Abstract
Nanoparticles have been employed in cancer management as vectors to deliver chemotherapeutic and/or imaging agents to tumors. Enhanced tumor accumulation occurs by virtue of the long circulation properties of the nanocarrier and the enhanced permeability and retention effect that is characteristic of solid tumors. The versatility of the nanoparticle platform has enabled the design and development of various nanocarriers differing in physicochemical properties such as surface composition, size, charge, and shape. While such properties can influence the pharmacokinetics and biodistribution of a formulation, total tumor deposition can be further impacted by inherent pathophysiology of the tissue. This chapter presents the nature and impact of nanoparticle design on tumor accumulation, particularly in the context of the tumor microenvironment. In vivo barriers, such as opsonization, impaired tumor blood flow, heterogeneous vascular and interstitial permeability impede the effective delivery of nanocarriers and their cargo and are discussed herein, while strategies to overcome them and enhance the effective delivery of nanoparticles are presented.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Barenholz Y (2012) Doxil®—the first FDA-approved nano-drug: lessons learned. J Control Release 160(2):117–134
Harrington KJ, Mohammadtaghi S, Uster PS, Glass D, Peters AM, Vile RG, Stewart JS (2001) Effective targeting of solid tumors in patients with locally advanced cancers by radiolabeled pegylated liposomes. Clin Cancer Res 7(2):243–254
White SC, Lorigan P, Margison GP, Margison JM, Martin F, Thatcher N, Anderson H, Ranson M (2006) Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer. Br J Cancer 95(7):822–828
Bae YH, Park K (2011) Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 153(3):198–205
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6(8):583–592
Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7(11):653–664
Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26(2):225–239
Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK (2011) Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu Rev Chem Biomol Eng 2:281–298
Marcucci F, Corti A (2012) How to improve exposure of tumor cells to drugs: promoter drugs increase tumor uptake and penetration of effector drugs. Adv Drug Deliv Rev 64(1):53–68
Lammers T, Kiessling F, Hennink WE, Storm G (2012) Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J Control Release 161(2):175–187
Bae YH (2009) Drug targeting and tumor heterogeneity. J Control Release 133(1):2–3
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(12 Pt 1):6387–6392
Noguchi Y, Wu J, Duncan R, Strohalm J, Ulbrich K, Akaike T, Maeda H (1998) Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer Res 89(3):307–314
Maeda H, Matsumura Y (1989) Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst 6(3):193–210
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(5):766–770
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(5):335–344
Seymour LW, Ulbrich K, Steyger PS, Brereton M, Subr V, Strohalm J, Duncan R (1994) Tumour tropism and anti-cancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16F10 melanoma. Br J Cancer 70(4):636–641
Takakura Y, Hashida M (1996) Macromolecular carrier systems for targeted drug delivery: pharmacokinetic considerations on biodistribution. Pharm Res 13(6):820–831
Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65(1–2):271–284
Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure – an obstacle in cancer therapy. Nat Rev Cancer 4(10):806–813
Grantab RH, Tannock IF (2012) Penetration of anticancer drugs through tumour tissue as a function of cellular packing density and interstitial fluid pressure and its modification by bortezomib. BMC Cancer 12:214
Taghian AG, Abi-Raad R, Assaad SI, Casty A, Ancukiewicz M, Yeh E, Molokhia P, Attia K, Sullivan T, Kuter I, Boucher Y, Powell SN (2005) Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol 23(9):1951–1961
Davies Cde L, Berk DA, Pluen A, Jain RK (2002) Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells. Br J Cancer 86(10):1639–1644
Au JL, Jang SH, Wientjes MG (2002) Clinical aspects of drug delivery to tumors. J Control Release 78(1–3):81–95
Grantab R, Sivananthan S, Tannock IF (2006) The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells. Cancer Res 66(2):1033–1039
Di Paolo A, Bocci G (2007) Drug distribution in tumors: mechanisms, role in drug resistance, and methods for modification. Curr Oncol Rep 9(2):109–114
Berk DA, Yuan F, Leunig M, Jain RK (1997) Direct in vivo measurement of targeted binding in a human tumor xenograft. Proc Natl Acad Sci U S A 94(5):1785–1790
Iyer AK, Khaled G, Fang J, Maeda H (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today 11(17–18):812–818
Wang M, Thanou M (2010) Targeting nanoparticles to cancer. Pharmacol Res 62(2):90–99
Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51(4):691–743
Li SD, Huang L (2008) Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm 5(4):496–504
Moghimi SM, Hunter AC, Andresen TL (2012) Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev Pharmacol Toxicol 52:481–503
Chrastina A, Massey KA, Schnitzer JE (2011) Overcoming in vivo barriers to targeted nanodelivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3(4):421–437
Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci U S A 105(38):14265–14270
Lynch I, Salvati A, Dawson KA (2009) Protein-nanoparticle interactions: what does the cell see? Nat Nanotechnol 4(9):546–547
Karmali PP, Simberg D (2011) Interactions of nanoparticles with plasma proteins: implication on clearance and toxicity of drug delivery systems. Expert Opin Drug Deliv 8(3):343–357
Moghimi SM, Hunter AC, Murray JC (2001) Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53(2):283–318
Kwon GS, Kataoka K (1995) Block copolymer micelles as long-circulating drug vehicles. Adv Drug Deliv Rev 16(2–3):295–309
Stolnik S, Illum L, Davis SS (1995) Long circulating microparticulate drug carriers. Adv Drug Deliv Rev 16(2–3):195–214
Gref R, Domb A, Quellec P, Blunk T, Müller RH, Verbavatz JM, Langer R (1995) The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres. Adv Drug Deliv Rev 16(2–3):215–233
Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268(1):235–237
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(1):29–36
Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnisch S, Blunk T, Muller RH (2000) “Stealth” corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B Biointerfaces 18(3–4):301–313
Stolnik S, Daudali B, Arien A, Whetstone J, Heald CR, Garnett MC, Davis SS, Illum L (2001) The effect of surface coverage and conformation of poly(ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers. Biochim Biophys Acta 1514(2):261–279
Mosqueira VC, Legrand P, Gulik A, Bourdon O, Gref R, Labarre D, Barratt G (2001) Relationship between complement activation, cellular uptake and surface physicochemical aspects of novel PEG-modified nanocapsules. Biomaterials 22(22):2967–2979
Hamad I, Al-Hanbali O, Hunter AC, Rutt KJ, Andresen TL, Moghimi SM (2010) Distinct polymer architecture mediates switching of complement activation pathways at the nanosphere-serum interface: implications for stealth nanoparticle engineering. ACS Nano 4(11):6629–6638
Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R (1994) Biodegradable long-circulating polymeric nanospheres. Science 263(5153):1600–1603
Perrault SD, Walkey C, Jennings T, Fischer HC, Chan WC (2009) Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett 9(5):1909–1915
Mosqueira VC, Legrand P, Morgat JL, Vert M, Mysiakine E, Gref R, Devissaguet JP, Barratt G (2001) Biodistribution of long-circulating PEG-grafted nanocapsules in mice: effects of PEG chain length and density. Pharm Res 18(10):1411–1419
Storm G, Belliot SO, Daemen T, Lasic DD (1995) Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system. Adv Drug Deliv Rev 17(1):31–48
Ishida T, Ichihara M, Wang X, Kiwada H (2006) Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes. J Control Release 115(3):243–250
Shiraishi K, Hamano M, Ma H, Kawano K, Maitani Y, Aoshi T, Ishii KJ, Yokoyama M (2012) Hydrophobic blocks of PEG-conjugates play a significant role in the accelerated blood clearance (ABC) phenomenon. J Control Release 165(3):183–190
Jokerst JV, Lobovkina T, Zare RN, Gambhir SS (2011) Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond) 6(4):715–728
Knop K, Hoogenboom R, Fischer D, Schubert US (2010) Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed Engl 49(36):6288–6308
Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm 5(4):505–515
Braet F, Wisse E, Bomans P, Frederik P, Geerts W, Koster A, Soon L, Ringer S (2007) Contribution of high-resolution correlative imaging techniques in the study of the liver sieve in three-dimensions. Microsc Res Tech 70(3):230–242
Moghimi SM, Porter CJ, Muir IS, Illum L, Davis SS (1991) Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. Biochem Biophys Res Commun 177(2):861–866
Seymour LW, Duncan R, Strohalm J, Kopecek J (1987) Effect of molecular weight (Mw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats. J Biomed Mater Res 21(11):1341–1358
Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, Bawendi MG, Frangioni JV (2007) Renal clearance of quantum dots. Nat Biotechnol 25(10):1165–1170
Tabata Y, Murakami Y, Ikada Y (1998) Tumor accumulation of poly(vinyl alcohol) of different sizes after intravenous injection. J Control Release 50(1–3):123–133
Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, Terada Y, Kano MR, Miyazono K, Uesaka M, Nishiyama N, Kataoka K (2011) Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol 6(12):815–823
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(9):e24374
Gessner A, Lieske A, Paulke B, Muller R (2002) Influence of surface charge density on protein adsorption on polymeric nanoparticles: analysis by two-dimensional electrophoresis. Eur J Pharm Biopharm 54(2):165–170
Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H, Dawson KA, Linse S (2007) Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A 104(7):2050–2055
Gratton SE, Ropp PA, Pohlhaus PD, Luft JC, Madden VJ, Napier ME, DeSimone JM (2008) The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci U S A 105(33):11613–11618
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(1–2):27–38
Loverde SM, Klein ML, Discher DE (2012) Nanoparticle shape improves delivery: rational coarse grain molecular dynamics (rCG-MD) of taxol in worm-like PEG-PCL micelles. Adv Mater 24(28):3823–3830
Geng Y, Dalhaimer P, Cai S, Tsai R, Tewari M, Minko T, Discher DE (2007) Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol 2(4):249–255
Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, Ferrari M (2010) Size and shape effects in the biodistribution of intravascularly injected particles. J Control Release 141(3):320–327
Kim Y, Dalhaimer P, Christian DA, Discher DE (2005) Polymeric worm micelles as nano-carriers for drug delivery. Nanotechnology 16(7):S484–S491
Christian DA, Cai S, Garbuzenko OB, Harada T, Zajac AL, Minko T, Discher DE (2009) Flexible filaments for in vivo imaging and delivery: persistent circulation of filomicelles opens the dosage window for sustained tumor shrinkage. Mol Pharm 6(5):1343–1352
Huang X, Li L, Liu T, Hao N, Liu H, Chen D, Tang F (2011) The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. ACS Nano 5(7):5390–5399
Champion JA, Katare YK, Mitragotri S (2007) Particle shape: a new design parameter for micro- and nanoscale drug delivery carriers. J Control Release 121(1–2):3–9
Drummond DC, Noble CO, Guo Z, Hayes ME, Park JW, Ou CJ, Tseng YL, Hong K, Kirpotin DB (2009) Improved pharmacokinetics and efficacy of a highly stable nanoliposomal vinorelbine. J Pharmacol Exp Ther 328(1):321–330
Pasqualini R, Koivunen E, Kain R, Lahdenranta J, Sakamoto M, Stryhn A, Ashmun RA, Shapiro LH, Arap W, Ruoslahti E (2000) Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60(3):722–727
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(4905):707–712
Gutierrez C, Schiff R (2011) HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 135(1):55–62
Chan C, Scollard DA, McLarty K, Smith S, Reilly RM (2011) A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT. EJNMMI Res 1(1):15
Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91
Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA (1995) Definition of two angiogenic pathways by distinct alpha v integrins. Science 270(5241):1500–1502
Dunne M, Zheng J, Rosenblat J, Jaffray DA, Allen C (2011) APN/CD13-targeting as a strategy to alter the tumor accumulation of liposomes. J Control Release 154(3):298–305
Sapra P, Allen TM (2003) Ligand-targeted liposomal anticancer drugs. Prog Lipid Res 42(5):439–462
ElBayoumi TA, Torchilin VP (2009) Tumor-targeted nanomedicines: enhanced antitumor efficacy in vivo of doxorubicin-loaded, long-circulating liposomes modified with cancer-specific monoclonal antibody. Clin Cancer Res 15(6):1973–1980
Fonge H, Huang H, Scollard D, Reilly RM, Allen C (2012) Influence of formulation variables on the biodistribution of multifunctional block copolymer micelles. J Control Release 157(3):366–374
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(13):6732–6740
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(24):11631–11638
Pirollo KF, Chang EH (2008) Does a targeting ligand influence nanoparticle tumor localization or uptake? Trends Biotechnol 26(10):552–558
Lammers T, Hennink WE, Storm G (2008) Tumour-targeted nanomedicines: principles and practice. Br J Cancer 99(3):392–397
Turk MJ, Waters DJ, Low PS (2004) Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma. Cancer Lett 213(2):165–172
Koukourakis MI, Koukouraki S, Giatromanolaki A, Archimandritis SC, Skarlatos J, Beroukas K, Bizakis JG, Retalis G, Karkavitsas N, Helidonis ES (1999) Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer. J Clin Oncol 17(11):3512–3521
Little RF, Wyvill KM, Pluda JM, Welles L, Marshall V, Figg WD, Newcomb FM, Tosato G, Feigal E, Steinberg SM, Whitby D, Goedert JJ, Yarchoan R (2000) Activity of thalidomide in AIDS-related Kaposi’s sarcoma. J Clin Oncol 18(13):2593–2602
Seymour LW, Ferry DR, Anderson D, Hesslewood S, Julyan PJ, Poyner R, Doran J, Young AM, Burtles S, Kerr DJ (2002) Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. J Clin Oncol 20(6):1668–1676
Seynhaeve AL, Hoving S, Schipper D, Vermeulen CE, de Wiel-Ambagtsheer G, van Tiel ST, Eggermont AM, Ten Hagen TL (2007) Tumor necrosis factor alpha mediates homogeneous distribution of liposomes in murine melanoma that contributes to a better tumor response. Cancer Res 67(19):9455–9462
Karathanasis E, Suryanarayanan S, Balusu SR, McNeeley K, Sechopoulos I, Karellas A, Annapragada AV, Bellamkonda RV (2009) Imaging nanoprobe for prediction of outcome of nanoparticle chemotherapy by using mammography. Radiology 250(2):398–406
Lammers T, Rizzo LY, Storm G, Kiessling F (2012) Personalized nanomedicine. Clin Cancer Res 18(18):4889–4894
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62
Chaplin DJ, Hill SA, Bell KM, Tozer GM (1998) Modification of tumor blood flow: current status and future directions. Semin Radiat Oncol 8(3):151–163
Suzuki M, Hori K, Abe I, Saito S, Sato H (1981) A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II. J Natl Cancer Inst 67(3):663–669
Hattori Y, Ubukata H, Kawano K, Maitani Y (2011) Angiotensin II-induced hypertension enhanced therapeutic efficacy of liposomal doxorubicin in tumor-bearing mice. Int J Pharm 403(1):178–184
Elizondo FG Jr, Sung C (1996) Effect of angiotensin II on immunotoxin uptake in tumor and normal tissue. Cancer Chemother Pharmacol 39(1):113–121
Maeda H (2010) Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjug Chem 21(5):797–802
Li CJ, Miyamoto Y, Kojima Y, Maeda H (1993) Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure. Br J Cancer 67(5):975–980
Jirtle RL (1988) Chemical modification of tumour blood flow. Int J Hyperthermia 4(4):355–371
Sagar SM, Klassen GA, Barclay KD, Aldrich JE (1993) Tumour blood flow: measurement and manipulation for therapeutic gain. Cancer Treat Rev 19(4):299–349
Zlotecki RA, Baxter LT, Boucher Y, Jain RK (1995) Pharmacologic modification of tumor blood flow and interstitial fluid pressure in a human tumor xenograft: network analysis and mechanistic interpretation. Microvasc Res 50(3):429–443
Suzuki M, Hori K, Abe I, Saito S, Sato H (1984) Functional characterization of the microcirculation in tumors. Cancer Metastasis Rev 3(2):115–126
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(3):319–328
Nagamitsu A, Greish K, Maeda H (2009) 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(11):756–766
Seki T, Fang J, Maeda H (2009) Enhanced delivery of macromolecular antitumor drugs to tumors by nitroglycerin application. Cancer Sci 100(12):2426–2430
Curnis F, Sacchi A, Corti A (2002) Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest 110(4):475–482
Sacchi A, Gasparri A, Gallo-Stampino C, Toma S, Curnis F, Corti A (2006) Synergistic antitumor activity of cisplatin, paclitaxel, and gemcitabine with tumor vasculature-targeted tumor necrosis factor-alpha. Clin Cancer Res 12(1):175–182
Corti A, Pastorino F, Curnis F, Arap W, Ponzoni M, Pasqualini R (2011) Targeted drug delivery and penetration into solid tumors. Med Res Rev 32(5):1078–1091
Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9(5):361–371
Ten Hagen TLM, Van Der Veen AH, Nooijen PTGA, Van Tiel ST, Seynhaeve ALB, Eggermont AMM (2000) Low-dose tumor necrosis factor a augments antitumor activity of stealth liposomal doxorubicin (DOXIL®) in soft tissue sarcoma-bearing rats. Int J Cancer 87(6):829–837
Brouckaert P, Takahashi N, van Tiel ST, Hostens J, Eggermont AMM, Seynhaeve ALB, Fiers W, ten Hagen TLM (2004) Tumor necrosis factor α augmented tumor response in B16BL6 melanoma‐bearing mice treated with stealth liposomal doxorubicin (Doxil®) correlates with altered Doxil® pharmacokinetics. Int J Cancer 109(3):442–448
Hoving S, Seynhaeve ALB, van Tiel ST, Eggermont AMM, ten Hagen TLM (2005) Addition of low-dose tumor necrosis factor-a to systemic treatment with STEALTH liposomal doxorubicin (Doxil) improved anti-tumor activity in osteosarcoma-bearing rats. Anti-Cancer Drugs 16(6):667–674
Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N, Kataoka K, Miyazono K (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci USA 104(9):3460–3465
Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328(5981):1031–1035
Kong G, Dewhirst MW (1999) Hyperthermia and liposomes. Int J Hyperthermia 15(5):345–370
Kong G, Braun RD, Dewhirst MW (2000) Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. Cancer Res 60(16):4440–4445
Lammers T, Peschke P, Kuhnlein R, Subr V, Ulbrich K, Debus J, Huber P, Hennink W, Storm G (2007) Effect of radiotherapy and hyperthermia on the tumor accumulation of HPMA copolymer-based drug delivery systems. J Control Release 117(3):333–341
Reinhold H, Endrich B (1986) Tumour microcirculation as a target for hyperthermia. Int J Hyperthermia 2(2):111–137
Jain RK, Ward-Hartley K (1984) Tumor blood flow-characterization, modifications, and role in hyperthermia. IEEE Trans Son Ultrason 31(5):504–526
Song C, Park H, Lee C, Griffin R (2005) Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia 21(8):761–767
Park JS, Qiao L, Su ZZ, Hinman D, Willoughby K, McKinstry R, Yacoub A, Duigou GJ, Young CS, Grant S, Hagan MP, Ellis E, Fisher PB, Dent P (2001) Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways. Oncogene 20(25):3266–3280
Chung YL, Jian JJ, Cheng SH, Tsai SY, Chuang VP, Soong T, Lin YM, Horng CF (2006) Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma. Clin Cancer Res 12(9):2706–2715
Lee YJ, Galoforo SS, Berns CM, Erdos G, Gupta AK, Ways DK, Corry PM (1995) Effect of ionizing radiation on AP-1 binding activity and basic fibroblast growth factor gene expression in drug-sensitive human breast carcinoma MCF-7 and multidrug-resistant MCF-7/ADR cells. J Biol Chem 270(48):28790–28796
Giustini AJ, Petryk AA, Hoopes PJ (2012) Ionizing radiation increases systemic nanoparticle tumor accumulation. Nanomedicine 8(6):818–821
Koukourakis MI (2000) High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas: rationale for combination with radiotherapy. Acta Oncol 39(2):207–211
Davies CL, Lundstrøm LM, Frengen J, Eikenes L, Bruland ØS, Kaalhus O, Hjelstuen MHB, Brekken C (2004) Radiation improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Cancer Res 64(2):547–553
Jain RK, Tong RT, Munn LL (2007) Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res 67(6):2729–2735
Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64(11):3731
Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, Bawendi MG, Fukumura D, Jain RK (2012) Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 7(6):383–388
Tailor TD, Hanna G, Yarmolenko PS, Dreher MR, Betof AS, Nixon AB, Spasojevic I, Dewhirst MW (2010) Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 9(6):1798–1808
Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP (2008) Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther 7(1):71–78
Jain RK (1987) Transport of molecules in the tumor interstitium: a review. Cancer Res 47(12):3039–3051
Eikenes L, Tari M, Tufto I, Bruland OS, de Lange Davies C (2005) Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer 93(1):81–88
Kovar JL, Johnson MA, Volcheck WM, Chen J, Simpson MA (2006) Hyaluronidase expression induces prostate tumor metastasis in an orthotopic mouse model. Am J Pathol 169(4):1415–1426
Roy R, Yang J, Moses MA (2009) Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 27(31):5287–5297
Lu D, Wientjes MG, Lu Z, Au JL (2007) Tumor priming enhances delivery and efficacy of nanomedicines. J Pharmacol Exp Ther 322(1):80–88
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(13):3352–3356
Gabizon A, Dagan A, Goren D, Barenholz Y, Fuks Z (1982) Liposomes as in vivo carriers of adriamycin: reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res 42(11):4734–4739
Mayhew E, Rustum Y, Vail WJ (1983) Inhibition of liver metastases of M 5076 tumor by liposome-entrapped adriamycin. Cancer Drug Deliv 1(1):43–58
van Hoesel QG, Steerenberg PA, Crommelin DJ, van Dijk A, van Oort W, Klein S, Douze JM, de Wildt DJ, Hillen FC (1984) Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes in the LOU/M Wsl rat. Cancer Res 44(9):3698–3705
Storm G, Roerdink FH, Steerenberg PA, de Jong WH, Crommelin DJ (1987) Influence of lipid composition on the antitumor activity exerted by doxorubicin-containing liposomes in a rat solid tumor model. Cancer Res 47(13):3366–3372
Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L (2012) TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci U S A 109(41):16618–16623
Boucher Y, Baxter LT, Jain RK (1990) Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res 50(15):4478–4484
Huxham LA, Kyle AH, Baker JH, Nykilchuk LK, Minchinton AI (2004) Microregional effects of gemcitabine in HCT-116 xenografts. Cancer Res 64(18):6537–6541
Shin SJ, Beech JR, Kelly KA (2012) Targeted nanoparticles in imaging: paving the way for personalized medicine in the battle against cancer. Integr Biol (Camb) 5(1):29–42
Lankelma J, Dekker H, Luque FR, Luykx S, Hoekman K, van der Valk P, van Diest PJ, Pinedo HM (1999) Doxorubicin gradients in human breast cancer. Clin Cancer Res 5(7):1703–1707
Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF (2005) The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors. Clin Cancer Res 11(24 Pt 1):8782–8788
Karathanasis E, Chan L, Karumbaiah L, McNeeley K, D’Orsi CJ, Annapragada AV, Sechopoulos I, Bellamkonda RV (2009) Tumor vascular permeability to a nanoprobe correlates to tumor-specific expression levels of angiogenic markers. PLoS One 4(6):e5843
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(6109):903–910
Choi HS, Liu W, Liu F, Nasr K, Misra P, Bawendi MG, Frangioni JV (2010) Design considerations for tumour-targeted nanoparticles. Nat Nanotechnol 5(1):42–47
Lammers T, Kiessling F, Hennink WE, Storm G (2010) Nanotheranostics and image-guided drug delivery: current concepts and future directions. Mol Pharm 7(6):1899–1912
Huang H, Dunne M, Lo J, Jaffray DA, Allen C (2013) Comparison of computed tomography- and optical image-based assessment of liposome distribution. Mol Imaging 12(3):148–160
Acknowledgments
This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to C.A., and D.A.J. S.N.E is supported by a fellowship from the CIHR Strategic Training Program in Biological Therapeutics.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Ekdawi, S.N. et al. (2013). Long Circulation and Tumor Accumulation. In: Bae, Y., Mrsny, R., Park, K. (eds) Cancer Targeted Drug Delivery. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7876-8_20
Download citation
DOI: https://doi.org/10.1007/978-1-4614-7876-8_20
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-7875-1
Online ISBN: 978-1-4614-7876-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)