannillo, J. A., Milshtein, A., Wolf, G. L. & Torchilin, V. P. Controlled delivery of Gd-containing liposomes to lymph nodes: surface modification may enhance MRI contrast properties. Magn. Reson. Imag. 13, 31–37 (1995).

    Article  CAS  Google Scholar 

  131. Erdogan, S., Medarova, Z. O., Roby, A., Moore, A. & Torchilin, V. P. Enhanced tumor MR imaging with gadolinium-loaded polychelating polymer-containing tumor-targeted liposomes. J. Magn. Reson. Imag. 27, 574–580 (2008).

    Article  Google Scholar 

  132. Torchilin, V. P. Surface-modified liposomes in gamma- and MR-imaging. Adv. Drug Deliv. Rev. 24, 301–313 (1997).

    Article  CAS  Google Scholar 

  133. Glogard, C., Stensrud, G., Hovland, R., Fossheim, S. L. & Klaveness, J. Liposomes as carriers of amphiphilic gadolinium chelates: the effect of membrane composition on incorporation efficacy and in vitro relaxivity. Int. J. Pharm. 233, 131–140 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Wen, C. J., Zhang, L. W., Al-Suwayeh, S. A., Yen, T. C. & Fang, J. Y. Theranostic liposomes loaded with quantum dots and apomorphine for brain targeting and bioimaging. Int. J. Nanomed. 7, 1599–1611 (2012).

    CAS  Google Scholar 

  135. Kenny, G. D. et al. Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain. Biomaterials 34, 9190–9200 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Lee, P. W. et al. Multifunctional core-shell polymeric nanoparticles for transdermal DNA delivery and epidermal Langerhans cells tracking. Biomaterials 31, 2425–2434 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Elbayoumi, T. A. & Torchilin, V. P. Enhanced accumulation of long-circulating liposomes modified with the nucleosome-specific monoclonal antibody 2C5 in various tumours in mice: gamma-imaging studies. Eur. J. Nucl. Med. Mol. Imag. 33, 1196–1205 (2006).

    Article  CAS  Google Scholar 

  138. Elbayoumi, T. A. & Torchilin, V. P. Enhanced cytotoxicity of monoclonal anticancer antibody 2C5-modified doxorubicin-loaded PEGylated liposomes against various tumor cell lines. Eur. J. Pharm. Sci. 32, 159–168 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Thomas, R., Park, I. K. & Jeong, Y. Y. Magnetic iron oxide nanoparticles for multimodal imaging and therapy of cancer. Int. J. Mol. Sci. 14, 15910–15930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Sun, C. et al. Tumor-targeted drug delivery and MRI contrast enhancement by chlorotoxin-conjugated iron oxide nanoparticles. Nanomed. 3, 495–505 (2008).

    Article  CAS  Google Scholar 

  141. Yang, L. et al. Receptor-targeted nanoparticles for in vivo imaging of breast cancer. Clin. Cancer Res. 15, 4722–4732 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kumar, M., Yigit, M., Dai, G., Moore, A. & Medarova, Z. Image-guided breast tumor therapy using a small interfering RNA nanodrug. Cancer Res. 70, 7553–7561 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Medarova, Z., Pham, W., Farrar, C., Petkova, V. & Moore, A. In vivo imaging of siRNA delivery and silencing in tumors. Nature Med. 13, 372–377 (2007).

    Article  CAS  PubMed  Google Scholar 

  144. Koo, H. et al. In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micelles. Chem. Commun. 46, 5668–5670 (2010).

    Article  CAS  Google Scholar 

  145. Kenny, G. D. et al. Novel multifunctional nanoparticle mediates siRNA tumour delivery, visualisation and therapeutic tumour reduction in vivo. J. Control. Release 149, 111–116 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Grange, C. et al. Combined delivery and magnetic resonance imaging of neural cell adhesion molecule-targeted doxorubicin-containing liposomes in experimentally induced Kaposi's sarcoma. Cancer Res. 70, 2180–2190 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Deng, L. et al. A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer. Int. J. Nanomed. 7, 5053–5065 (2012).

    CAS  Google Scholar 

  148. Koning, G. A. & Krijger, G. C. Targeted multifunctional lipid-based nanocarriers for image-guided drug delivery. Anticancer Agents Med. Chem. 7, 425–440 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Sajja, H. K. et al. Development of multifunctional nanoparticles for targeted drug delivery and noninvasive imaging of therapeutic effect. Curr. Drug Discov. Technol. 6, 43–51 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Parhi, P., Mohanty, C. & Sahoo, S. K. Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov. Today 17, 1044–1052 (2012).

    Article  CAS  PubMed  Google Scholar 

  151. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    Article  CAS  PubMed  Google Scholar 

  153. Xiao, W. et al. Co-delivery of doxorubicin and plasmid by a novel FGFR-mediated cationic liposome. Int. J. Pharm. 393, 119–126 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Grossman, D., Kim, P. J., Schechner, J. S. & Altieri, D. C. Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc. Natl Acad. Sci. USA 98, 635–640 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhang, Y. et al. Incorporation of a selective sigma-2 receptor ligand enhances uptake of liposomes by multiple cancer cells. Int. J. Nanomed. 7, 4473–4485 (2012).

    CAS  Google Scholar 

  156. Riviere, K., Huang, Z., Jerger, K., Macaraeg, N. & Szoka, F. C. Jr. Antitumor effect of folate-targeted liposomal doxorubicin in KB tumor-bearing mice after intravenous administration. J. Drug Target 19, 14–24 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Adrian, J. E. et al. Targeted SAINT-O-Somes for improved intracellular delivery of siRNA and cytotoxic drugs into endothelial cells. J. Control. Release 144, 341–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  158. Batist, G. et al. Safety, pharmacokinetics, and efficacy of CPX-1 liposome injection in patients with advanced solid tumors. Clin. Cancer Res. 15, 692–700 (2009).

    Article  CAS  PubMed  Google Scholar 

  159. Bartlett, D. W., Su, H., Hildebrandt, I. J., Weber, W. A. & Davis, M. E. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl Acad. Sci. USA 104, 15549–15554 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Kirpotin, D. B. et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 66, 6732–6740 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Bae, Y. H. & Park, K. Targeted drug delivery to tumors: myths, reality and possibility. J. Control. Release 153, 198–205 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Venditto, V. J. & Szoka, F. C. Jr. Cancer nanomedicines: so many papers and so few drugs! Adv. Drug Deliv. Rev. 65, 80–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Wei, A., Mehtala, J. G. & Patri, A. K. Challenges and opportunities in the advancement of nanomedicines. J. Control. Release 164, 236–246 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Crommelin, D. J. & Florence, A. T. Towards more effective advanced drug delivery systems. Int. J. Pharm. 454, 496–511 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Barenholz, Y. Doxil® — the first FDA-approved nano-drug: lessons learned. J. Control. Release 160, 117–134 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Zhang, Q., Huang, X. E. & Gao, L. L. A clinical study on the premedication of paclitaxel liposome in the treatment of solid tumors. Biomed. Pharmacother. 63, 603–607 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Petre, C. E. & Dittmer, D. P. Liposomal daunorubicin as treatment for Kaposi's sarcoma. Int. J. Nanomed. 2, 277–288 (2007).

    CAS  Google Scholar 

  168. Park, J. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 4, 95–99 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Batist, G. et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J. Clin. Oncol. 19, 1444–1454 (2001).

    Article  CAS  PubMed  Google Scholar 

  170. Ayen, W. Y. & Kumar, N. In vivo evaluation of doxorubicin-loaded (PEG)3-PLA nanopolymersomes (PolyDoxSome) using DMBA-induced mammary carcinoma rat model and comparison with marketed LipoDox. Pharm. Res. 29, 2522–2533 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Taiwanese Gynecologic Oncology Group et al. Pegylated liposomal doxorubicin (Lipo-Dox) for platinum-resistant or refractory epithelial ovarian carcinoma: a Taiwanese gynecologic oncology group study with long-term follow-up. Gynecol. Oncol. 101, 423–428 (2006).

  172. Silverman, J. A. & Deitcher, S. R. Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother. Pharmacol. 71, 555–564 (2013).

    Article  CAS  PubMed  Google Scholar 

  173. Rodriguez, M. A. et al. Vincristine sulfate liposomes injection (Marqibo) in heavily pretreated patients with refractory aggressive non-Hodgkin lymphoma: report of the pivotal phase 2 study. Cancer 115, 3475–3482 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Sarris, A. H. et al. Liposomal vincristine in relapsed non-Hodgkin's lymphomas: early results of an ongoing phase II trial. Ann. Oncol. 11, 69–72 (2000).

    Article  CAS  PubMed  Google Scholar 

  175. Immordino, M. L., Dosio, F. & Cattel, L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int. J. Nanomed. 1, 297–315 (2006).

    Article  CAS  Google Scholar 

  176. Fasol, U. et al. Vascular and pharmacokinetic effects of EndoTAG-1 in patients with advanced cancer and liver metastasis. Ann. Oncol. 23, 1030–1036 (2012).

    Article  CAS  PubMed  Google Scholar 

  177. Fantini, M. et al. Lipoplatin treatment in lung and breast cancer. Chemother. Res. Pract. 2011, 125192 (2011).

    PubMed  Google Scholar 

  178. Stathopoulos, G. P. et al. Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer. Cancer Chemother. Pharmacol. 68, 945–950 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Stathopoulos, G. P. & Boulikas, T. Lipoplatin formulation review article. J. Drug Deliv. 2012, 581363 (2012).

    Article  CAS  PubMed  Google Scholar 

  180. Newman, M. S., Colbern, G. T., Working, P. K., Engbers, C. & Amantea, M. A. Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice. Cancer Chemother. Pharmacol. 43, 1–7 (1999).

    Article  CAS  PubMed  Google Scholar 

  181. Seetharamu, N., Kim, E., Hochster, H., Martin, F. & Muggia, F. Phase II study of liposomal cisplatin (SPI-77) in platinum-sensitive recurrences of ovarian cancer. Anticancer Res. 30, 541–545 (2010).

    CAS  PubMed  Google Scholar 

  182. Dicko, A., Mayer, L. D. & Tardi, P. G. Use of nanoscale delivery systems to maintain synergistic drug ratios in vivo. Expert Opin. Drug Deliv. 7, 1329–1341 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Poon, R. T. P. & Borys, N. Lyso-thermosensitive liposomal doxorubicin: an adjuvant to increase the cure rate of radiofrequency ablation in liver cancer. Future Oncol. 7, 937–945 (2011).

    Article  CAS  PubMed  Google Scholar 

  184. Staruch, R., Chopra, R. & Hynynen, K. Localised drug release using MRI-controlled focused ultrasound hyperthermia. Int. J. Hyperthermia 27, 156–171 (2011).

    Article  CAS  PubMed  Google Scholar 

  185. Pal, A. et al. Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation. Anticancer Res. 25, 331–341 (2005).

    CAS  PubMed  Google Scholar 

  186. Booser, D. J. et al. Phase II study of liposomal annamycin in the treatment of doxorubicin-resistant breast cancer. Cancer Chemother. Pharmacol. 50, 6–8 (2002).

    Article  CAS  PubMed  Google Scholar 

  187. Apostolidou, E., Swords, R., Alvarado, Y. & Giles, F. J. Treatment of acute lymphoblastic leukaemia: a new era. Drugs 67, 2153–2171 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. Semple, S. C. et al. Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity. J. Pharm. Sci. 94, 1024–1038 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Dong, D. W. et al. pH-responsive complexes using prefunctionalized polymers for synchronous delivery of doxorubicin and siRNA to cancer cells. Biomaterials 34, 4849–4859 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Kim, S. H., Jeong, J. H., Kim, T. I., Kim, S. W. & Bull, D. A. VEGF siRNA delivery system using arginine-grafted bioreducible poly(disulfide amine). Mol. Pharm. 6, 718–726 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Vader, P., van der Aa, L. J., Engbersen, J. F., Storm, G. & Schiffelers, R. M. Disulfide-based poly(amido amine)s for siRNA delivery: effects of structure on siRNA complexation, cellular uptake, gene silencing and toxicity. Pharm. Res. 28, 1013–1022 (2011).

    Article  CAS  PubMed  Google Scholar 

  192. Kurtoglu, Y. E. et al. Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery. Biomaterials 30, 2112–2121 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Musacchio, T., Vaze, O., D'Souza, G. & Torchilin, V. P. Effective stabilization and delivery of siRNA: reversible siRNA-phospholipid conjugate in nanosized mixed polymeric micelles. Bioconjug. Chem. 21, 1530–1536 (2010).

    Article  CAS  PubMed  Google Scholar 

  194. Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Pradhan, P. et al. Targeted temperature sensitive magnetic liposomes for thermo-chemotherapy. J. Control Release 142, 108–121 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Sherlock, S. P., Tabakman, S. M., Xie, L. & Dai, H. Photothermally enhanced drug delivery by ultrasmall multifunctional FeCo/graphitic shell nanocrystals. ACS Nano. 5, 1505–1512 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Schroeder, A. et al. Ultrasound triggered release of cisplatin from liposomes in murine tumors. J. Control. Release 137, 63–68 (2009).

    Article  CAS  PubMed  Google Scholar 

  198. Ibsen, S. et al. A novel nested liposome drug delivery vehicle capable of ultrasound triggered release of its payload. J. Control. Release 155, 358–366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Liu, D. et al. Conjugation of paclitaxel to iron oxide nanoparticles for tumor imaging and therapy. Nanoscale 4, 2306–2310 (2012).

    Article  CAS  PubMed  Google Scholar 

  200. Zhu, L. & Torchilin, V. P. Stimulus-responsive nanopreparations for tumor targeting. Integr. Biol. 5, 96–107 (2013).

    Article  CAS  Google Scholar 

  201. Sun, L., Yang, Y., Dong, C. M. & Wei, Y. Two-photon-sensitive and sugar-targeted nanocarriers from degradable and dendritic amphiphiles. Small 7, 401–406 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Slingerland, M. et al. Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) formulation and paclitaxel in polyethoxylated castor oil: a randomized, two-period crossover study in patients with advanced cancer. Clin Ther. 35, 1946–1954 (2013).

    Article  CAS  PubMed  Google Scholar 

  203. de Jonge, M. J. et al. Early cessation of the clinical development of LiPlaCis, a liposomal cisplatin formulation. Eur. J.Cancer 46, 3016–3021 (2010).

    Article  CAS  PubMed  Google Scholar 

  204. Saif, M. W. MM-398 achieves primary endpoint of overall survival in phase III study in patients with gemcitabine refractory metastatic pancreatic cancer. JOP 15, 278–279 (2014).

    PubMed  Google Scholar 

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Acknowledgements

The author acknowledges US National Institutes of Health grant U54CA151881 and tremendous help by T. Levchenko.

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Glossary

Enhanced permeability and retention (EPR) effect

The property through which macromolecules (such as nanoparticles) accumulate in areas of inflammation including tumours, owing to the increased vascular permeability or abnormal blood vessel architecture.

Passive targeting

The mechanism through which nanoparticulate pharmaceutical drug delivery systems tend to accumulate in tumours, probably through the enhanced permeability and retention effect.

Quantum dots

Nanometre-scale particles of semiconductor materials that have quantum mechanical properties.

Active targeting

The mechanism through which specific moieties attached to nanoparticulate pharmaceutical drug delivery systems force them to interact with a specific type of cell or tissue.

HIV TAT peptide

An amino acid sequence within the HIV transactivator of transcription (TAT) protein. This peptide promotes cell entry as it is a key part of a protein transduction domain.

Theranostics

The simultaneous use of nanoparticulate pharmaceutical drug delivery systems for therapeutic as well as diagnostic and/or imaging purposes.

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Torchilin, V. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 13, 813–827 (2014). https://doi.org/10.1038/nrd4333

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