Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study
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The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches.
We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR.
To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOSR2 and SKOV-3TR in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells.
Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOSR2.
Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs.
Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.
- Abeylath SC, Amiji MM. “Click” synthesis of dextran macrostructures for combinatorial-designed self-assembled nanoparticles encapsulating diverse anticancer therapeutics. Bioorg Med Chem. 2011;19:6167–6173. CrossRef
- Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3:502–516. CrossRef
- Baldini N, Scotlandi K, Barbanti-Brodano G, Manara MC, Maurici D, Bacci G, Bertoni F, Picci P, Sottili S, Campanacci M, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med. 1995;333:1380–1385. CrossRef
- Belpomme D, Gauthier S, Pujade-Lauraine E, Facchini T, Goudier MJ, Krakowski I, Netter-Pinon G, Frenay M, Gousset C, Marie FN, Benmiloud M, Sturtz F. Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma. Ann Oncol. 2000;11:1471–1476. CrossRef
- Bhavsar MD, Amiji MM. Gastrointestinal distribution and in vivo gene transfection studies with nanoparticles-in-microsphere oral system (NiMOS). J Control Release. 2007;119:339–348. CrossRef
- Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776–790. CrossRef
- Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991;66:85–94. CrossRef
- Chen AM, Zhang M, Wei D, Stueber D, Taratula O, Minko T, He H. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small. 2009;5:2673–2677. CrossRef
- Devalapally H, Duan Z, Seiden MV, Amiji MM. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res. 2008;14:3193–3203. CrossRef
- Dillen K, Vandervoort J, Van den Mooter G, Ludwig A. Evaluation of ciprofloxacin-loaded Eudragit RS100 or RL100/PLGA nanoparticles. Int J Pharm. 2006;314:72–82. CrossRef
- Duan Z, Brakora KA, Seiden MV. Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol Cancer Ther. 2004;3:833–838.
- Ferrandina G, Corrado G, Licameli A, Lorusso D, Fuoco G, Pisconti S, Scambia G. Pegylated liposomal doxorubicin in the management of ovarian cancer. Ther Clin Risk Manag. 2010;6:463–483.
- Fletcher JI, Haber M, Henderson MJ, Norris MD. ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer. 2010;10:147–156. CrossRef
- Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 2010;8:705–718.
- Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol Biol. 2010;596:47–76. CrossRef
- Han HK. Role of transporters in drug interactions. Arch Pharm Res. 2011;34:1865–1877. CrossRef
- Hindenburg AA, Baker MA, Gleyzer E, Stewart VJ, Case N, Taub RN. Effect of verapamil and other agents on the distribution of anthracyclines and on reversal of drug resistance. Cancer Res. 1987;47:1421–1425.
- Hornicek FJ, Gebhardt MC, Wolfe MW, Kharrazi FD, Takeshita H, Parekh SG, Zurakowski D, Mankin HJ. P-glycoprotein levels predict poor outcome in patients with osteosarcoma. Clin Orthop Relat Res. 2000;373:11–17. CrossRef
- Iyer AK, Khaled G, Fang J, Maeda H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today. 2006;11:812–818. CrossRef
- Kandel RA, Campbell S, Noble-Topham S, Bell R, Andrulis IL. Correlation of p-glycoprotein detection by immunohistochemistry with mdr-1 mRNA levels in osteosarcomas: pilot study. Diagn Mol Pathol. 1995;4:59–65. CrossRef
- Kaye SB. Reversal of drug resistance in ovarian cancer: where do we go from here? J Clin Oncol. 2008;26:2616–2618. CrossRef
- Keizer HG, Schuurhuis GJ, Broxterman HJ, Lankelma J, Schoonen WG, van Rijn J, Pinedo HM, Joenje H. Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution, and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells. Cancer Res. 1989;49:2988–2993.
- Klimecki WT, Futscher BW, Grogan TM, Dalton WS. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood. 1994;83:2451–2458.
- Kolitz JE, George SL, Dodge RK, Hurd DD, Powell BL, Allen SL, Velez-Garcia E, Moore JO, Shea TC, Hoke E, Caligiuri MA, Vardiman JW, Bloomfield CD, Larson RA. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621. J Clin Oncol. 2004;22:4290–4301. CrossRef
- Lamendola DE, Duan Z, Yusuf RZ, Seiden MV. Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line. Cancer Res. 2003;63:2200–2205.
- Licht T, Pastan I, Gottesman M, Herrmann F. P-glycoprotein-mediated multidrug resistance in normal and neoplastic hematopoietic cells. Ann Hematol. 1994;69:159–171. CrossRef
- MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt VN, Phillips L, Pattison ST, Petti C, Stillman B, Graham RM, Brahmbhatt H. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol. 2009;27:643–651. CrossRef
- Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul. 2001;41:189–207. CrossRef
- Meng H, Liong M, Xia T, Li Z, Ji Z, Zink JI, Nel AE. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano. 2010;4:4539–4550. CrossRef
- Milane L, Duan Z, Amiji M. Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells. Mol Pharm. 2010;8:185–203. CrossRef
- Minko T, Kopeckova P, Pozharov V, Kopecek J. HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J Control Release. 1998;54:223–233. CrossRef
- Nieth C, Priebsch A, Stege A, Lage H. Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi). FEBS Lett. 2003;545:144–150. CrossRef
- Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol. 1996;36:55–63.
- O’Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, Fowler JM, Copeland LJ, Cohn DE, Backes FJ. Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol Oncol. 2011;121:269–272. CrossRef
- Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK. RNA interference in the clinic: challenges and future directions. Nat Rev Cancer. 2011;11:59–67. CrossRef
- Poveda A, Lopez-Pousa A, Martin J, Del Muro JG, Bernabe R, Casado A, Balana C, Sanmartin O, Menendez MD, Escudero P, Cruz J, Belyakova E, Menendez D, Buesa JM. Phase II clinical trial with pegylated liposomal doxorubicin (Caelyx®/Doxil®) and quality of life evaluation (EORTC QLQ-C30) in adult patients with advanced soft tissue sarcomas: a study of the Spanish Group for Research in Sarcomas (GEIS). Sarcoma. 2005;9:127–132. CrossRef
- Riganti C, Voena C, Kopecka J, Corsetto PA, Montorfano G, Enrico E, Costamagna C, Rizzo AM, Ghigo D, Bosia A. Liposome-encapsulated doxorubicin reverses drug resistance by inhibiting P-glycoprotein in human cancer cells. Mol Pharm. 2011;8:683–700. CrossRef
- Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (Lond). 2008;3:761–776. CrossRef
- Schuurhuis GJ, Broxterman HJ, Cervantes A, van Heijningen TH, de Lange JH, Baak JP, Pinedo HM, Lankelma J. Quantitative determination of factors contributing to doxorubicin resistance in multidrug-resistant cells. J Natl Cancer Inst. 1989;81:1887–1892. CrossRef
- Schwartz CL, Gorlick R, Teot L, Krailo M, Chen Z, Goorin A, Grier HE, Bernstein ML, Meyers P. Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children’s Oncology Group. J Clin Oncol. 2007;25:2057–2062. CrossRef
- Shapira A, Livney YD, Broxterman HJ, Assaraf YG. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist Updat. 2011;14:150–163. CrossRef
- Shnyder SD, Hayes AJ, Pringle J, Archer CW. P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma. Br J Cancer. 1998;78:757–759. CrossRef
- Sikic BI. Pharmacologic approaches to reversing multidrug resistance. Semin Hematol. 1997;34:40–47.
- Smeets M, Raymakers R, Vierwinden G, Pennings A, van de Locht L, Wessels H, Boezeman J, de Witte T. A low but functionally significant MDR1 expression protects primitive haemopoietic progenitor cells from anthracycline toxicity. Br J Haematol. 1997;96:346–355. CrossRef
- Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova R, Solbu G, Lokhorst H, van der Lelie J, Dohner H, Gerhartz H, Segeren CM, Willemze R, Lowenberg B. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol. 2001;115:895–902. CrossRef
- Sugawara I, Kataoka I, Morishita Y, Hamada H, Tsuruo T, Itoyama S, Mori S. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res. 1988;48:1926–1929.
- Sun HW, Wu C, Tan HY, Wang QS. Combination DLL4 with Jagged1-siRNA can enhance inhibition of the proliferation and invasiveness activity of human gastric carcinoma by Notch1/VEGF pathway. Hepatogastroenterology. 2012;59:924–929.
- Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, Milane L, Amiji MM, Duan Z. Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma. PLoS One. 2010;5:e10764. CrossRef
- Susa M, Iyer AK, Ryu K, Hornicek FJ, Mankin H, Amiji MM, Duan Z. Doxorubicin loaded polymeric nanoparticulate delivery system to overcome drug resistance in osteosarcoma. BMC Cancer. 2009;9:399. CrossRef
- Talekar M, Kendall J, Denny W, Garg S. Targeting of nanoparticles in cancer: drug delivery and diagnostics. Anticancer Drugs. 2011;22:949–962. CrossRef
- Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4:145–160. CrossRef
- Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99:3181–3198. CrossRef
- van der Valk P, van Kalken CK, Ketelaars H, Broxterman HJ, Scheffer G, Kuiper CM, Tsuruo T, Lankelma J, Meijer CJ, Pinedo HM, et al. Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic human tissues: analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol. 1990;1:56–64.
- van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 2007;67:4843–4850. CrossRef
- van Vlerken LE, Vyas TK, Amiji MM. Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery. Pharm Res. 2007;24:1405–1414. CrossRef
- Whelan JS, Jinks RC, McTiernan A, Sydes MR, Hook JM, Trani L, Uscinska B, Bramwell V, Lewis IJ, Nooij MA, van Glabbeke M, Grimer RJ, Hogendoorn PC, Taminiau AH, Gelderblom H. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol. 2012;23:1607–1616. CrossRef
- Willingham MC, Cornwell MM, Cardarelli CO, Gottesman MM, Pastan I. Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs. Cancer Res. 1986;46:5941–5946.
- Wunder JS, Bull SB, Aneliunas V, Lee PD, Davis AM, Beauchamp CP, Conrad EU, Grimer RJ, Healey JH, Rock MJ, Bell RS, Andrulis IL. MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study. J Clin Oncol. 2000;18:2685–2694.
- Zheng L, Ren JQ, Li H, Kong ZL, Zhu HG. Downregulation of wild-type p53 protein by HER-2/neu mediated PI3 K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy. Cell Res. 2004;14:497–506. CrossRef
- Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study
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Volume 471, Issue 3 , pp 915-925
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- 1. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St, Jackson 1115, Boston, MA, 02114, USA
- 2. Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, USA
- 3. Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
- 4. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA