Skip to main content
SpringerLink
Log in
Book cover

Nano-Oncologicals pp 3–45Cite as

Passive vs. Active Targeting: An Update of the EPR Role in Drug Delivery to Tumors

  • Chapter
  • First Online:

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

A variety of active pharmaceutical ingredients (APIs) currently used for cancer treatment are cytotoxic, and show nonspecific distribution when administered systemically resulting in toxicity to normal tissues, hence limiting their clinical application. To overcome these challenges, nanocarriers such as liposomes and micelles have been widely used to deliver APIs for cancer chemotherapy. Delivery of nanocarriers is achieved either via “passive targeting” owing to the enhanced permeability and retention (EPR) effect or via “active targeting” due to the presence of various ligands on the surface of nanocarriers, such as antibodies, peptides, etc. Numerous factors are involved in successful delivery of chemotherapeutic agents; these depend on the tumor microenvironment, formulation factors such as choice of ligand use, physiochemical properties of the nanocarriers, and the choice of target. In this chapter, we discuss the fundamentals of EPR effect, factors affecting passive and active targeting, and current clinical update of various actively and passively targeted liposomes and micelles.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abra RM, Bankert RB, Chen F, Egilmez NK, Huang K, Saville R, Slater JL, Sugano M, Yokota SJ (2002) The next generation of liposome delivery systems: recent experience with tumor-targeted, sterically-stabilized immunoliposomes and active-loading gradients. J Liposome Res 12:1–3

    PubMed  CAS  Google Scholar 

  • Abuchowski A, Kazo GM, Verhoest CR Jr, Van Es T, Kafkewitz D, Nucci ML, Viau AT, Davis FF (1984) Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates. Cancer Biochem Biophys 7:175–186

    PubMed  CAS  Google Scholar 

  • Acharya S, Dilnawaz F, Sahoo SK (2009) Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy. Biomaterials 30:5737–5750

    PubMed  CAS  Google Scholar 

  • Alexander-Bryant AA, Vanden Berg-Foels WS, Wen X (2013) Bioengineering strategies for designing targeted cancer therapies (chapter one). In: Kenneth DT, Paul BF (eds) Advances in cancer research. Academic, pp 1–59

    Google Scholar 

  • Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 5:505–515

    PubMed  CAS  PubMed Central  Google Scholar 

  • Aliabadi HM, Lavasanifar A (2006) Polymeric micelles for drug delivery. Expert Opin Drug Deliv 3:139–162

    PubMed  CAS  Google Scholar 

  • Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2:750–763

    PubMed  CAS  Google Scholar 

  • Allen TM, Cullis PR (2004) Drug delivery systems: entering the mainstream. Science 303:1818–1822

    PubMed  CAS  Google Scholar 

  • Allen TM, Hansen C, Martin F, Redemann C, Yau-Young A (1991) Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta 1066:29–36

    PubMed  CAS  Google Scholar 

  • Almalik A, Karimi S, Ouasti S, Donno R, Wandrey C, Day PJ, Tirelli N (2013) Hyaluronic acid (HA) presentation as a tool to modulate and control the receptor-mediated uptake of HA-coated nanoparticles. Biomaterials 34:5369–5380

    PubMed  CAS  Google Scholar 

  • Anders CK, Adamo B, Karginova O, Deal AM, Rawal S, Darr D, Schorzman A, Santos C, Bash R, Kafri T, Carey L, Miller CR, Perou CM, Sharpless N, Zamboni WC (2013) Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer. PLoS One 8:e61359

    PubMed  CAS  PubMed Central  Google Scholar 

  • Arvizo RR, Miranda OR, Moyano DF, Walden CA, Giri K, Bhattacharya R, Robertson JD, Rotello VM, Reid JM, Mukherjee P (2011) Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles. PLoS One 6:e24374

    PubMed  CAS  PubMed Central  Google Scholar 

  • Asselin BL (1999) The three asparaginases: comparative pharmacology and optimal use in childhood leukemia. Adv Exp Med Biol 457:621–629

    PubMed  CAS  Google Scholar 

  • Bae YH (2009) Drug targeting and tumor heterogeneity. J Control Release 133:2–3

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bae Y, Nishiyama N, Fukushima S, Koyama H, Yasuhiro M, Kataoka K (2005) Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy. Bioconjug Chem 16:122–130

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME (2007) Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc Natl Acad Sci U S A 104:15549–15554

    PubMed  CAS  PubMed Central  Google Scholar 

  • Baselga J (2006) Targeting tyrosine kinases in cancer: the second wave. Science 312:1175–1178

    PubMed  CAS  Google Scholar 

  • Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L (1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737–744

    PubMed  CAS  Google Scholar 

  • Batist G, Gelmon KA, Chi KN, Miller WH Jr, Chia SK, Mayer LD, Swenson CE, Janoff AS, Louie AC (2009) Safety, pharmacokinetics, and efficacy of CPX-1 liposome injection in patients with advanced solid tumors. Clin Cancer Res 15:692–700

    PubMed  CAS  Google Scholar 

  • Bayne WF, Mayer LD, Swenson CE (2009) Pharmacokinetics of CPX-351 (cytarabine/daunorubicin HCl) liposome injection in the mouse. J Pharm Sci 98:2540–2548

    PubMed  CAS  Google Scholar 

  • Benesch M, Urban C (2008) Liposomal cytarabine for leukemic and lymphomatous meningitis: recent developments. Expert Opin Pharmacother 9:301–309

    PubMed  CAS  Google Scholar 

  • Benhar I, Padlan EA, Jung SH, Lee B, Pastan I (1994) Rapid humanization of the Fv of monoclonal antibody B3 by using framework exchange of the recombinant immunotoxin B3(Fv)-PE38. Proc Natl Acad Sci U S A 91:12051–12055

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bertrand N, Leroux JC (2012) The journey of a drug-carrier in the body: an anatomo-physiological perspective. J Control Release 161:152–163

    PubMed  CAS  Google Scholar 

  • Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC (2014) Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 66:2–25

    PubMed  CAS  Google Scholar 

  • Biswas S, Torchilin VP (2014) Nanopreparations for organelle-specific delivery in cancer. Adv Drug Deliv Rev 66:26–41

    PubMed  CAS  Google Scholar 

  • Bogner JR, Goebel FD (1995) Efficacy of DOX-SL (Stelath liposomal doxorubicin) in the treatment of advanced AIDS-related Kaposi sarcoma. In: Lasic DD, Martin FJ (eds) Stealth liposomes. CRC, Boca Raton, pp 267–278

    Google Scholar 

  • Boomer JA, Qualls MM, Inerowicz HD, Haynes RH, Patri VS, Kim JM, Thompson DH (2009) Cytoplasmic delivery of liposomal contents mediated by an acid-labile cholesterol-vinyl ether-PEG conjugate. Bioconjug Chem 20:47–59

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bukowski R, Ernstoff MS, Gore ME, Nemunaitis JJ, Amato R, Gupta SK, Tendler CL (2002) Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study. J Clin Oncol 20:3841–3849

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Cai LL, Liu P, Li X, Huang X, Ye YQ, Chen FY, Yuan H, Hu FQ, Du YZ (2011) RGD peptide-mediated chitosan-based polymeric micelles targeting delivery for integrin-overexpressing tumor cells. Int J Nanomedicine 6:3499–3508

    PubMed  CAS  PubMed Central  Google Scholar 

  • Campbell RB, Fukumura D, Brown EB, Mazzola LM, Izumi Y, Jain RK, Torchilin VP, Munn LL (2002) Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors. Cancer Res 62:6831–6836

    PubMed  CAS  Google Scholar 

  • Carmeliet P (2005) VEGF as a key mediator of angiogenesis in cancer. Oncology 69(Suppl 3):4–10

    PubMed  CAS  Google Scholar 

  • Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A 89:4285–4289

    PubMed  CAS  PubMed Central  Google Scholar 

  • Chen J, Wu H, Han D, Xie C (2006) Using anti-VEGF McAb and magnetic nanoparticles as double-targeting vector for the radioimmunotherapy of liver cancer. Cancer Lett 231:169–175

    PubMed  CAS  Google Scholar 

  • Chen H, Khemtong C, Yang X, Chang X, Gao J (2011) Nanonization strategies for poorly water-soluble drugs. Drug Discov Today 16:354–360

    PubMed  CAS  Google Scholar 

  • Chen Z, Deng J, Zhao Y, Tao T (2012) Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats. Int J Nanomedicine 7:3803–3811

    PubMed  CAS  PubMed Central  Google Scholar 

  • Chen H, Zhang T, Zhou Z, Guan M, Wang J, Liu L, Zhang Q (2013) Enhanced uptake and cytotoxity of folate-conjugated mitoxantrone-loaded micelles via receptor up-regulation by dexamethasone. Int J Pharm 448:142–149

    PubMed  CAS  Google Scholar 

  • Cheng C, Wei H, Zhu JL, Chang C, Cheng H, Li C, Cheng SX, Zhang XZ, Zhuo RX (2008) Functionalized thermoresponsive micelles self-assembled from biotin-PEG-b-P(NIPAAm-co-HMAAm)-b-PMMA for tumor cell target. Bioconjug Chem 19:1194–1201

    PubMed  CAS  Google Scholar 

  • Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A (2012) Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338:903–910

    PubMed  CAS  PubMed Central  Google Scholar 

  • Cheng W, Ping Y, Zhang Y, Chuang KH, Liu Y (2013) Magnetic resonance imaging (MRI) contrast agents for tumor diagnosis. J Healthc Eng 4:23–45

    PubMed  Google Scholar 

  • Cho K, Wang X, Nie S, Chen ZG, Shin DM (2008) Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 14:1310–1316

    PubMed  CAS  Google Scholar 

  • Chonn A, Cullis PR, Devine DV (1991) The role of surface charge in the activation of the classical and alternative pathways of complement by liposomes. J Immunol 146:4234–4241

    PubMed  CAS  Google Scholar 

  • Cluzel C, Saltel F, Lussi J, Paulhe F, Imhof BA, Wehrle-Haller B (2005) The mechanisms and dynamics of (alpha)v(beta)3 integrin clustering in living cells. J Cell Biol 171:383–392

    PubMed  CAS  PubMed Central  Google Scholar 

  • Croll TI, O’Connor AJ, Stevens GW, Cooper-White JJ (2006) A blank slate? Layer-by-layer deposition of hyaluronic acid and chitosan onto various surfaces. Biomacromolecules 7:1610–1622

    PubMed  CAS  Google Scholar 

  • Danhier F, Vroman B, Lecouturier N, Crokart N, Pourcelle V, Freichels H, Jerome C, Marchand-Brynaert J, Feron O, Preat V (2009) Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles loaded with paclitaxel. J Control Release 140:166–173

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Daniels DA, Chen H, Hicke BJ, Swiderek KM, Gold L (2003) A tenascin-C aptamer identified by tumor cell SELEX: systematic evolution of ligands by exponential enrichment. Proc Natl Acad Sci U S A 100:15416–15421

    PubMed  CAS  PubMed Central  Google Scholar 

  • Davis ME, Chen ZG, Shin DM (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov 7:771–782

    PubMed  CAS  Google Scholar 

  • de Smet M, Heijman E, Langereis S, Hijnen NM, Grull H (2011) Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study. J Control Release 150:102–110

    PubMed  Google Scholar 

  • Deckers R, Moonen CT (2010) Ultrasound triggered, image guided, local drug delivery. J Control Release 148:25–33

    PubMed  CAS  Google Scholar 

  • des Rieux A, Pourcelle V, Cani PD, Marchand-Brynaert J, Preat V (2013) Targeted nanoparticles with novel non-peptidic ligands for oral delivery. Adv Drug Deliv Rev 65:833–844

    PubMed  CAS  Google Scholar 

  • Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22

    PubMed  CAS  Google Scholar 

  • Deshpande PP, Biswas S, Torchilin VP (2013) Current trends in the use of liposomes for tumor targeting. Nanomedicine 8:1509–1528

    PubMed  CAS  Google Scholar 

  • Dienst A, Grunow A, Unruh M, Rabausch B, Nor JE, Fries JW, Gottstein C (2005) Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins. J Natl Cancer Inst 97:733–747

    PubMed  CAS  Google Scholar 

  • Ding HM, Ma YQ (2013) Controlling cellular uptake of nanoparticles with pH-sensitive polymers. Sci Rep 3:2804

    PubMed  PubMed Central  Google Scholar 

  • Dixon KH, Mulligan T, Chung KN, Elwood PC, Cowan KH (1992) Effects of folate receptor expression following stable transfection into wild type and methotrexate transport-deficient ZR-75-1 human breast cancer cells. J Biol Chem 267:24140–24147

    PubMed  CAS  Google Scholar 

  • Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A (2006) Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst 98:335–344

    PubMed  CAS  Google Scholar 

  • Du H, Cui C, Wang L, Liu H, Cui G (2011) Novel tetrapeptide, RGDF, mediated tumor specific liposomal doxorubicin (DOX) preparations. Mol Pharm 8:1224–1232

    PubMed  CAS  Google Scholar 

  • Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347–360

    PubMed  CAS  Google Scholar 

  • Edwards KA, Wang Y, Baeumner AJ (2010) Aptamer sandwich assays: human alpha-thrombin detection using liposome enhancement. Anal Bioanal Chem 398:2645–2654

    PubMed  CAS  Google Scholar 

  • Elbayoumi TA, Pabba S, Roby A, Torchilin VP (2007) Antinucleosome antibody-modified liposomes and lipid-core micelles for tumor-targeted delivery of therapeutic and diagnostic agents. J Liposome Res 17:1–14

    PubMed  CAS  Google Scholar 

  • Elias DR, Poloukhtine A, Popik V, Tsourkas A (2013) Effect of ligand density, receptor density, and nanoparticle size on cell targeting. Nanomedicine 9:194–201

    PubMed  CAS  PubMed Central  Google Scholar 

  • Eliason JF (2006) PEGilated proteins in immunotherapy of cancer. Delivery of protein and peptide drugs in cancer. Imperial College Press, London, pp 111–126

    Google Scholar 

  • Esmaeili F, Ghahremani MH, Ostad SN, Atyabi F, Seyedabadi M, Malekshahi MR, Amini M, Dinarvand R (2008) Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA-PEG-folate conjugate. J Drug Target 16:415–423

    PubMed  CAS  Google Scholar 

  • Fakhari A, Baoum A, Siahaan TJ, Le KB, Berkland C (2011) Controlling ligand surface density optimizes nanoparticle binding to ICAM-1. J Pharm Sci 100:1045–1056

    PubMed  CAS  Google Scholar 

  • Fang X, Tan W (2010) Aptamers generated from cell-SELEX for molecular medicine: a chemical biology approach. Acc Chem Res 43:48–57

    PubMed  CAS  PubMed Central  Google Scholar 

  • Fang J, Nakamura H, Maeda H (2011) The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63:136–151

    PubMed  CAS  Google Scholar 

  • Farokhzad OC, Jon S, Khademhosseini A, Tran TN, Lavan DA, Langer R (2004) Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res 64:7668–7672

    PubMed  CAS  Google Scholar 

  • Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, Richie JP, Langer R (2006a) Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A 103:6315–6320

    PubMed  CAS  PubMed Central  Google Scholar 

  • Farokhzad OC, Karp JM, Langer R (2006b) Nanoparticle-aptamer bioconjugates for cancer targeting. Expert Opin Drug Deliv 3:311–324

    PubMed  CAS  Google Scholar 

  • Florence AT (2012) “Targeting” nanoparticles: the constraints of physical laws and physical barriers. J Control Release 164:115–124

    PubMed  CAS  Google Scholar 

  • Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31

    PubMed  CAS  Google Scholar 

  • Fujimori K, Covell DG, Fletcher JE, Weinstein JN (1989) Modeling analysis of the global and microscopic distribution of immunoglobulin G, F(ab’)2, and Fab in tumors. Cancer Res 49:5656–5663

    PubMed  CAS  Google Scholar 

  • Fujimori K, Covell DG, Fletcher JE, Weinstein JN (1990) A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J Nucl Med 31:1191–1198

    PubMed  CAS  Google Scholar 

  • Gabizon AA (2001) Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest 19:424–436

    PubMed  CAS  Google Scholar 

  • Gabizon A, Papahadjopoulos D (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci U S A 85:6949–6953

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gabizon A, Papahadjopoulos D (1992) The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim Biophys Acta 1103:94–100

    PubMed  CAS  Google Scholar 

  • Gabizon A, Huang A, Martin FJ, Barenholz Y (1995) Doxorubicin encapsulated in polyethylene-glycol coated liposomes: initial clinical pharmacokinetic studies in solid tumors. In: Lasic DD, Martin FJ (eds) Stealth liposomes. CRC, Boca Raton, pp 245–256

    Google Scholar 

  • Gabizon A, Horowitz AT, Goren D, Tzemach D, Shmeeda H, Zalipsky S (2003) In vivo fate of folate-targeted polyethylene-glycol liposomes in tumor-bearing mice. Clin Cancer Res 9:6551–6559

    PubMed  CAS  Google Scholar 

  • Gao Z, Lukyanov AN, Chakilam AR, Torchilin VP (2003) PEG-PE/phosphatidylcholine mixed immunomicelles specifically deliver encapsulated taxol to tumor cells of different origin and promote their efficient killing. J Drug Target 11:87–92

    PubMed  CAS  Google Scholar 

  • Gao ZG, Lee DH, Kim DI, Bae YH (2005) Doxorubicin loaded pH-sensitive micelle targeting acidic extracellular pH of human ovarian A2780 tumor in mice. J Drug Target 13:391–397

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gao H, Yang Z, Zhang S, Cao S, Shen S, Pang Z, Jiang X (2013) Ligand modified nanoparticles increases cell uptake, alters endocytosis and elevates glioma distribution and internalization. Sci Rep 3:2534

    PubMed  PubMed Central  Google Scholar 

  • Garg A, Tisdale AW, Haidari E, Kokkoli E (2009) Targeting colon cancer cells using PEGylated liposomes modified with a fibronectin-mimetic peptide. Int J Pharm 366:201–210

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gaviani P, Corsini E, Salmaggi A, Lamperti E, Botturi A, Erbetta A, Milanesi I, Legnani F, Pollo B, Silvani A (2013) Liposomal cytarabine in neoplastic meningitis from primary brain tumors: a single institutional experience. Neurol Sci 34:2151–2157

    PubMed  CAS  Google Scholar 

  • Ghandehari H, Sharan R, Rubas W, Killing WM (2001) Molecular modeling of arginine-glycine-aspartic acid (RGD) analogs: relevance to transepithelial transport. J Pharm Pharm Sci 4:32–41

    PubMed  CAS  Google Scholar 

  • Goodwill PW, Saritas EU, Croft LR, Kim TN, Krishnan KM, Schaffer DV, Conolly SM (2012) X-space MPI: magnetic nanoparticles for safe medical imaging. Adv Mater 24:3870–3877

    PubMed  CAS  Google Scholar 

  • Greish K (2007) Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J Drug Target 15:457–464

    PubMed  CAS  Google Scholar 

  • Gu F, Zhang L, Teply BA, Mann N, Wang A, Radovic-Moreno AF, Langer R, Farokhzad OC (2008) Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc Natl Acad Sci U S A 105:2586–2591

    PubMed  CAS  PubMed Central  Google Scholar 

  • Guida V (2010) Thermodynamics and kinetics of vesicles formation processes. Adv Colloid Interface Sci 161:77–88

    PubMed  CAS  Google Scholar 

  • Guo X, Szoka FC Jr (2001) Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG–diortho ester–lipid conjugate. Bioconjug Chem 12:291–300

    PubMed  CAS  Google Scholar 

  • Hafez IM, Maurer N, Cullis PR (2001) On the mechanism whereby cationic lipids promote intracellular delivery of polynucleic acids. Gene Ther 8:1188–1196

    PubMed  CAS  Google Scholar 

  • Hakem IF, Leech AM, Johnson JD, Donahue SJ, Walker JP, Bockstaller MR (2010) Understanding ligand distributions in modified particle and particlelike systems. J Am Chem Soc 132:16593–16598

    PubMed  CAS  Google Scholar 

  • Hamaguchi T, Matsumura Y, Suzuki M, Shimizu K, Goda R, Nakamura I, Nakatomi I, Yokoyama M, Kataoka K, Kakizoe T (2005) NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel. Br J Cancer 92:1240–1246

    PubMed  CAS  PubMed Central  Google Scholar 

  • Han HS, Martin JD, Lee J, Harris DK, Fukumura D, Jain RK, Bawendi M (2013) Spatial charge configuration regulates nanoparticle transport and binding behavior in vivo. Angew Chem Int Ed Engl 52:1414–1419

    PubMed  CAS  PubMed Central  Google Scholar 

  • Harding JA, Engbers CM, Newman MS, Goldstein NI, Zalipsky S (1997) Immunogenicity and pharmacokinetic attributes of poly(ethylene glycol)-grafted immunoliposomes. Biochim Biophys Acta 1327:181–192

    PubMed  CAS  Google Scholar 

  • Hatakeyama H, Akita H, Ishida E, Hashimoto K, Kobayashi H, Aoki T, Yasuda J, Obata K, Kikuchi H, Ishida T, Kiwada H, Harashima H (2007) Tumor targeting of doxorubicin by anti-MT1-MMP antibody-modified PEG liposomes. Int J Pharm 342:194–200

    PubMed  CAS  Google Scholar 

  • He C, Hu Y, Yin L, Tang C, Yin C (2010) Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31:3657–3666

    PubMed  CAS  Google Scholar 

  • Heath TD, Fraley RT, Papahdjopoulos D (1980) Antibody targeting of liposomes: cell specificity obtained by conjugation of F(ab’)2 to vesicle surface. Science 210:539–541

    PubMed  CAS  Google Scholar 

  • Hein CD, Liu XM, Wang D (2008) Click chemistry, a powerful tool for pharmaceutical sciences. Pharm Res 25:2216–2230

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hilger I, Kaiser WA (2012) Iron oxide-based nanostructures for MRI and magnetic hyperthermia. Nanomedicine 7:1443–1459

    PubMed  CAS  Google Scholar 

  • Ho EA, Ramsay E, Ginj M, Anantha M, Bregman I, Sy J, Woo J, Osooly-Talesh M, Yapp DT, Bally MB (2010) Characterization of cationic liposome formulations designed to exhibit extended plasma residence times and tumor vasculature targeting properties. J Pharm Sci 99:2839–2853

    PubMed  CAS  Google Scholar 

  • Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 95:4607–4612

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580

    PubMed  CAS  Google Scholar 

  • Hofheinz RD, Gnad-Vogt SU, Beyer U, Hochhaus A (2005) Liposomal encapsulated anti-cancer drugs. Anticancer Drugs 16:691–707

    PubMed  CAS  Google Scholar 

  • Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404–2407

    PubMed  CAS  Google Scholar 

  • Hosokawa S, Tagawa T, Niki H, Hirakawa Y, Nohga K, Nagaike K (2003) Efficacy of immunoliposomes on cancer models in a cell-surface-antigen-density-dependent manner. Br J Cancer 89:1545–1551

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hu Z, Luo F, Pan Y, Hou C, Ren L, Chen J, Wang J, Zhang Y (2008) Arg-Gly-Asp (RGD) peptide conjugated poly(lactic acid)-poly(ethylene oxide) micelle for targeted drug delivery. J Biomed Mater Res A 85:797–807

    PubMed  Google Scholar 

  • Huang SK, Mayhew E, Gilani S, Lasic DD, Martin FJ, Papahadjopoulos D (1992) Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma. Cancer Res 52:6774–6781

    PubMed  CAS  Google Scholar 

  • Huang SK, Stauffer PR, Hong K, Guo JW, Phillips TL, Huang A, Papahadjopoulos D (1994) Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes. Cancer Res 54:2186–2191

    PubMed  CAS  Google Scholar 

  • Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ (2005) Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res 65:8984–8992

    PubMed  CAS  Google Scholar 

  • Ignjatovic T, Stanisavljevic S, Brovkovych V, Skidgel RA, Erdos EG (2004) Kinin B1 receptors stimulate nitric oxide production in endothelial cells: signaling pathways activated by angiotensin I-converting enzyme inhibitors and peptide ligands. Mol Pharmacol 66:1310–1316

    PubMed  CAS  Google Scholar 

  • Ishida T, Iden DL, Allen TM (1999) A combinatorial approach to producing sterically stabilized (Stealth) immunoliposomal drugs. FEBS Lett 460:129–133

    PubMed  CAS  Google Scholar 

  • Iyer AK, Khaled G, Fang J, Maeda H (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11:812–818

    PubMed  CAS  Google Scholar 

  • Jain RK (1989) Delivery of novel therapeutic agents in tumors: physiological barriers and strategies. J Natl Cancer Inst 81:570–576

    PubMed  CAS  Google Scholar 

  • Jain RK (1994) Barriers to drug delivery in solid tumors. Sci Am 271:58–65

    PubMed  CAS  Google Scholar 

  • Jain RK (1999) Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng 1:241–263

    PubMed  CAS  Google Scholar 

  • Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7:653–664

    PubMed  CAS  PubMed Central  Google Scholar 

  • Jiang W, Kim BY, Rutka JT, Chan WC (2008) Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol 3:145–150

    PubMed  CAS  Google Scholar 

  • Jones M, Leroux J (1999) Polymeric micelles – a new generation of colloidal drug carriers. Eur J Pharm Biopharm 48:101–111

    PubMed  CAS  Google Scholar 

  • Juweid M, Neumann R, Paik C, Perez-Bacete MJ, Sato J, van Osdol W, Weinstein JN (1992) Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier. Cancer Res 52:5144–5153

    PubMed  CAS  Google Scholar 

  • Kagaya H, Oba M, Miura Y, Koyama H, Ishii T, Shimada T, Takato T, Kataoka K, Miyata T (2012) Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions. Gene Ther 19:61–69

    PubMed  CAS  Google Scholar 

  • Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC (2012) Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev 41:2971–3010

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kang N, Perron ME, Prud’homme RE, Zhang Y, Gaucher G, Leroux JC (2005) Stereocomplex block copolymer micelles: core-shell nanostructures with enhanced stability. Nano Lett 5:315–319

    PubMed  CAS  Google Scholar 

  • Kang H, O’Donoghue MB, Liu H, Tan W (2010) A liposome-based nanostructure for aptamer directed delivery. Chem Commun 46:249–251

    CAS  Google Scholar 

  • Kang DI, Lee S, Lee JT, Sung BJ, Yoon JY, Kim JK, Chung J, Lim SJ (2011) Preparation and in vitro evaluation of anti-VCAM-1-Fab’-conjugated liposomes for the targeted delivery of the poorly water-soluble drug celecoxib. J Microencapsul 28:220–227

    PubMed  CAS  Google Scholar 

  • Kaufmann R, Muller P, Hildenbrand G, Hausmann M, Cremer C (2011) Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy. J Microsc 242:46–54

    PubMed  CAS  Google Scholar 

  • Kim ES, Lu C, Khuri FR, Tonda M, Glisson BS, Liu D, Jung M, Hong WK, Herbst RS (2001) A phase II study of STEALTH cisplatin (SPI-77) in patients with advanced non-small cell lung cancer. Lung Cancer 34:427–432

    PubMed  CAS  Google Scholar 

  • Kim SH, Jeong JH, Chun KW, Park TG (2005) Target-specific cellular uptake of PLGA nanoparticles coated with poly(l-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 21:8852–8857

    PubMed  CAS  Google Scholar 

  • Kim K, Kim JH, Park H, Kim YS, Park K, Nam H, Lee S, Park JH, Park RW, Kim IS, Choi K, Kim SY, Park K, Kwon IC (2010) Tumor-homing multifunctional nanoparticles for cancer theragnosis: simultaneous diagnosis, drug delivery, and therapeutic monitoring. J Control Release 146:219–227

    PubMed  CAS  Google Scholar 

  • Kirpotin DB, Drummond DC, Shao Y, Shalaby MR, Hong K, Nielsen UB, Marks JD, Benz CC, Park JW (2006) Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res 66:6732–6740

    PubMed  CAS  Google Scholar 

  • Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235–237

    PubMed  CAS  Google Scholar 

  • Knudsen NO, Schiffelers RM, Jorgensen L, Hansen J, Frokjaer S, Foged C (2012) Design of cyclic RKKH peptide-conjugated PEG liposomes targeting the integrin alpha(2)beta(1) receptor. Int J Pharm 428:171–177

    PubMed  CAS  Google Scholar 

  • Kondo M, Asai T, Katanasaka Y, Sadzuka Y, Tsukada H, Ogino K, Taki T, Baba K, Oku N (2004) Anti-neovascular therapy by liposomal drug targeted to membrane type-1 matrix metalloproteinase. Int J Cancer 108:301–306

    PubMed  CAS  Google Scholar 

  • Kopecek J, Kopeckova P, Minko T, Lu Z (2000) HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action. Eur J Pharm Biopharm 50:61–81

    PubMed  CAS  Google Scholar 

  • Kopecek J, Kopeckova P, Minko T, Lu ZR, Peterson CM (2001) Water soluble polymers in tumor targeted delivery. J Control Release 74:147–158

    PubMed  CAS  Google Scholar 

  • Koshkaryev A, Sawant R, Deshpande M, Torchilin V (2013) Immunoconjugates and long circulating systems: origins, current state of the art and future directions. Adv Drug Deliv Rev 65:24–35

    PubMed  CAS  PubMed Central  Google Scholar 

  • Koss M, Pfeiffer GR 2nd, Wang Y, Thomas ST, Yerukhimovich M, Gaarde WA, Doerschuk CM, Wang Q (2006) Ezrin/radixin/moesin proteins are phosphorylated by TNF-alpha and modulate permeability increases in human pulmonary microvascular endothelial cells. J Immunol 176:1218–1227

    PubMed  CAS  Google Scholar 

  • Krasnici S, Werner A, Eichhorn ME, Schmitt-Sody M, Pahernik SA, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M (2003) Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels. Int J Cancer 105:561–567

    PubMed  CAS  Google Scholar 

  • Kripp M, Hofheinz RD (2008) Treatment of lymphomatous and leukemic meningitis with liposomal encapsulated cytarabine. Int J Nanomedicine 3:397–401

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lam KS, Salmon SE, Hersh EM, Hruby VJ, Kazmierski WM, Knapp RJ (1991) A new type of synthetic peptide library for identifying ligand-binding activity. Nature 354:82–84

    PubMed  CAS  Google Scholar 

  • Lammers T, Hennink WE, Storm G (2008) Tumour-targeted nanomedicines: principles and practice. Br J Cancer 99:392–397

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lammers T, Kiessling F, Hennink WE, Storm G (2012) Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release 161:175–187

    PubMed  CAS  Google Scholar 

  • Lao J, Madani J, Puertolas T, Alvarez M, Hernandez A, Pazo-Cid R, Artal A, Anton Torres A (2013) Liposomal Doxorubicin in the treatment of breast cancer patients: a review. J Drug Deliv 2013:456409

    PubMed  PubMed Central  Google Scholar 

  • Lapointe J, Truong TQ, Falstrault L, Brissette L (2006) Differential abilities of mouse liver parenchymal and nonparenchymal cells in HDL and LDL (native and oxidized) association and cholesterol efflux. Biochem Cell Biol 84:250–256

    PubMed  CAS  Google Scholar 

  • Lasic DD, Martin FJ, Gabizon A, Huang SK, Papahadjopoulos D (1991) Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta 1070:187–192

    PubMed  CAS  Google Scholar 

  • Lavasanifar A, Samuel J, Kwon GS (2002) The effect of fatty acid substitution on the in vitro release of amphotericin B from micelles composed of poly(ethylene oxide)-block-poly(N-hexyl stearate-l-aspartamide). J Control Release 79:165–172

    PubMed  CAS  Google Scholar 

  • Lee KS, Chung HC, Im SA, Park YH, Kim CS, Kim SB, Rha SY, Lee MY, Ro J (2008) Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res Treat 108:241–250

    PubMed  CAS  Google Scholar 

  • Leserman LD, Barbet J, Kourilsky F, Weinstein JN (1980) Targeting to cells of fluorescent liposomes covalently coupled with monoclonal antibody or protein A. Nature 288:602–604

    PubMed  CAS  Google Scholar 

  • Levchenko TS, Rammohan R, Lukyanov AN, Whiteman KR, Torchilin VP (2002) Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating. Int J Pharm 240:95–102

    PubMed  CAS  Google Scholar 

  • Li L, Wartchow CA, Danthi SN, Shen Z, Dechene N, Pease J, Choi HS, Doede T, Chu P, Ning S, Lee DY, Bednarski MD, Knox SJ (2004) A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles. Int J Radiat Oncol Biol Phys 58:1215–1227

    PubMed  CAS  Google Scholar 

  • Li W, Huang Z, MacKay JA, Grube S, Szoka FC Jr (2005) Low-pH-sensitive poly(ethylene glycol) (PEG)-stabilized plasmid nanolipoparticles: effects of PEG chain length, lipid composition and assembly conditions on gene delivery. J Gene Med 7:67–79

    PubMed  Google Scholar 

  • Liang B, He ML, Chan CY, Chen YC, Li XP, Li Y, Zheng D, Lin MC, Kung HF, Shuai XT, Peng Y (2009) The use of folate-PEG-grafted-hybranched-PEI nonviral vector for the inhibition of glioma growth in the rat. Biomaterials 30:4014–4020

    PubMed  CAS  Google Scholar 

  • Liechty WB, Peppas NA (2012) Expert opinion: responsive polymer nanoparticles in cancer therapy. Eur J Pharm Biopharm 80:241–246

    PubMed  CAS  PubMed Central  Google Scholar 

  • Liu J, Weller GE, Zern B, Ayyaswamy PS, Eckmann DM, Muzykantov VR, Radhakrishnan R (2010a) Computational model for nanocarrier binding to endothelium validated using in vivo, in vitro, and atomic force microscopy experiments. Proc Natl Acad Sci U S A 107: 16530–16535

    PubMed  CAS  PubMed Central  Google Scholar 

  • Liu AP, Aguet F, Danuser G, Schmid SL (2010b) Local clustering of transferrin receptors promotes clathrin-coated pit initiation. J Cell Biol 191:1381–1393

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lord MS, Pasqui D, Barbucci R, Milthorpe BK (2009) Protein adsorption on derivatives of hyaluronic acid and subsequent cellular response. J Biomed Mater Res A 91:635–646

    PubMed  Google Scholar 

  • Low PS, Kularatne SA (2009) Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol 13:256–262

    PubMed  CAS  Google Scholar 

  • Lukyanov AN, Gao Z, Mazzola L, Torchilin VP (2002) Polyethylene glycol-diacyllipid micelles demonstrate increased accumulation in subcutaneous tumors in mice. Pharm Res 19:1424–1429

    PubMed  CAS  Google Scholar 

  • Luo Y, Prestwich GD (2002) Cancer-targeted polymeric drugs. Curr Cancer Drug Targets 2:209–226

    PubMed  CAS  Google Scholar 

  • Lurje G, Lenz HJ (2009) EGFR signaling and drug discovery. Oncology 77:400–410

    PubMed  CAS  Google Scholar 

  • Maeda H (2012) Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 164:138–144

    PubMed  CAS  Google Scholar 

  • Maeda H, Matsumura Y (1989) Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst 6:193–210

    PubMed  CAS  Google Scholar 

  • Maeda H, Yamamoto T (1996) Pathogenic mechanisms induced by microbial proteases in microbial infections. Biol Chem Hoppe Seyler 377:217–226

    PubMed  CAS  Google Scholar 

  • Maeda H, Takeshita J, Kanamaru R (1979) A lipophilic derivative of neocarzinostatin. A polymer conjugation of an antitumor protein antibiotic. Int J Pept Protein Res 14:81–87

    PubMed  CAS  Google Scholar 

  • Maeda H, Matsumura Y, Kato H (1988) Purification and identification of [hydroxyprolyl3]bradykinin in ascitic fluid from a patient with gastric cancer. J Biol Chem 263:16051–16054

    PubMed  CAS  Google Scholar 

  • Maeda H, Fang J, Inutsuka T, Kitamoto Y (2003) Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol 3: 319–328

    PubMed  CAS  Google Scholar 

  • Maeda H, Bharate GY, Daruwalla J (2009) Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur J Pharm Biopharm 71:409–419

    PubMed  CAS  Google Scholar 

  • Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev 65:71–79

    PubMed  CAS  Google Scholar 

  • Mamot C, Drummond DC, Noble CO, Kallab V, Guo Z, Hong K, Kirpotin DB, Park JW (2005) Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo. Cancer Res 65:11631–11638

    PubMed  CAS  Google Scholar 

  • Mamot C, Ritschard R, Wicki A, Stehle G, Dieterle T, Bubendorf L, Hilker C, Deuster S, Herrmann R, Rochlitz C (2012) Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study. Lancet Oncol 13:1234–1241

    PubMed  CAS  Google Scholar 

  • Managit C, Kawakami S, Nishikawa M, Yamashita F, Hashida M (2003) Targeted and sustained drug delivery using PEGylated galactosylated liposomes. Int J Pharm 266:77–84

    PubMed  CAS  Google Scholar 

  • Martin A (1993) Physical pharmacy. Lippincott Williams and Wilkins, Philadelphia

    Google Scholar 

  • Matsumura Y (2011) Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect. Adv Drug Deliv Rev 63:184–192

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Matsumura Y, Oda T, Maeda H (1987) General mechanism of intratumor accumulation of macromolecules: advantage of macromolecular therapeutics. Gan To Kagaku Ryoho 14:821–829

    Google Scholar 

  • Matsumura Y, Kimura M, Yamamoto T, Maeda H (1988) Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn J Cancer Res 79:1327–1334

    PubMed  CAS  Google Scholar 

  • Matsumura Y, Maruo K, Kimura M, Yamamoto T, Konno T, Maeda H (1991) Kinin-generating cascade in advanced cancer patients and in vitro study. Jpn J Cancer Res 82:732–741

    PubMed  CAS  Google Scholar 

  • Matsumura Y, Hamaguchi T, Ura T, Muro K, Yamada Y, Shimada Y, Shirao K, Okusaka T, Ueno H, Ikeda M, Watanabe N (2004a) Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin. Br J Cancer 91:1775–1781

    PubMed  CAS  PubMed Central  Google Scholar 

  • Matsumura Y, Gotoh M, Muro K, Yamada Y, Shirao K, Shimada Y, Okuwa M, Matsumoto S, Miyata Y, Ohkura H, Chin K, Baba S, Yamao T, Kannami A, Takamatsu Y, Ito K, Takahashi K (2004b) Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer. Ann Oncol 15:517–525

    PubMed  CAS  Google Scholar 

  • Mayer LD, Harasym TO, Tardi PG, Harasym NL, Shew CR, Johnstone SA, Ramsay EC, Bally MB, Janoff AS (2006) Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol Cancer Ther 5:1854–1863

    PubMed  CAS  Google Scholar 

  • McGuire MJ, Li S, Brown KC (2009) Biopanning of phage displayed peptide libraries for the isolation of cell-specific ligands. Methods Mol Biol 504:291–321

    PubMed  CAS  PubMed Central  Google Scholar 

  • Meng H, Xue M, Xia T, Ji Z, Tarn DY, Zink JI, Nel AE (2011) Use of size and a copolymer design feature to improve the biodistribution and the enhanced permeability and retention effect of doxorubicin-loaded mesoporous silica nanoparticles in a murine xenograft tumor model. ACS Nano 5:4131–4144

    PubMed  CAS  PubMed Central  Google Scholar 

  • Metselaar JM, Bruin P, de Boer LW, de Vringer T, Snel C, Oussoren C, Wauben MH, Crommelin DJ, Storm G, Hennink WE (2003) A novel family of l-amino acid-based biodegradable polymer-lipid conjugates for the development of long-circulating liposomes with effective drug-targeting capacity. Bioconjug Chem 14:1156–1164

    PubMed  CAS  Google Scholar 

  • Millard M, Odde S, Neamati N (2011) Integrin targeted therapeutics. Theranostics 1:154–188

    PubMed  CAS  PubMed Central  Google Scholar 

  • Minko T (2004) Drug targeting to the colon with lectins and neoglycoconjugates. Adv Drug Deliv Rev 56:491–509

    PubMed  CAS  Google Scholar 

  • Modi S, Prakash Jain J, Domb AJ, Kumar N (2006) Exploiting EPR in polymer drug conjugate delivery for tumor targeting. Curr Pharm Des 12:4785–4796

    PubMed  CAS  Google Scholar 

  • Moein Moghimi S, Hamad I, Bunger R, Andresen TL, Jorgensen K, Hunter AC, Baranji L, Rosivall L, Szebeni J (2006) Activation of the human complement system by cholesterol-rich and PEGylated liposomes-modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels. J Liposome Res 16:167–174

    PubMed  CAS  Google Scholar 

  • Monopoli MP, Aberg C, Salvati A, Dawson KA (2012) Biomolecular coronas provide the biological identity of nanosized materials. Nat Nanotechnol 7:779–786

    PubMed  CAS  Google Scholar 

  • Montana M, Ducros C, Verhaeghe P, Terme T, Vanelle P, Rathelot P (2011) Albumin-bound paclitaxel: the benefit of this new formulation in the treatment of various cancers. J Chemother 23:59–66

    PubMed  CAS  Google Scholar 

  • Moreira da Silva L, Moreira da Silva L (1975) Prognosis of neurotic patients under ambulatory care. Arq Neuropsiquiatr 33:376–381

    Google Scholar 

  • Mu L, Elbayoumi TA, Torchilin VP (2005) Mixed micelles made of poly(ethylene glycol)-phosphatidylethanolamine conjugate and d-alpha-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin. Int J Pharm 306:142–149

    PubMed  CAS  PubMed Central  Google Scholar 

  • Murphy EA, Majeti BK, Barnes LA, Makale M, Weis SM, Lutu-Fuga K, Wrasidlo W, Cheresh DA (2008) Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proc Natl Acad Sci U S A 105:9343–9348

    PubMed  CAS  PubMed Central  Google Scholar 

  • Musacchio T, Torchilin VP (2009) Lipid-based delivery systems: liposomes and lipid-core micelles—properties and applications. Biodrug delivery systems: fundamentals, applications, and clinical development. Informa Healthcare, pp 260–292

    Google Scholar 

  • Nair KL, Jagadeeshan S, Nair SA, Kumar GS (2013) Folic acid conjugated delta-valerolactone-poly(ethylene glycol) based triblock copolymer as a promising carrier for targeted doxorubicin delivery. PLoS One 8:e70697

    Google Scholar 

  • Nakamura K, Yamashita K, Itoh Y, Yoshino K, Nozawa S, Kasukawa H (2012) Comparative studies of polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochim Biophys Acta 1818:2801–2807

    PubMed  CAS  Google Scholar 

  • Napper DH (1983) Polymeric stabilization of colloidal dispersions. Academic, London/New York

    Google Scholar 

  • Nasongkla N, Shuai X, Ai H, Weinberg BD, Pink J, Boothman DA, Gao J (2004) cRGD-functionalized polymer micelles for targeted doxorubicin delivery. Angew Chem Int Ed Engl 43:6323–6327

    PubMed  CAS  Google Scholar 

  • Needels MC, Jones DG, Tate EH, Heinkel GL, Kochersperger LM, Dower WJ, Barrett RW, Gallop MA (1993) Generation and screening of an oligonucleotide-encoded synthetic peptide library. Proc Natl Acad Sci U S A 90:10700–10704

    PubMed  CAS  PubMed Central  Google Scholar 

  • Needham D, McIntosh TJ, Lasic DD (1992) Repulsive interactions and mechanical stability of polymer-grafted lipid membranes. Biochim Biophys Acta 1108:40–48

    PubMed  CAS  Google Scholar 

  • Negussie AH, Yarmolenko PS, Partanen A, Ranjan A, Jacobs G, Woods D, Bryant H, Thomasson D, Dewhirst MW, Wood BJ, Dreher MR (2011) Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound. Int J Hyperthermia 27:140–155

    PubMed  CAS  PubMed Central  Google Scholar 

  • Nishida K, Mihara K, Takino T, Nakane S, Takakura Y, Hashida M, Sezaki H (1991) Hepatic disposition characteristics of electrically charged macromolecules in rat in vivo and in the perfused liver. Pharm Res 8:437–444

    PubMed  CAS  Google Scholar 

  • O’Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C, Group CBCS (2004) Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15:440–449

    PubMed  Google Scholar 

  • Ohannesian DW, Lotan D, Thomas P, Jessup JM, Fukuda M, Gabius HJ, Lotan R (1995) Carcinoembryonic antigen and other glycoconjugates act as ligands for galectin-3 in human colon carcinoma cells. Cancer Res 55:2191–2199

    PubMed  CAS  Google Scholar 

  • Okamoto T, Akaike T, Nagano T, Miyajima S, Suga M, Ando M, Ichimori K, Maeda H (1997) Activation of human neutrophil procollagenase by nitrogen dioxide and peroxynitrite: a novel mechanism for procollagenase activation involving nitric oxide. Arch Biochem Biophys 342:261–274

    PubMed  CAS  Google Scholar 

  • Orlova A, Magnusson M, Eriksson TL, Nilsson M, Larsson B, Hoiden-Guthenberg I, Widstrom C, Carlsson J, Tolmachev V, Stahl S, Nilsson FY (2006) Tumor imaging using a picomolar affinity HER2 binding affibody molecule. Cancer Res 66:4339–4348

    PubMed  CAS  Google Scholar 

  • Park BW, Zhang HT, Wu C, Berezov A, Zhang X, Dua R, Wang Q, Kao G, O’Rourke DM, Greene MI, Murali R (2000) Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo. Nat Biotechnol 18:194–198

    PubMed  CAS  Google Scholar 

  • Park JW, Kirpotin DB, Hong K, Shalaby R, Shao Y, Nielsen UB, Marks JD, Papahadjopoulos D, Benz CC (2001) Tumor targeting using anti-her2 immunoliposomes. J Control Release 74:95–113

    PubMed  CAS  Google Scholar 

  • Park JW, Hong K, Kirpotin DB, Colbern G, Shalaby R, Baselga J, Shao Y, Nielsen UB, Marks JD, Moore D, Papahadjopoulos D, Benz CC (2002) Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery. Clin Cancer Res 8:1172–1181

    PubMed  CAS  Google Scholar 

  • Pasqualini R, Ruoslahti E (1996) Organ targeting in vivo using phage display peptide libraries. Nature 380:364–366

    PubMed  CAS  Google Scholar 

  • Pastorino F, Brignole C, Marimpietri D, Cilli M, Gambini C, Ribatti D, Longhi R, Allen TM, Corti A, Ponzoni M (2003) Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Res 63:7400–7409

    PubMed  CAS  Google Scholar 

  • Pauwels EK, Erba P (2007) Towards the use of nanoparticles in cancer therapy and imaging. Drug News Perspect 20:213–220

    PubMed  CAS  Google Scholar 

  • Peer D, Margalit R (2004a) Tumor-targeted hyaluronan nanoliposomes increase the antitumor activity of liposomal doxorubicin in syngeneic and human xenograft mouse tumor models. Neoplasia 6:343–353

    PubMed  CAS  PubMed Central  Google Scholar 

  • Peer D, Margalit R (2004b) Loading mitomycin C inside long circulating hyaluronan targeted nano-liposomes increases its antitumor activity in three mice tumor models. Int J Cancer 108:780–789

    PubMed  CAS  Google Scholar 

  • Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2:751–760

    PubMed  CAS  Google Scholar 

  • Perche F, Torchilin VP (2013) Recent trends in multifunctional liposomal nanocarriers for enhanced tumor targeting. J Drug Deliv 2013:705265

    PubMed  PubMed Central  Google Scholar 

  • Perez AT, Domenech GH, Frankel C, Vogel CL (2002) Pegylated liposomal doxorubicin (Doxil) for metastatic breast cancer: the Cancer Research Network, Inc., experience. Cancer Invest 20(Suppl 2):22–29

    PubMed  CAS  Google Scholar 

  • Peterson CM, Shiah JG, Sun Y, Kopeckova P, Minko T, Straight RC, Kopecek J (2003) HPMA copolymer delivery of chemotherapy and photodynamic therapy in ovarian cancer. Adv Exp Med Biol 519:101–123

    PubMed  CAS  Google Scholar 

  • Pourbaghi-Masouleh M, Hosseini V (2013) Amorphous calcium phosphate nanoparticles could function as a novel cancer therapeutic agent by employing a suitable targeted drug delivery platform. Nanoscale Res Lett 8:449

    PubMed  PubMed Central  Google Scholar 

  • Roby A, Erdogan S, Torchilin VP (2006) Solubilization of poorly soluble PDT agent, meso-tetraphenylporphin, in plain or immunotargeted PEG-PE micelles results in dramatically improved cancer cell killing in vitro. Eur J Pharm Biopharm 62:235–240

    PubMed  CAS  PubMed Central  Google Scholar 

  • Roux E, Lafleur M, Lataste E, Moreau P, Leroux JC (2003) On the characterization of pH-sensitive liposome/polymer complexes. Biomacromolecules 4:240–248

    PubMed  CAS  Google Scholar 

  • Rudnick SI, Adams GP (2009) Affinity and avidity in antibody-based tumor targeting. Cancer Biother Radiopharm 24:155–161

    PubMed  CAS  PubMed Central  Google Scholar 

  • Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A (2000) Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11:1029–1033

    PubMed  CAS  Google Scholar 

  • Sahoo SK, Ma W, Labhasetwar V (2004) Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 112:335–340

    PubMed  CAS  Google Scholar 

  • Salmaso S, Pappalardo JS, Sawant RR, Musacchio T, Rockwell K, Caliceti P, Torchilin VP (2009) Targeting glioma cells in vitro with ascorbate-conjugated pharmaceutical nanocarriers. Bioconjug Chem 20:2348–2355

    PubMed  CAS  Google Scholar 

  • Salvador-Morales C, Zhang L, Langer R, Farokhzad OC (2009) Immunocompatibility properties of lipid-polymer hybrid nanoparticles with heterogeneous surface functional groups. Biomaterials 30:2231–2240

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sawant RR, Torchilin VP (2012a) Multifunctional nanocarriers and intracellular drug delivery. Curr Opin Solid State Mater Sci 16:269–275

    CAS  Google Scholar 

  • Sawant RR, Torchilin VP (2012b) Challenges in development of targeted liposomal therapeutics. AAPS J 14:303–315

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sawant RR, Sawant RM, Torchilin VP (2008) Mixed PEG-PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: improved drug solubilization and enhanced in vitro cytotoxicity. Eur J Pharm Biopharm 70:51–57

    PubMed  CAS  PubMed Central  Google Scholar 

  • Scaltriti M, Baselga J (2006) The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res 12:5268–5272

    PubMed  CAS  Google Scholar 

  • Scherphof GL, Kamps JA (2001) The role of hepatocytes in the clearance of liposomes from the blood circulation. Prog Lipid Res 40:149–166

    PubMed  CAS  Google Scholar 

  • Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M, Michaelis U, Naujoks K, Dellian M (2003) Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy. Clin Cancer Res 9:2335–2341

    PubMed  CAS  Google Scholar 

  • Seki T, Fang J, Maeda H (2009) Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application. Cancer Sci 100:2426–2430

    PubMed  CAS  Google Scholar 

  • Seki T, Carroll F, Illingworth S, Green N, Cawood R, Bachtarzi H, Subr V, Fisher KD, Seymour LW (2011) Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway. J Control Release 156:381–389

    PubMed  CAS  Google Scholar 

  • Senzer NN, Matsuno K, Yamagata N, Fujisawa T, Wasserman E, Sutherland W, Sharma S, Phan A (2009) MBP-426, a novel liposome-encapsulated oxaliplatin, in combination with 5-FU/leucovorin (LV): phase I results of a phase I/II study in gastro-esophageal adenocarcinoma, with pharmacokinetics. In: AACR‐NCI‐EORTC international conference: molecular targets and cancer therapeutics, Molecular Cancer Therapeutics, Boston, 2009

    Google Scholar 

  • Senzer N, Nemunaitis J, Nemunaitis D, Bedell C, Edelman G, Barve M, Nunan R, Pirollo KF, Rait A, Chang EH (2013) Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors. Mol Ther 21:1096–1103

    PubMed  CAS  PubMed Central  Google Scholar 

  • Seymour LW, Miyamoto Y, Maeda H, Brereton M, Strohalm J, Ulbrich K, Duncan R (1995) Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier. Eur J Cancer 31A:766–770

    PubMed  CAS  Google Scholar 

  • Shangguan D, Li Y, Tang Z, Cao ZC, Chen HW, Mallikaratchy P, Sefah K, Yang CJ, Tan W (2006) Aptamers evolved from live cells as effective molecular probes for cancer study. Proc Natl Acad Sci U S A 103:11838–11843

    PubMed  CAS  PubMed Central  Google Scholar 

  • Shi J, Xiao Z, Kamaly N, Farokhzad OC (2011) Self-assembled targeted nanoparticles: evolution of technologies and bench to bedside translation. Acc Chem Res 44:1123–1134

    PubMed  CAS  Google Scholar 

  • Shuai X, Merdan T, Schaper AK, Xi F, Kissel T (2004) Core-cross-linked polymeric micelles as paclitaxel carriers. Bioconjug Chem 15:441–448

    PubMed  CAS  Google Scholar 

  • Siegal T, Horowitz A, Gabizon A (1995) Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 83:1029–1037

    PubMed  CAS  Google Scholar 

  • Skidan I, Dholakia P, Torchilin V (2008) Photodynamic therapy of experimental B-16 melanoma in mice with tumor-targeted 5,10,15,20-tetraphenylporphin-loaded PEG-PE micelles. J Drug Target 16:486–493

    PubMed  CAS  Google Scholar 

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    PubMed  CAS  Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    PubMed  CAS  Google Scholar 

  • Smart EJ, Mineo C, Anderson RG (1996) Clustered folate receptors deliver 5-methyltetrahydrofolate to cytoplasm of MA104 cells. J Cell Biol 134:1169–1177

    PubMed  CAS  Google Scholar 

  • Stefanick JF, Ashley JD, Kiziltepe T, Bilgicer B (2013) A systematic analysis of peptide linker length and liposomal polyethylene glycol coating on cellular uptake of peptide-targeted liposomes. ACS Nano 7:2935–2947

    PubMed  CAS  Google Scholar 

  • Stella B, Arpicco S, Peracchia MT, Desmaele D, Hoebeke J, Renoir M, D’Angelo J, Cattel L, Couvreur P (2000) Design of folic acid-conjugated nanoparticles for drug targeting. J Pharm Sci 89:1452–1464

    PubMed  CAS  Google Scholar 

  • Strebhardt K, Ullrich A (2008) Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer 8:473–480

    PubMed  CAS  Google Scholar 

  • Svenson S (2012) Clinical translation of nanomedicines. Curr Opin Solid State Mater Sci 16:287–294

    CAS  Google Scholar 

  • Tagami T, Ernsting MJ, Li SD (2011a) Optimization of a novel and improved thermosensitive liposome formulated with DPPC and a Brij surfactant using a robust in vitro system. J Control Release 154:290–297

    PubMed  CAS  Google Scholar 

  • Tagami T, Ernsting MJ, Li SD (2011b) Efficient tumor regression by a single and low dose treatment with a novel and enhanced formulation of thermosensitive liposomal doxorubicin. J Control Release 152:303–309

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Tardi PG, Gallagher RC, Johnstone S, Harasym N, Webb M, Bally MB, Mayer LD (2007) Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo. Biochim Biophys Acta 1768:678–687

    PubMed  CAS  Google Scholar 

  • Tardi P, Johnstone S, Harasym N, Xie S, Harasym T, Zisman N, Harvie P, Bermudes D, Mayer L (2009) In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy. Leuk Res 33:129–139

    PubMed  CAS  Google Scholar 

  • Taurin S, Nehoff H, Greish K (2012) Anticancer nanomedicine and tumor vascular permeability; where is the missing link? J Control Release 164:265–275

    PubMed  CAS  Google Scholar 

  • Thurber GM, Weissleder R (2011) Quantitating antibody uptake in vivo: conditional dependence on antigen expression levels. Mol Imaging Biol 13:623–632

    PubMed  PubMed Central  Google Scholar 

  • Torchilin VP (1996) How do polymers prolong circulation times of liposomes. J Liposome Res 9:99–116

    Google Scholar 

  • Torchilin VP (2000) Drug targeting. Eur J Pharm Sci 11(Suppl 2):S81–S91

    PubMed  CAS  Google Scholar 

  • Torchilin VP (2001a) Structure and design of polymeric surfactant-based drug delivery systems. J Control Release 73:137–172

    PubMed  CAS  Google Scholar 

  • Torchilin VP (2001b) Diacyl lipid-polyethene glycols as pharmaceutical carriers. In: 28th international symposium on controlled release of bioactive materials, Controlled Release Society, Inc., San Diego, 2001, pp 57–58

    Google Scholar 

  • Torchilin VP (2002) PEG-based micelles as carriers of contrast agents for different imaging modalities. Adv Drug Deliv Rev 54:235–252

    PubMed  CAS  Google Scholar 

  • Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 4:145–160

    PubMed  CAS  Google Scholar 

  • Torchilin VP (2007) Micellar nanocarriers: pharmaceutical perspectives. Pharm Res 24:1–16

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  PubMed Central  Google Scholar 

  • Torchilin VP (2010) Passive and active drug targeting: drug delivery to tumors as an example. Handb Exp Pharmacol (197):3–53.

    Google Scholar 

  • Torchilin V (2011) Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev 63:131–135

    PubMed  CAS  Google Scholar 

  • Torchilin VP, Weissig V (2003) Liposomes: a practical approach. Practical approach series, vol 264. Oxford University Press, Oxford/New York, pp xxiii, 396 p

    Google Scholar 

  • Torchilin VP, Klibanov AL, Huang L, O’Donnell S, Nossiff ND, Khaw BA (1992) Targeted accumulation of polyethylene glycol-coated immunoliposomes in infarcted rabbit myocardium. FASEB J 6:2716–2719

    PubMed  CAS  Google Scholar 

  • Torchilin VP, Levchenko TS, Whiteman KR, Yaroslavov AA, Tsatsakis AM, Rizos AK, Michailova EV, Shtilman MI (2001a) Amphiphilic poly-N-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials 22:3035–3044

    PubMed  CAS  Google Scholar 

  • Torchilin VP, Rammohan R, Weissig V, Levchenko TS (2001b) 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 U S A 98:8786–8791

    PubMed  CAS  PubMed Central  Google Scholar 

  • Torchilin VP, Levchenko TS, Lukyanov AN, Khaw BA, Klibanov AL, Rammohan R, Samokhin GP, Whiteman KR (2001c) 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

    PubMed  CAS  Google Scholar 

  • Torchilin VP, Lukyanov AN, Gao Z, Papahadjopoulos-Sternberg B (2003) Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc Natl Acad Sci U S A 100:6039–6044

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tu C, Louie AY (2012) Nanoformulations for molecular MRI. Wiley Interdiscip Rev Nanomed Nanobiotechnol 4:448–457

    PubMed  CAS  PubMed Central  Google Scholar 

  • Uchino H, Matsumura Y, Negishi T, Koizumi F, Hayashi T, Honda T, Nishiyama N, Kataoka K, Naito S, Kakizoe T (2005) Cisplatin-incorporating polymeric micelles (NC-6004) can reduce nephrotoxicity and neurotoxicity of cisplatin in rats. Br J Cancer 93:678–687

    PubMed  CAS  PubMed Central  Google Scholar 

  • Upadhyay KK, Agrawal HG, Upadhyay C, Schatz C, Le Meins JF, Misra A, Lecommandoux S (2009) Role of block copolymer nanoconstructs in cancer therapy. Crit Rev Ther Drug Carrier Syst 26:157–205

    PubMed  CAS  Google Scholar 

  • Valencia PM, Hanewich-Hollatz MH, Gao W, Karim F, Langer R, Karnik R, Farokhzad OC (2011) Effects of ligands with different water solubilities on self-assembly and properties of targeted nanoparticles. Biomaterials 32:6226–6233

    PubMed  CAS  PubMed Central  Google Scholar 

  • van der Meel R, Vehmeijer LJ, Kok RJ, Storm G, van Gaal EV (2013) Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status. Adv Drug Deliv Rev 65:1284–1298

    PubMed  Google Scholar 

  • van Osdol W, Fujimori K, Weinstein JN (1991) An analysis of monoclonal antibody distribution in microscopic tumor nodules: consequences of a “binding site barrier”. Cancer Res 51:4776–4784

    PubMed  Google Scholar 

  • Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K (2000) Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60:203–212

    PubMed  CAS  Google Scholar 

  • Wacker M (2013) Nanocarriers for intravenous injection – the long hard road to the market. Int J Pharm 457:50–62

    PubMed  CAS  Google Scholar 

  • Wang J, Tian S, Petros RA, Napier ME, Desimone JM (2010) The complex role of multivalency in nanoparticles targeting the transferrin receptor for cancer therapies. J Am Chem Soc 132: 11306–11313

    PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Warenius HM, Galfre G, Bleehen NM, Milstein C (1981) Attempted targeting of a monoclonal antibody in a human tumour xenograft system. Eur J Cancer Clin Oncol 17:1009–1015

    PubMed  CAS  Google Scholar 

  • Watanabe K, Kaneko M, Maitani Y (2012) Functional coating of liposomes using a folate- polymer conjugate to target folate receptors. Int J Nanomedicine 7:3679–3688

    PubMed  CAS  PubMed Central  Google Scholar 

  • Weinstein JN, van Osdol W (1992) The macroscopic and microscopic pharmacology of monoclonal antibodies. Int J Immunopharmacol 14:457–463

    PubMed  CAS  Google Scholar 

  • Weissig V, Lasch J, Erdos G, Meyer HW, Rowe TC, Hughes J (1998) DQAsomes: a novel potential drug and gene delivery system made from Dequalinium. Pharm Res 15:334–337

    PubMed  CAS  Google Scholar 

  • Whiteman KR, Subr V, Ulbrich K, Torchilin VP (2001) Poly(HPMA)-coated liposomes demonstrate prolonged circulation in mice. J Liposome Res 11:153–164

    PubMed  CAS  Google Scholar 

  • Wickham T, Futch K (2012) A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2- positive breast cancer. In: Thirty-fifth annual CTRC-AACR San Antonio Breast Cancer Symposium, Cancer Research, San Antonio, 2012

    Google Scholar 

  • Wu J, Chu C-C (2013) Water insoluble cationic poly(ester amide)s: synthesis, characterization and applications. J Mater Chem B 1:353–360

    CAS  Google Scholar 

  • Wu J, Akaike T, Hayashida K, Okamoto T, Okuyama A, Maeda H (2001) Enhanced vascular permeability in solid tumor involving peroxynitrite and matrix metalloproteinases. Jpn J Cancer Res 92:439–451

    PubMed  CAS  Google Scholar 

  • Xiao Z, Farokhzad OC (2012) Aptamer-functionalized nanoparticles for medical applications: challenges and opportunities. ACS Nano 6:3670–3676

    PubMed  CAS  PubMed Central  Google Scholar 

  • Xiao K, Li Y, Luo J, Lee JS, Xiao W, Gonik AM, Agarwal RG, Lam KS (2011) The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials 32:3435–3446

    PubMed  CAS  PubMed Central  Google Scholar 

  • Xiong XB, Huang Y, Lu WL, Zhang X, Zhang H, Nagai T, Zhang Q (2005) Intracellular delivery of doxorubicin with RGD-modified sterically stabilized liposomes for an improved antitumor efficacy: in vitro and in vivo. J Pharm Sci 94:1782–1793

    PubMed  CAS  Google Scholar 

  • Yamada A, Taniguchi Y, Kawano K, Honda T, Hattori Y, Maitani Y (2008) Design of folate-linked liposomal doxorubicin to its antitumor effect in mice. Clin Cancer Res 14:8161–8168

    PubMed  CAS  Google Scholar 

  • Yamamoto Y, Nagasaki Y, Kato Y, Sugiyama Y, Kataoka K (2001) Long-circulating poly(ethylene glycol)-poly(d, l-lactide) block copolymer micelles with modulated surface charge. J Control Release 77:27–38

    PubMed  CAS  Google Scholar 

  • Yang C, Zhao H, Yuan H, Yu R, Lan M (2013) Preparation and characterization of thermosensitive and folate functionalized Pluronic micelles. J Nanosci Nanotechnol 13:6553–6559

    PubMed  CAS  Google Scholar 

  • Yasuda H, Nakayama K, Watanabe M, Suzuki S, Fuji H, Okinaga S, Kanda A, Zayasu K, Sasaki T, Asada M, Suzuki T, Yoshida M, Yamanda S, Inoue D, Kaneta T, Kondo T, Takai Y, Sasaki H, Yanagihara K, Yamaya M (2006a) Nitroglycerin treatment may enhance chemosensitivity to docetaxel and carboplatin in patients with lung adenocarcinoma. Clin Cancer Res 12: 6748–6757

    PubMed  CAS  Google Scholar 

  • Yasuda H, Yamaya M, Nakayama K, Sasaki T, Ebihara S, Kanda A, Asada M, Inoue D, Suzuki T, Okazaki T, Takahashi H, Yoshida M, Kaneta T, Ishizawa K, Yamanda S, Tomita N, Yamasaki M, Kikuchi A, Kubo H, Sasaki H (2006b) Randomized phase II trial comparing nitroglycerin plus vinorelbine and cisplatin with vinorelbine and cisplatin alone in previously untreated stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 24:688–694

    PubMed  CAS  Google Scholar 

  • Yigit MV, Moore A, Medarova Z (2012) Magnetic nanoparticles for cancer diagnosis and therapy. Pharm Res 29:1180–1188

    PubMed  CAS  PubMed Central  Google Scholar 

  • Ying X, Wen H, Lu WL, Du J, Guo J, Tian W, Men Y, Zhang Y, Li RJ, Yang TY, Shang DW, Lou JN, Zhang LR, Zhang Q (2010) Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals. J Control Release 141:183–192

    PubMed  CAS  Google Scholar 

  • Yoo HS, Park TG (2004) Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release 96:273–283

    PubMed  CAS  Google Scholar 

  • Yoshino K, Nakamura K, Terajima Y, Kurita A, Matsuzaki T, Yamashita K, Isozaki M, Kasukawa H (2012) Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochim Biophys Acta 1818:2901–2907

    PubMed  CAS  Google Scholar 

  • Yu B, Tai HC, Xue W, Lee LJ, Lee RJ (2010) Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol 27:286–298

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yu J, Xie X, Wu J, Liu Y, Liu P, Xu X, Yu H, Lu L, Che X (2013) Folic acid conjugated glycol chitosan micelles for targeted delivery of doxorubicin: preparation and preliminary evaluation in vitro. J Biomater Sci Polym Ed 24:606–620

    PubMed  CAS  Google Scholar 

  • Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK (1994) Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 54:3352–3356

    PubMed  CAS  Google Scholar 

  • Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, Jain RK (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756

    PubMed  CAS  Google Scholar 

  • Yuan X, Harada A, Yamasaki Y, Kataoka K (2005) Stabilization of lysozyme-incorporated polyion complex micelles by the omega-end derivatization of poly(ethylene glycol)-poly(alpha, beta-aspartic acid) block copolymers with hydrophobic groups. Langmuir 21:2668–2674

    PubMed  CAS  Google Scholar 

  • Zalipsky S, Qazen M, Walker JA 2nd, Mullah N, Quinn YP, Huang SK (1999) New detachable poly(ethylene glycol) conjugates: cysteine-cleavable lipopolymers regenerating natural phospholipid, diacyl phosphatidylethanolamine. Bioconjug Chem 10:703–707

    PubMed  CAS  Google Scholar 

  • Zeng F, Lee H, Allen C (2006) Epidermal growth factor-conjugated poly(ethylene glycol)-block- poly(delta-valerolactone) copolymer micelles for targeted delivery of chemotherapeutics. Bioconjug Chem 17:399–409

    PubMed  CAS  Google Scholar 

  • Zeng J, Zhang J, Tanaka T, Rabbitts T (2013) Single domain antibody fragments as drug surrogates targeting protein–protein interactions inside cells. Antibodies 2:306–320

    CAS  Google Scholar 

  • Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC (2008) Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther 83:761–769

    PubMed  CAS  Google Scholar 

  • Zhang L, Gong F, Zhang F, Ma J, Zhang P, Shen J (2013) Targeted therapy for human hepatic carcinoma cells using folate-functionalized polymeric micelles loaded with superparamagnetic iron oxide and sorafenib in vitro. Int J Nanomedicine 8:1517–1524

    PubMed  PubMed Central  Google Scholar 

  • Zhao G, Rodriguez BL (2013) Molecular targeting of liposomal nanoparticles to tumor microenvironment. Int J Nanomedicine 8:61–71

    PubMed  PubMed Central  Google Scholar 

  • Zhao W, Zhuang S, Qi XR (2011) Comparative study of the in vitro and in vivo characteristics of cationic and neutral liposomes. Int J Nanomedicine 6:3087–3098

    PubMed  CAS  PubMed Central  Google Scholar 

  • Zhou Y, Drummond DC, Zou H, Hayes ME, Adams GP, Kirpotin DB, Marks JD (2007) Impact of single-chain Fv antibody fragment affinity on nanoparticle targeting of epidermal growth factor receptor-expressing tumor cells. J Mol Biol 371:934–947

    PubMed  CAS  PubMed Central  Google Scholar 

  • Zhu CL, Lu CH, Song XY, Yang HH, Wang XR (2011) Bioresponsive controlled release using mesoporous silica nanoparticles capped with aptamer-based molecular gate. J Am Chem Soc 133:1278–1281

    PubMed  CAS  Google Scholar 

  • Zhu H, Cao J, Cui S, Qian Z, Gu Y (2013) Enhanced tumor targeting and antitumor efficacy via hydroxycamptothecin-encapsulated folate-modified N-succinyl-N′-octyl chitosan micelles. J Pharm Sci 102:1318–1332

    PubMed  CAS  Google Scholar 

  • Zou S, Cao N, Cheng D, Zheng R, Wang J, Zhu K, Shuai X (2012) Enhanced apoptosis of ovarian cancer cells via nanocarrier-mediated codelivery of siRNA and doxorubicin. Int J Nanomedicine 7:3823–3835

    PubMed  CAS  PubMed Central  Google Scholar 

  • Zubieta MR, Furman D, Barrio M, Bravo AI, Domenichini E, Mordoh J (2006) Galectin-3 expression correlates with apoptosis of tumor-associated lymphocytes in human melanoma biopsies. Am J Pathol 168:1666–1675

    PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway, Room 214, 360 Huntington Avenue, Boston, MA, 02115, USA

    Jaydev R. Upponi & Vladimir P. Torchilin

Authors
  1. Jaydev R. Upponi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladimir P. Torchilin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vladimir P. Torchilin .

Editor information

Editors and Affiliations

  1. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Pharmacy and Pharmaceutical Technology and the Health Research Institute of Santiago de, Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain

    Maria José Alonso

  2. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Department of Pharmacy and Pharmaceutical Technology and the Health Research Institute of Santiago de, Compostela (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain

    Marcos Garcia-Fuentes

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Controlled Release Society

About this chapter

Cite this chapter

Upponi, J.R., Torchilin, V.P. (2014). Passive vs. Active Targeting: An Update of the EPR Role in Drug Delivery to Tumors. In: Alonso, M., Garcia-Fuentes, M. (eds) Nano-Oncologicals. Advances in Delivery Science and Technology. Springer, Cham. https://doi.org/10.1007/978-3-319-08084-0_1

Download citation

Publish with us

Policies and ethics

Search

Navigation