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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Pro-efferocytic macrophage membrane biomimetic nanoparticles for the synergistic treatment of atherosclerosis via competition effect
Journal of Nanobiotechnology Open Access 01 December 2022
Journal of Nanobiotechnology Open Access 02 August 2022
Journal of Nanobiotechnology Open Access 24 March 2022
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Torchilin, V. P. (ed.) Nanoparticulates as Drug Carriers (Imperial College Press, 2006).
Thassu, D., Deleers, M. & Pathak, Y. (eds) Nanoparticulate Drug Delivery Systems (Informa Healthcare USA, 2007).
Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nature Rev. Cancer 5, 161–171 (2005).
van Vlerken, L. E. & Amiji, M. M. Multi-functional polymeric nanoparticles for tumour-targeted drug delivery. Expert Opin. Drug Deliv. 3, 205–216 (2006).
Torchilin, V. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur. J. Pharm. Biopharm. 71, 431–444 (2009).
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).
Jain, R. K. Transport of molecules, particles, and cells in solid tumors. Annu. Rev. Biomed. Eng. 1, 241–263 (1999).
Maeda, H. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjugate Chem. 21, 797–802 (2010).
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).
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).
Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nature Rev. Clin. Oncol. 7, 653–664 (2010).
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).
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).
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).
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).
Torchilin, V. P. et al. Amphiphilic poly-N-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials 22, 3035–3044 (2001).
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).
Geng, Y. et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nature Nanotechnol. 2, 249–255 (2007).
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).
Niidome, T. et al. PEG-modified gold nanorods with a stealth character for in vivo applications. J. Control. Release 114, 343–347 (2006).
von Maltzahn, G. et al. Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas. Cancer Res. 69, 3892–3900 (2009).
Kaminskas, L. M. et al. Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-L-lysine dendrimers. Mol. Pharm. 6, 1190–1204 (2009).
Wang, W. et al. The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress. Nanotechnology 20, 105103 (2009).
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).
Sawant, R. R. & Torchilin, V. P. Challenges in development of targeted liposomal therapeutics. AAPS J. 14, 303–315 (2012).
Trapani, G., Denora, N., Trapani, A. & Laquintana, V. Recent advances in ligand targeted therapy. J. Drug Target 20, 1–22 (2012).
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).
Gao, J. et al. Tumor-targeted PE38KDEL delivery via PEGylated anti-HER2 immunoliposomes. Int. J. Pharm. 374, 145–152 (2009).
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).
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).
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).
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).
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).
Kang, H., O'Donoghue, M. B., Liu, H. & Tan, W. A liposome-based nanostructure for aptamer directed delivery. Chem. Commun. 46, 249–251 (2010).
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).
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).
Shen, M. et al. Multifunctional drug delivery system for targeting tumor and its acidic microenvironment. J. Control. Release 161, 884–892 (2012).
Binsalamah, Z. M., Paul, A., Prakash, S. & Shum-Tim, D. Nanomedicine in cardiovascular therapy: recent advancements. Expert Rev. Cardiovasc. Ther. 10, 805–815 (2012).
Psarros, C., Lee, R., Margaritis, M. & Antoniades, C. Nanomedicine for the prevention, treatment and imaging of atherosclerosis. Nanomedicine 8 (Suppl. 1), 59–68 (2012).
Peters, D. et al. Targeting atherosclerosis by using modular, multifunctional micelles. Proc. Natl Acad. Sci. USA 106, 9815–9819 (2009).
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).
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).
Mulder, W. J. et al. Molecular imaging of macrophages in atherosclerotic plaques using bimodal PEG-micelles. Magn. Reson. Med. 58, 1164–1170 (2007).
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).
Bowey, K., Tanguay, J. F. & Tabrizian, M. Liposome technology for cardiovascular disease treatment and diagnosis. Expert Opin. Drug Deliv. 9, 249–265 (2012).
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).
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).
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).
McCarthy, J. R. et al. Multifunctional nanoagent for thrombus-targeted fibrinolytic therapy. Nanomed. 7, 1017–1028 (2012).
Mehendale, R., Joshi, M. & Patravale, V. B. Nanomedicines for treatment of viral diseases. Crit. Rev. Ther. Drug Carrier Syst. 30, 1–49 (2013).
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).
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).
Seleem, M. N. et al. Silica-antibiotic hybrid nanoparticles for targeting intracellular pathogens. Antimicrob. Agents Chemother. 53, 4270–4274 (2009).
Xiong, M. H. et al. Bacteria-responsive multifunctional nanogel for targeted antibiotic delivery. Adv. Mater. 24, 6175–6180 (2012).
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).
Lu, Y. & Low, P. S. Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv. Drug Deliv. Rev. 54, 675–693 (2002).
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).
Lee, R. J. & Low, P. S. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim. Biophys. Acta 1233, 134–144 (1995).
Liu, Y. et al. Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand. Anticancer Res. 31, 1521–1525 (2011).
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).
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).
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).
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).
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).
Ito, Y. et al. Disposition of TF-PEG-Liposome-BSH in tumor-bearing mice. Appl. Radiat. Isot. 67, S109–110 (2009).
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).
Kim, S. K. & Huang, L. Nanoparticle delivery of a peptide targeting EGFR signaling. J. Control. Release 157, 279–286 (2012).
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).
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).
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).
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).
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).
Li, S. D., Chono, S. & Huang, L. Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA. Mol. Ther. 16, 942–946 (2008).
Chang, D. K. et al. Antiangiogenic targeting liposomes increase therapeutic efficacy for solid tumors. J. Biol. Chem. 284, 12905–12916 (2009).
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).
Hatakeyama, H. et al. Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes. Int. J. Pharm. 342, 194–200 (2007).
Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nature Mater. 12, 991–1003 (2013).
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).
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).
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).
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).
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).
Farhood, H., Serbina, N. & Huang, L. The role of dioleoyl phosphatidylethanolamine in cationic liposome mediated gene transfer. Biochim. Biophys. Acta 1235, 289–295 (1995).
Sawant, R. R. et al. Polyethyleneimine-lipid conjugate-based pH-sensitive micellar carrier for gene delivery. Biomaterials 33, 3942–3951 (2012).
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).
Sawant, R. M. et al. “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers. Bioconjug Chem. 17, 943–949 (2006).
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).
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).
Schwerdt, A. et al. Hyperthermia-induced targeting of thermosensitive gene carriers to tumors. Hum. Gene Ther. 19, 1283–1292 (2008).
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).
Meers, P. Enzyme-activated targeting of liposomes. Adv. Drug Deliv. Rev. 53, 265–272 (2001).
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).
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).
Zhu, L. et al. Targeted delivery of methotrexate to skeletal muscular tissue by thermosensitive magnetoliposomes. Int. J. Pharm. 370, 136–143 (2009).
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).
Sawant, R. M. et al. Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles. J. Nanoparticle Res. 11, 1777–1785 (2009).
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).
Lee, J. H. et al. Exchange-coupled magnetic nanoparticles for efficient heat induction. Nature Nanotechnol. 6, 418–422 (2011).
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).
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).
Zhu, L. & Mahato, R. I. Targeted delivery of siRNA to hepatocytes and hepatic stellate cells by bioconjugation. Bioconjug Chem. 21, 2119–2127 (2010).
Yudina, A. et al. Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes. J. Control. Release 155, 442–448 (2011).
Kang, H. et al. Near-infrared light-responsive core-shell nanogels for targeted drug delivery. ACS Nano. 5, 5094–5099 (2011).
Chen, J. et al. pH and reduction dual-sensitive copolymeric micelles for intracellular doxorubicin delivery. Biomacromolecules 12, 3601–3611 (2011).
Zhu, L., Kate, P. & Torchilin, V. P. Matrix metalloprotease 2-responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. ACS Nano 6, 3491–3498 (2012).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Galluzzi, L. et al. Mitochondrial gateways to cancer. Mol. Aspects Med. 31, 1–20 (2010).
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).
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).
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).
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).
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).
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).
Wen, S. et al. Multifunctional dendrimer-entrapped gold nanoparticles for dual mode CT/MR imaging applications. Biomaterials 34, 1570–1580 (2013).
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).
Mitchell, N. et al. Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imaging. Biomaterials 34, 1179–1192 (2013).
Mitra, A., Nan, A., Line, B. R. & Ghandehari, H. Nanocarriers for nuclear imaging and radiotherapy of cancer. Curr. Pharm. Des. 12, 4729–4749 (2006).
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).
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).
Torchilin, V. P. Surface-modified liposomes in gamma- and MR-imaging. Adv. Drug Deliv. Rev. 24, 301–313 (1997).
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).
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).
Kenny, G. D. et al. Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain. Biomaterials 34, 9190–9200 (2013).
Lee, P. W. et al. Multifunctional core-shell polymeric nanoparticles for transdermal DNA delivery and epidermal Langerhans cells tracking. Biomaterials 31, 2425–2434 (2010).
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).
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).
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).
Sun, C. et al. Tumor-targeted drug delivery and MRI contrast enhancement by chlorotoxin-conjugated iron oxide nanoparticles. Nanomed. 3, 495–505 (2008).
Yang, L. et al. Receptor-targeted nanoparticles for in vivo imaging of breast cancer. Clin. Cancer Res. 15, 4722–4732 (2009).
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).
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).
Koo, H. et al. In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micelles. Chem. Commun. 46, 5668–5670 (2010).
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).
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).
Deng, L. et al. A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer. Int. J. Nanomed. 7, 5053–5065 (2012).
Koning, G. A. & Krijger, G. C. Targeted multifunctional lipid-based nanocarriers for image-guided drug delivery. Anticancer Agents Med. Chem. 7, 425–440 (2007).
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).
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).
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).
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).
Xiao, W. et al. Co-delivery of doxorubicin and plasmid by a novel FGFR-mediated cationic liposome. Int. J. Pharm. 393, 119–126 (2010).
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).
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).
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).
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).
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).
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).
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).
Bae, Y. H. & Park, K. Targeted drug delivery to tumors: myths, reality and possibility. J. Control. Release 153, 198–205 (2011).
Venditto, V. J. & Szoka, F. C. Jr. Cancer nanomedicines: so many papers and so few drugs! Adv. Drug Deliv. Rev. 65, 80–88 (2013).
Wei, A., Mehtala, J. G. & Patri, A. K. Challenges and opportunities in the advancement of nanomedicines. J. Control. Release 164, 236–246 (2012).
Crommelin, D. J. & Florence, A. T. Towards more effective advanced drug delivery systems. Int. J. Pharm. 454, 496–511 (2013).
Barenholz, Y. Doxil® — the first FDA-approved nano-drug: lessons learned. J. Control. Release 160, 117–134 (2012).
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).
Petre, C. E. & Dittmer, D. P. Liposomal daunorubicin as treatment for Kaposi's sarcoma. Int. J. Nanomed. 2, 277–288 (2007).
Park, J. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 4, 95–99 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
Fantini, M. et al. Lipoplatin treatment in lung and breast cancer. Chemother. Res. Pract. 2011, 125192 (2011).
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).
Stathopoulos, G. P. & Boulikas, T. Lipoplatin formulation review article. J. Drug Deliv. 2012, 581363 (2012).
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).
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).
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).
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).
Staruch, R., Chopra, R. & Hynynen, K. Localised drug release using MRI-controlled focused ultrasound hyperthermia. Int. J. Hyperthermia 27, 156–171 (2011).
Pal, A. et al. Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation. Anticancer Res. 25, 331–341 (2005).
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).
Apostolidou, E., Swords, R., Alvarado, Y. & Giles, F. J. Treatment of acute lymphoblastic leukaemia: a new era. Drugs 67, 2153–2171 (2007).
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).
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).
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).
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).
Kurtoglu, Y. E. et al. Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery. Biomaterials 30, 2112–2121 (2009).
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).
Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).
Pradhan, P. et al. Targeted temperature sensitive magnetic liposomes for thermo-chemotherapy. J. Control Release 142, 108–121 (2010).
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).
Schroeder, A. et al. Ultrasound triggered release of cisplatin from liposomes in murine tumors. J. Control. Release 137, 63–68 (2009).
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).
Liu, D. et al. Conjugation of paclitaxel to iron oxide nanoparticles for tumor imaging and therapy. Nanoscale 4, 2306–2310 (2012).
Zhu, L. & Torchilin, V. P. Stimulus-responsive nanopreparations for tumor targeting. Integr. Biol. 5, 96–107 (2013).
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).
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).
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).
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).
The author acknowledges US National Institutes of Health grant U54CA151881 and tremendous help by T. Levchenko.
The author declares no competing financial interests.
- 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.
The simultaneous use of nanoparticulate pharmaceutical drug delivery systems for therapeutic as well as diagnostic and/or imaging purposes.
About this article
Cite this article
Torchilin, V. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat Rev Drug Discov 13, 813–827 (2014). https://doi.org/10.1038/nrd4333
This article is cited by
Pro-efferocytic macrophage membrane biomimetic nanoparticles for the synergistic treatment of atherosclerosis via competition effect
Journal of Nanobiotechnology (2022)
Journal of Nanobiotechnology (2022)
Journal of Nanobiotechnology (2022)
Nature Reviews Materials (2022)
Journal of Porous Materials (2022)