Targeting cancer cells in the tumor microenvironment: Opportunities and challenges in combinatorial nanomedicine

Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology

Volumn 8, Issue 2, 2016, Pages 208-222

  Linton, Samuel S ^a   Sherwood, Samantha G ^b   Drews, Kelly C ^b   Kester, Mark ^b  

^a PENN STATE COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF VIRGINIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DISEASES; ENZYME INHIBITION; MEDICAL NANOTECHNOLOGY; ONCOLOGY;

ANTICANCER DRUG; CANCER THERAPY; CLINICAL TRIAL; COMMERCIAL POTENTIAL; DRUG DELIVERY VEHICLES; NANOMEDICINES; PATHOLOGICAL CONDITIONS; TUMOR MICROENVIRONMENT;

TUMORS;

ANTINEOPLASTIC AGENT; LIPID; NANOCARRIER; DRUG CARRIER;

CANCER CELL; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG POTENTIATION; ENDOTHELIUM CELL; FOOD AND DRUG ADMINISTRATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MOLECULARLY TARGETED THERAPY; NEXT GENERATION SEQUENCING; NONHUMAN; NUCLEAR REPROGRAMMING; PRIORITY JOURNAL; REVIEW; TARGET CELL; THERANOSTIC NANOMEDICINE; TUMOR MICROENVIRONMENT; UNITED STATES; ANIMAL; COMBINATORIAL CHEMISTRY; NANOMEDICINE; NEOPLASMS; PATHOLOGY; PROCEDURES;

ANIMALS; COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG CARRIERS; DRUG DELIVERY SYSTEMS; HUMANS; NANOMEDICINE; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 84959237388     PISSN: 19395116     EISSN: 19390041     Source Type: Journal    
DOI: 10.1002/wnan.1358     Document Type: Review

References (98)

1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
2. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013, 501:328-337.
3. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013, 19:1423-1437.
4. Reisfeld RA. The tumor microenvironment: a target for combination therapy of breast cancer. Crit Rev Oncog 2013, 18:115-133.
5. Neesse A, Krug S, Gress TM, Tuveson DA, Michl P. Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. Onco Targets Ther 2013, 7:33-43.
6. Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2014, 2:154-166.
7. Ko SY, Naora H. Therapeutic strategies for targeting the ovarian tumor stroma. World J Clin Cases 2014, 2:194-200.
8. Liss AS, Thayer SP. Therapeutic targeting of pancreatic stroma. In: Grippo PJ, Munshi HG, eds. Pancreatic Cancer and Tumor Microenvironment. Trivandrum: Transworld Research Network; 2012. Chapter 9. Available from: http://www.ncbi.nlm.nih.gov/books/NBK98931/
9. Hiscox S, Barrett-Lee P, Nicholson RI. Therapeutic targeting of tumor-stroma interactions. Expert Opin Ther Targets 2011, 15:609-621.
10. Franco OE, Hayward SW. Targeting the tumor stroma as a novel therapeutic approach for prostate cancer. Adv Pharmacol 2012, 65:267-313.
11. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014, 371:1609-1618.
12. Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Crit Rev Ther Drug Carrier Syst 1989, 6:193-210.
13. Liu J, Huang Y, Kumar A, Tan A, Jin S, Mozhi A, Liang XJ. pH-sensitive nano-systems for drug delivery in cancer therapy. Biotechnol Adv 2014, 32:693-710.
14. Lee ES, Gao Z, Bae YH. Recent progress in tumor pH targeting nanotechnology. J Control Release 2008, 132:164-170.
15. Shen Y, Tang H, Radosz M, Van Kirk E, Murdoch WJ. pH-responsive nanoparticles for cancer drug delivery. Methods Mol Biol 2008, 437:183-216.
16. Jhaveri A, Deshpande P, Torchilin V. Stimuli-sensitive nanopreparations for combination cancer therapy. J Control Release 2014, 190:352-370.
17. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014, 159:80-93.
18. Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 2014, 158:564-578.
19. Clark RA, McCoy GA, Folkvord JM, McPherson JM. TGF-beta 1 stimulates cultured human fibroblasts to proliferate and produce tissue-like fibroplasia: a fibronectin matrix-dependent event. J Cell Physiol 1997, 170:69-80.
20. Park J, Wrzesinski SH, Stern E, Look M, Criscione J, Ragheb R, Jay SM, Demento SL, Agawu A, Licona Limon P, et al. Combination delivery of TGF-beta inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat Mater 2012, 11:895-905.
21. Miao L, Guo S, Zhang J, Kim WY, Huang L. Nanoparticles with precise ratiometric co-loading and co-delivery of gemcitabine monophosphate and cisplatin for treatment of bladder cancer. Adv Funct Mater 2014, 24:6601-6611.
22. Xu X, Xie K, Zhang XQ, Pridgen EM, Park GY, Cui DS, Shi J, Wu J, Kantoff PW, Lippard SJ, et al. Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug. Proc Natl Acad Sci USA 2013, 110:18638-18643.
23. Liao D, Liu Z, Wrasidlo WJ, Luo Y, Nguyen G, Chen T, Xiang R, Reisfeld RA. Targeted therapeutic remodeling of the tumor microenvironment improves an HER-2 DNA vaccine and prevents recurrence in a murine breast cancer model. Cancer Res 2011, 71:5688-5696.
24. Yokoi K, Godin B, Oborn CJ, Alexander JF, Liu X, Fidler IJ, Ferrari M. Porous silicon nanocarriers for dual targeting tumor associated endothelial cells and macrophages in stroma of orthotopic human pancreatic cancers. Cancer Lett 2013, 334:319-327.
25. Abraham SA, McKenzie C, Masin D, Ng R, Harasym TO, Mayer LD, Bally MB. In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading. Clin Cancer Res 2004, 10:728-738.
26. Morton SW, Lee MJ, Deng ZJ, Dreaden EC, Siouve E, Shopsowitz KE, Shah NJ, Yaffe MB, Hammond PT. A nanoparticle-based combination chemotherapy delivery system for enhanced tumor killing by dynamic rewiring of signaling pathways. Sci Signal 2014, 7:ra44.
27. Riviere K, Kieler-Ferguson HM, Jerger K, Szoka FC Jr. Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan. J Control Release 2011, 153:288-296.
28. Prasad P, Shuhendler A, Cai P, Rauth AM, Wu XY. Doxorubicin and mitomycin C co-loaded polymer-lipid hybrid nanoparticles inhibit growth of sensitive and multidrug resistant human mammary tumor xenografts. Cancer Lett 2013, 334:263-273.
29. Shuhendler AJ, Prasad P, Zhang RX, Amini MA, Sun M, Liu PP, Bristow RG, Rauth AM, Wu XY. Synergistic nanoparticulate drug combination overcomes multidrug resistance, increases efficacy, and reduces cardiotoxicity in a nonimmunocompromised breast tumor model. Mol Pharm 2014, 11:2659-2674.
30. Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010, 70:440-446.
31. Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, Goldlust IS, Yasgar A, McKnight C, Boxer MB, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA 2014, 111:2349-2354.
32. Upreti M, Jamshidi-Parsian A, Koonce NA, Webber JS, Sharma SK, Asea AA, Mader MJ, Griffin RJ. Tumor-endothelial cell three-dimensional spheroids: new aspects to enhance radiation and drug therapeutics. Transl Oncol 2011, 4:365-376.
33. Grandhi BK, Thakkar A, Wang J, Prabhu S. A novel combinatorial nanotechnology-based oral chemopreventive regimen demonstrates significant suppression of pancreatic cancer neoplastic lesions. Cancer Prev Res (Phila) 2013, 6:1015-1025.
34. Kanthamneni N, Chaudhary A, Wang J, Prabhu S. Nanoparticulate delivery of novel drug combination regimens for the chemoprevention of colon cancer. Int J Oncol 2010, 37:177-185.
35. Chang HI, Yeh MK. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomedicine 2012, 7:49-60.
36. Kheirolomoom A, Lai CY, Tam SM, Mahakian LM, Ingham ES, Watson KD, Ferrara KW. Complete regression of local cancer using temperature-sensitive liposomes combined with ultrasound-mediated hyperthermia. J Control Release 2013, 172:266-273.
37. Xu H, Hu M, Yu X, Li Y, Fu Y, Zhou X, Zhang D, Li J. Design and evaluation of pH-sensitive liposomes constructed by poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate for doxorubicin delivery. Eur J Pharm Biopharm 2015, 91:66-74.
38. Adhikari C, Das A, Chakraborty A. Controlled release of a sparingly water-soluble anticancer drug through pH-responsive functionalized gold-nanoparticle-decorated liposomes. Chemphyschem 2015, 16:866-871.
39. Yuba E, Tajima N, Yoshizaki Y, Harada A, Hayashi H, Kono K. Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy. Biomaterials 2014, 35:3091-3101.
40. Wang L, Geng D, Su H. Safe and efficient pH sensitive tumor targeting modified liposomes with minimal cytotoxicity. Colloids Surf B Biointerfaces 2014, 123:395-402.
41. Ghanbarzadeh S, Arami S, Pourmoazzen Z, Khorrami A. Improvement of the antiproliferative effect of rapamycin on tumor cell lines by poly (monomethylitaconate)-based pH-sensitive, plasma stable liposomes. Colloids Surf B Biointerfaces 2014, 115:323-330.
42. Chiang YT, Lo CL. pH-responsive polymer-liposomes for intracellular drug delivery and tumor extracellular matrix switched-on targeted cancer therapy. Biomaterials 2014, 35:5414-5424.
43. Bersani S, Vila-Caballer M, Brazzale C, Barattin M, Salmaso S. pH-sensitive stearoyl-PEG-poly(methacryloyl sulfadimethoxine) decorated liposomes for the delivery of gemcitabine to cancer cells. Eur J Pharm Biopharm 2014, 88:670-682.
44. Bertrand N, Fleischer JG, Wasan KM, Leroux JC. Pharmacokinetics and biodistribution of N-isopropylacrylamide copolymers for the design of pH-sensitive liposomes. Biomaterials 2009, 30:2598-2605.
45. Garg A, Kokkoli E. pH-sensitive PEGylated liposomes functionalized with a fibronectin-mimetic peptide show enhanced intracellular delivery to colon cancer cell. Curr Pharm Biotechnol 2011, 12:1135-1143.
46. Staruch RM, Hynynen K, Chopra R. Hyperthermia-mediated doxorubicin release from thermosensitive liposomes using MR-HIFU: therapeutic effect in rabbit Vx2 tumours. Int J Hyperthermia 2015, 31:118-133.
47. Lopez-Noriega A, Hastings CL, Ozbakir B, O'Donnell KE, O'Brien FJ, Storm G, Hennink WE, Duffy GP, Ruiz-Hernandez E. Hyperthermia-induced drug delivery from thermosensitive liposomes encapsulated in an injectable hydrogel for local chemotherapy. Adv Healthc Mater 2014, 3:854-859.
48. Al-Ahmady ZS, Chaloin O, Kostarelos K. Monoclonal antibody-targeted, temperature-sensitive liposomes: in vivo tumor chemotherapeutics in combination with mild hyperthermia. J Control Release 2014, 196:332-343.
49. Mannaris C, Efthymiou E, Meyre ME, Averkiou MA. In vitro localized release of thermosensitive liposomes with ultrasound-induced hyperthermia. Ultrasound Med Biol 2013, 39:2011-2020.
50. Li L, ten Hagen TL, Hossann M, Suss R, van Rhoon GC, Eggermont AM, Haemmerich D, Koning GA. Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy. J Control Release 2013, 168:142-150.
51. Grull H, Langereis S. Hyperthermia-triggered drug delivery from temperature-sensitive liposomes using MRI-guided high intensity focused ultrasound. J Control Release 2012, 161:317-327.
52. Smith B, Lyakhov I, Loomis K, Needle D, Baxa U, Yavlovich A, Capala J, Blumenthal R, Puri A. Hyperthermia-triggered intracellular delivery of anticancer agent to HER2(+) cells by HER2-specific affibody (ZHER2-GS-Cys)-conjugated thermosensitive liposomes (HER2(+) affisomes). J Control Release 2011, 153:187-194.
53. Gabizon A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylated liposomal doxorubicin: review of animal and human studies. Clin Pharmacokinet 2003, 42:419-436.
54. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003, 97:2869-2879.
55. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998, 339:900-905.
56. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, et al. 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 2004, 15:440-449.
57. Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A. Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 2000, 11:1029-1033.
58. Ramadass SK, Anantharaman NV, Subramanian S, Sivasubramanian S, Madhan B. Paclitaxel/Epigallocatechin gallate coloaded liposome: a synergistic delivery to control the invasiveness of MDA-MB-231 breast cancer cells. Colloids Surf B Biointerfaces 2015, 125:65-72.
59. Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Komrokji R, Solomon SR, Kolitz JE, Cooper M, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 2014, 123:3239-3246.
60. Shim G, Lee S, Choi J, Lee S, Kim CW, Oh YK. Liposomal co-delivery of omacetaxine mepesuccinate and doxorubicin for synergistic potentiation of antitumor activity. Pharm Res 2014, 31:2178-2185.
61. Patankar NA, Pritchard J, van Grinsven M, Osooly M, Bally MB. Topotecan and doxorubicin combination to treat recurrent ovarian cancer: the influence of drug exposure time and delivery systems to achieve optimum therapeutic activity. Clin Cancer Res 2013, 19:865-877.
62. Shaikh IM, Tan KB, Chaudhury A, Liu Y, Tan BJ, Tan BM, Chiu GN. Liposome co-encapsulation of synergistic combination of irinotecan and doxorubicin for the treatment of intraperitoneally grown ovarian tumor xenograft. J Control Release 2013, 172:852-861.
63. Batist G, Gelmon KA, Chi KN, Miller WH Jr, Chia SK, Mayer LD, Swenson CE, Janoff AS, Louie AC. Safety, pharmacokinetics, and efficacy of CPX-1 liposome injection in patients with advanced solid tumors. Clin Cancer Res 2009, 15:692-700.
64. Tran MA, Smith CD, Kester M, Robertson GP. Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin Cancer Res 2008, 14:3571-3581.
65. Mohan A, Narayanan S, Sethuraman S, Krishnan UM. Novel resveratrol and 5-fluorouracil coencapsulated in PEGylated nanoliposomes improve chemotherapeutic efficacy of combination against head and neck squamous cell carcinoma. Biomed Res Int 2014, 2014:424239.
66. Crist RM, Grossman JH, Patri AK, Stern ST, Dobrovolskaia MA, Adiseshaiah PP, Clogston JD, McNeil SE. Common pitfalls in nanotechnology: lessons learned from NCI's nanotechnology characterization laboratory. Integr Biol (Camb) 2013, 5:66-73.
67. Duncan R, Gaspar R. Nanomedicine(s) under the microscope. Mol Pharm 2011, 8:2101-2141.
68. Guo S, Wang Y, Miao L, Xu Z, Lin CM, Zhang Y, Huang L. Lipid-coated Cisplatin nanoparticles induce neighboring effect and exhibit enhanced anticancer efficacy. ACS Nano 2013, 7:9896-9904.
69. van Vlerken LE, Duan Z, Little SR, Seiden MV, Amiji MM. Biodistribution and pharmacokinetic analysis of Paclitaxel and ceramide administered in multifunctional polymer-blend nanoparticles in drug resistant breast cancer model. Mol Pharm 2008, 5:516-526.
70. Jiang Y, DiVittore NA, Kaiser JM, Shanmugavelandy SS, Fritz JL, Heakal Y, Tagaram HR, Cheng H, Cabot MC, Staveley-O'Carroll KF, et al. Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther 2011, 12:574-585.
71. Dhule SS, Penfornis P, He J, Harris MR, Terry T, John V, Pochampally R. The combined effect of encapsulating curcumin and C6 ceramide in liposomal nanoparticles against osteosarcoma. Mol Pharm 2014, 11:417-427.
72. Fonseca NA, Gomes-da-Silva LC, Moura V, Simoes S, Moreira JN. Simultaneous active intracellular delivery of doxorubicin and C6-ceramide shifts the additive/antagonistic drug interaction of non-encapsulated combination. J Control Release 2014, 196:122-131.
73. Adiseshaiah PP, Clogston JD, McLeland CB, Rodriguez J, Potter TM, Neun BW, Skoczen SL, Shanmugavelandy SS, Kester M, Stern ST, et al. Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models. Cancer Lett 2013, 337:254-265.
74. Zolnik BS, Stern ST, Kaiser JM, Heakal Y, Clogston JD, Kester M, McNeil SE. Rapid distribution of liposomal short-chain ceramide in vitro and in vivo. Drug Metab Dispos 2008, 36:1709-1715.
75. Abuchowski A, McCoy JR, Palczuk NC, van Es T, Davis FF. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J Biol Chem 1977, 252:3582-3586.
76. Wang H, Zhao Y, Wu Y, Hu YL, Nan K, Nie G, Chen H. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials 2011, 32:8281-8290.
77. Qian X, Peng XH, Ansari DO, Yin-Goen Q, Chen GZ, Shin DM, Yang L, Young AN, Wang MD, Nie S. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat Biotechnol 2008, 26:83-90.
78. Kirpotin DB, Drummond DC, Shao Y, Shalaby MR, Hong K, Nielsen UB, Marks JD, Benz CC, Park JW. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res 2006, 66:6732-6740.
79. Shen J, Meng Q, Sui H, Yin Q, Zhang Z, Yu H, Li Y. iRGD conjugated TPGS mediates codelivery of paclitaxel and survivin shRNA for the reversal of lung cancer resistance. Mol Pharm 2014, 11:2579-2591.
80. Wei W, Lv PP, Chen XM, Yue ZG, Fu Q, Liu SY, Yue H, Ma GH. Codelivery of mTERT siRNA and paclitaxel by chitosan-based nanoparticles promoted synergistic tumor suppression. Biomaterials 2013, 34:3912-3923.
81. Qu MH, Zeng RF, Fang S, Dai QS, Li HP, Long JT. Liposome-based co-delivery of siRNA and docetaxel for the synergistic treatment of lung cancer. Int J Pharm 2014, 474:112-122.
82. Ganesh S, Iyer AK, Gattacceca F, Morrissey DV, Amiji MM. In vivo biodistribution of siRNA and cisplatin administered using CD44-targeted hyaluronic acid nanoparticles. J Control Release 2013, 172:699-706.
83. Mayer LD, Harasym TO, Tardi PG, Harasym NL, Shew CR, Johnstone SA, Ramsay EC, Bally MB, Janoff AS. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Mol Cancer Ther 2006, 5:1854-1863.
84. Tardi PG, Dos Santos N, Harasym TO, Johnstone SA, Zisman N, Tsang AW, Bermudes DG, Mayer LD. Drug ratio-dependent antitumor activity of irinotecan and cisplatin combinations in vitro and in vivo. Mol Cancer Ther 2009, 8:2266-2275.
85. Hecht JR. Gastrointestinal toxicity or irinotecan. Oncology (Williston Park) 1998, 12:72-78.
86. von Roemeling R, Hrushesky WJ. Circadian patterning of continuous floxuridine infusion reduces toxicity and allows higher dose intensity in patients with widespread cancer. J Clin Oncol 1989, 7:1710-1719.
87. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000, 355:1041-1047.
88. Douillard JY, Sobrero A, Carnaghi C, Comella P, Diaz-Rubio E, Santoro A, Van Cutsem E. Metastatic colorectal cancer: integrating irinotecan into combination and sequential chemotherapy. Ann Oncol 2003, 14(Suppl 2):ii7-ii12.
89. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004, 22:23-30.
90. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004, 22:229-237.
91. Lee DS, Im HJ, Lee YS. Radionanomedicine: widened perspectives of molecular theragnosis. Nanomedicine 2015, 11:795-810.
92. Iyer AK, He J, Amiji MM. Image-guided nanosystems for targeted delivery in cancer therapy. Curr Med Chem 2012, 19:3230-3240.
93. http://www.bindtherapeutics.com/
94. http://www.celatorpharma.com/
95. Cosco D, Paolino D, Cilurzo F, Casale F, Fresta M. Gemcitabine and tamoxifen-loaded liposomes as multidrug carriers for the treatment of breast cancer diseases. Int J Pharm 2012, 422:229-237.
96. Harasym TO, Tardi PG, Harasym NL, Harvie P, Johnstone SA, Mayer LD. Increased preclinical efficacy of irinotecan and floxuridine coencapsulated inside liposomes is associated with tumor delivery of synergistic drug ratios. Oncol Res 2007, 16:361-374.
97. Kim HP, Gerhard B, Harasym TO, Mayer LD, Hogge DE. Liposomal encapsulation of a synergistic molar ratio of cytarabine and daunorubicin enhances selective toxicity for acute myeloid leukemia progenitors as compared to analogous normal hematopoietic cells. Exp Hematol 2011, 39:741-750.
98. Tardi P, Johnstone S, Harasym N, Xie S, Harasym T, Zisman N, Harvie P, Bermudes D, Mayer L. In vivo maintenance of synergistic cytarabine: daunorubicin ratios greatly enhances therapeutic efficacy. Leuk Res 2009, 33:129-139.