JBNB  Vol.3 No.1 , January 2012
Multidrug Delivery Systems with Single Formulation——Current status and Future Perspective
Development of new way and system for multidrug delivery has recently attracted much attention and became one of major issue in drug delivery research. Although this research field is still immature compared to the single drug delivery system, intensive efforts have recently been devoted by researchers in order to realize more efficient, functional, and safe combination therapy using multiple drugs or agents. In this review article, we outline several targets in terms of application for biochemical modulation together with various concrete attempts of simultaneous and sequential delivery of multiple drugs or agents with single formulation. Finally, we will also summarize the possible contribution of biomaterial sciences and nanobiotechnology for improvement of future multidrug delivery system.

Cite this paper
T. Okuda and S. Kidoaki, "Multidrug Delivery Systems with Single Formulation——Current status and Future Perspective," Journal of Biomaterials and Nanobiotechnology, Vol. 3 No. 1, 2012, pp. 50-60. doi: 10.4236/jbnb.2012.31007.
[1]   D. S. Martin, R. L. Stolfi, R. C. Sawyer and C. W. Young, “Application of Biochemical modulation with a Therapeutically Inactive Modulating Agent in Clinical Trials of Cancer Chemotherapy,” Cancer Treatment Report, Vol. 69, No. 4, 1985, pp. 421-423.

[2]   B. Leyland-Jones and P. J. O’Dwyer, “Biochemical Modulation: Application of Labolatory Models to the Clinic,” Cancer Treatment Report, Vol. 70, No. 1, 1986, pp. 219-229.

[3]   J. R. Bertino, W. L. Sawicki, C. A. Lindquist and V. S. Gupta, “Schedule-Dependent Antitumor Effects of Methotrexate and 5-Fluorouracil,” Cancer Research, Vol. 37, No. 1, 1977, pp. 327-328.

[4]   C. Tournigand et al., “FOLFIRI followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study,” Journal of Clinical Oncology, Vol. 22, No. 2, 2004, pp. 229-237. doi:10.1200/JCO.2004.05.113

[5]   F. Maindrault-Goebe et al., “High-dose Intensity Oxaliplatin Added to the Simplified Bimonthly Leucovorin and 5-Fluorouracil Regimen as Second-Line Therapy for Metastatic Colorectal Cancer (FOLFOX 7),” European Journal of Cancer, Vol. 37, No. 8, 2001, pp. 1000-1005. doi:10.1016/S0959-8049(01)00068-5

[6]   J. C. Bendell, et al., “Randomized Phase II Study of Perifosine in combination with Capecitabine (P-CAP) versus Capecitabine Plus Placebo (CAP) in Patients with second- or Third-line Metastatic Colon Cancer (mCRC): Updated Results,” Gastrointestinal Cancers Symposium, Orland, 22-24 January 2010.

[7]   M. Peeters, et al., “Randomized Phase III Study of Panitumumab (pmab) with FOLFIRI versus FOLFIRI Alone as Second-Line Treatment (tx) in Patients (pts) with Metastatic Colorectal Cancer (mCRC): Patient-Reported Outcomes (PRO),” Gastrointestinal Cancers Symposium, Orland, 22-24 January 2010.

[8]   V. Torchilin, “Recent Advances with Liposomes as Pharmaceutical Carriers,” Nature Reviews Drug Discovery, Vol. 4, No. 2, 2005, pp. 145-160. doi:10.1038/nrd1632

[9]   Y. Kakizawa and K. Kataoka, “Block Copolymer Micelles for Delivery of Gene and Related Compounds,” Advanced Drug Delivery Reviews, Vol. 54, No. 2, 2002, pp. 203-222. doi:10.1016/S0169-409X(02)00017-0

[10]   M. Yokoyama, “Polymeric Micelles as a New Drug Carrier System and Their Required Considerations for Clinical Trials,” Expert Opinion on Drug Delivery, Vol. 7, No. 2, 2010, pp. 145-158. doi:10.1517/17425240903436479

[11]   C. Amin, N. Mackman, and N. S. Key, “Microparticles and Cancer,” Pathophysiology of Haemostasis and Thrombosis, Vol. 36, No. 3-4, 2008, pp. 177-183. doi:10.1159/000175155

[12]   H. Maeda, T. Sawa and T. Konno, “Mechanism of Tumor-Targeted Delivery of Macromolecular Drugs, Including the EPR Effect in Solid Tumor and Clinical Overview of the Prototype Polymeric Drug SMANCS,” Journal of Controlled Release, Vol. 74, No. 1-3, 2001, pp. 47-61. doi:10.1016/S0168-3659(01)00309-1

[13]   N. D. James, et al., “Liposomal Doxorubicin (Doxil): An Effective New Treatment for Kaposi’s Sarcoma in AIDS,” Clinical oncology, Vol. 6, No. 5, 1994, pp. 294-296. doi: 10.1016/S0936-6555(05)80269-9

[14]   S. de Marie, R. Janknegt, and I. A. Bakker-Woudenberg, “Clinical Use of Liposomal and Lipid-Complexed Amphotericin B,” The Journal of Antimicrobial Chemotherapy, Vol. 33, No. 5, 1994, pp. 907-916. |doi:10.1093/jac/33.5.907

[15]   M. Harries, P. Ellis and P. Harper, “Nanoparticle Albumin-Bound Paclitaxel for Metastatic Breast Cancer,” Journal of clinical oncology, Vol. 23, No. 31, 2005, pp. 7768-7771. doi:10.1200/JCO.2005.08.002

[16]   F. Greco and M. J. Vicent, “Combination Therapy: Opportunities and Challenges for Polymer-Drug Conjugates as Anticancer Nanomedicines,” Advanced Drug Delivery Reviews, Vol. 61, No. 13, 2009, pp. 1203-1213. doi:10.1016/j.addr.2009.05.006

[17]   C.-M. J. Hu, S. Aryal and L. Zhang, “Nanoparticle-Assisted Combination Therapies for Effective Cancer Treatment,” Therapeutic Delivery, Vol. 1, No. 2, 2010, pp. 323-334. doi:10.4155/tde.10.13

[18]   H. Zhang, G. Wang, and H. Yang, “Drug Delivery Systems for Differential Release in Combination Therapy,” Expert Opinion on Drug Delivery, Vol. 8, No. 2, 2011, pp. 171-190. doi:10.1517/17425247.2011.547470

[19]   L. Santucci, et al., “Nitric Oxide Modulates Proapoptotic and Antiapoptotic Properties of Chemotherapy Agents: The Case of NO-Pegylated Epirubicin,” The FASEB Journal, Vol. 20, No. 6, 2006, pp. 765-767. doi:10.1096/fj.05-4452fje

[20]   G. Pasut, et al., “Polymer-Drug Conjugates for Combination Anticancer Therapy: Investigating the Mechanism of Action,” Journal of Medicinal Chemistry, Vol. 52, No. 20, 2009, pp. 6499-6502. doi:10.1021/jm900804m

[21]   Q. Wu, R. Kreienberg and I. B. Runnebaum, “Growth Suppression of Human Ovarian Carcinoma OV-MZ-2a and OV-MZ-32 Cells Mediated by Gene Transfer of Wild-Type p53 Enhanced by Chemotherapy in Vitro,” Journal of Cancer Research and Clinical Oncology, Vol. 126, No. 3, 2000, pp. 139-144. doi:10.1007/s004320050023

[22]   N. Wiradharma, Y. W. Tong and Y. Y. Yang, “Self-Assembled Oligopeptide Nanostructures for Co-Delivery of Drug and Gene with Synergistic Therapeutic Effect,” Biomaterials, Vol. 30, No. 17, 2009, pp. 3100-3109. doi: 10.1016/j.biomaterials.2009.03.006

[23]   S. Shin, et al., “An anti-Apoptotic Protein Human Survivin Is a Direct Inhibitor of Caspase-3 and -7,” Biochemistry, Vol. 40, No. 4, 2001, pp. 1117-1123. doi:10.1021/bi001603q

[24]   A. Chandele, V. Prasad, J. C. Jagtap, R. Shukla and P. R. Shastry, “Upregulation of Survivin in G2/M Cells and Inhibition of Caspase 9 Activity Enhances Resistance in Staurosporine-Induced Apoptosis,” Neoplasia, Vol. 6, No. 1, 2004, pp. 29-40.

[25]   J. C. Reed, “The Survivin Saga Goes in Vivo,” The Jour- nal of Clinical Investigation, Vol. 108, No. 7, 2001, pp. 965-969. doi:10.1172/JCI14123

[26]   W. Xiao, X. Chen, L. Yang, Y. Mao, Y. Wei and L. Chen, “Co-Delivery of Doxorubicin and Plasmid by a Novel FGFR-Mediated Cationic Liposome,” International Journal of Pharmaceutics, Vol. 393, No. 1-2, 2010, pp. 119-126. doi:10.1016/j.ijpharm.2010.04.018

[27]   Z. Xu, Z. Zhang, Y. Chen, L. Chen, L. Lin and Y. Li, “The Characteristics and Performance of a Multifunctional Nanoassembly System for the Co-Delivery of Docetaxel and iSur-pDNA in a Mouse Hepatocellular Carcinoma Model,” Biomaterials, Vol. 31, No. 5, 2010, pp. 916-922. doi:10.1016/j.biomaterials.2009.09.103

[28]   G. M. Tozer, C. Kanthou and B. C. Baguley, “Disrupting Tumour Blood Vessels,” Nature Reviews Cancer, Vol. 5, No. 6, 2005, pp. 423-435. doi:10.1038/nrc1628

[29]   Y.-F. Zhang, J.-C. Wang, D.-Y. Bian, X. Zhang and Q. Zhang, “Targeted Delivery of RGD-Modified Liposomes Encapsulating both Combretastatin A-4 and Doxorubicin for Tumor Therapy: In Vitro and in Vivo Studies,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 74, No. 3, 2010, pp. 467-473. doi:10.1016/j.ejpb.2010.01.002

[30]   Z. Wang and P. C. Ho, “A Nanocapsular Combinatorial Sequential Drug Delivery System for Antiangiogenesis and Anticancer Activities,” Biomaterials, Vol. 31, No. 27, 2010, pp. 7115-7123. doi:10.1016/j.biomaterials.2010.05.075

[31]   T. Yang, et al., “Targeted Delivery of a Combination Therapy Consisting of Combretastatin A4 and Low-Dose Doxorubicin against Tumor Neovasculature,” Nanomedicine: nanotechnology, biology, and medicine, 2011, in press. doi:10.1016/j.nano.2011.05.003

[32]   D. Ingber, et al., “Synthetic Analogues of Fumagillin that Inhibit Angiogenesis and Suppress Tumour Growth,” Nature, Vol. 348, No. 6301, 1990, pp. 555-557. doi:10.1038/348555a0

[33]   R. Satchi-Fainaro, et al., “Targeting Angiogenesis with a Conjugate of HPMA Copolymer and TNP-470” Nature Medicine, Vol. 10, No. 3, 2004, pp. 255-261. doi:10.1038/nm1002

[34]   E. Segal, et al., “Targeting Angiogenesis-Dependent Calcified Neoplasms Using Combined Polymer Therapeutics,” PloS One, Vol. 4, No. 4, 2009, p. e5233. doi:10.1371/journal.pone.0005233

[35]   C. Zhu, et al., “Co-Delivery of siRNA and Paclitaxel into Cancer Cells by Biodegradable Cationic Micelles Based on PDMAEMA-PCL-PDMAEMA Triblock Copolymers,” Bioma-terials, Vol. 31, No. 8, 2010, pp. 2408-2416. doi:10.1016/j.biomaterials.2009.11.077

[36]   H.-Y. Huang, W.-T. Kuo, M.-J. Chou and Y.-Y. Huang, “Co-Delivery of Anti-Vascular Endothelial Growth Factor siRNA and Doxorubicin by Multifunctional Polymeric Micelle for Tumor Growth Suppression,” Journal of Biomedical Materials Re-search Part A, Vol. 97, No. 3, 2011, pp. 330-338. doi:10.1002/jbm.a.33055

[37]   J. Wang, et al., “In Vitro Cytotoxicity of Stealth Lipo- somes Co-Encapsulating Doxorubicin and Verapamil on Doxorubicin-Resistant Tumor Cells,” Biological & Pharmaceutical Bulletin, Vol. 28, No. 5, 2005, pp. 822-828. doi:10.1248/bpb.28.822

[38]   J. Wu, et al., “Reversal of Multidrug Resistance by Transferrin-Conjugated Liposomes Co-Encapsulating Doxorubicin and Verapamil,” Journal of Pharmacy & Pharmaceutical Sciences, Vol. 10, No. 3, 2007, pp. 350-357.

[39]   Z. Liu, X. Y. Wu and R. Bendayan, “In Vitro Investigation of Ionic Polysaccharide Microspheres for Simultaneous Delivery of Chemosensitizer and Antineoplastic Agent to Multidrug-Resistant Cells,” Journal of Pharmaceutical Sciences, Vol. 88, No. 4, 1999, pp. 412-418. doi:10.1021/js9803353

[40]   C. E. Soma, C. Dubernet, D. Bentolila, S. Benita and P. Couvreur, “Reversion of Multidrug Resistance by Co-Encapsulation of Doxorubicin and Cyclosporin A in Polyalkylcyanoacrylate Nanoparticles,” Biomaterials, Vol. 21, No. 1, 2000, pp. 1-7. doi:10.1016/S0142-9612(99)00125-8

[41]   X. Song, et al., “PLGA Nanoparticles Simultaneously Loaded with Vincristine Sulfate and Verapamil Hydrochloride: Systematic Study of Particle Size and Drug Entrapment Efficiency,” International Journal of Pharmaceutics, Vol. 350, No. 1-2, 2008, pp. 320-329. doi:10.1016/j.ijpharm.2007.08.034

[42]   X. R. Song, et al., “Reversion of Multidrug Resistance by Co-Encapsulation of Vincristine and Verapamil in PLGA Nanoparticles,” European Journal of Pharmaceutical Sciences, Vol. 37, No. 3-4, 2009, pp. 300-305. doi:10.1016/j.ejps.2009.02.018

[43]   Y. Patil, T. Sadhukha, L. Ma and J. Panyam, “Nanoparticle-Mediated Simultaneous and Targeted Delivery of Paclitaxel and Tariquidar Overcomes Tumor Drug Resistance,” Journal of Controlled Release, Vol. 136, No. 1, 2009, pp. 21-29. doi:10.1016/j.jconrel.2009.01.021

[44]   H. L. Wong, R. Bendayan, A. M. Rauth and X. Y. Wu, “Development of Solid Lipid Nanoparticles Containing Ionically Complexed Chemotherapeutic Drugs and Chemosensitizers,” Journal of Pharmaceutical Sciences, Vol. 93, No. 8, 2004, pp. 1993-2008. doi:10.1002/jps.20100

[45]   H. L. Wong, R. Bendayan, A. M. Rauth and X. Y. Wu, “Simultaneous Delivery of Doxorubicin and GG918 (Elacridar) by New Polymer-Lipid Hybrid Nanoparticles (PLN) for Enhanced Treatment of Multidrug-Resistant Breast Cancer,” Journal of Controlled Release, Vol. 116, No. 3, 2006, pp. 275-284. doi:10.1016/j.jconrel.2006.09.007

[46]   R. I. Pakunlu, Y. Wang, M. Saad, J. J. Khandare, V. Starovoytov and T. Minko, “In Vitro and in Vivo Intracellular Liposomal Delivery of Antisense Oligonucleotides and Anticancer Drug,” Journal of controlled release, Vol. 114, No. 2, 2006, pp. 153-162. doi: 0.1016/j.jconrel.2006.06.010

[47]   X.-B. Xiong and A. Lavasanifar, “Traceable Multifunctional Micellar Nanocarriers for Cancer-Targeted Co-Delivery of MDR-1 siRNA and Doxorubicin,” ACS Nano, Vol. 5, No. 6, 2011, pp. 5202-5213. doi:10.1021/nn2013707

[48]   S. Sengupta, et al., “Temporal Targeting of Tumour Cells and Neovasculature with a Nano-scale Delivery System,” Nature, Vol. 436, No. 7050, 2005, pp. 568-572. doi:10.1038/nature03794

[49]   H. Nie, Z. Dong, D. Y. Arifin, Y. Hu and C.-H. Wang, “Core/Shell Microspheres via Coaxial Electrohydrodynamic Atomization for Sequential and parallel Release of Drugs,” Journal of Biomedical Materials Research Part A, Vol. 95, No. 3, 2010, pp. 709-716. doi:10.1002/jbm.a.32867

[50]   X. Hao, et al., “Angiogenic Effects of Sequential Release of VEGF-A165 and PDGF-BB with Alginate Hydrogels after Myocardial Infarction,” Cardiovascular Research, Vol. 75, No. 1, 2007, pp. 178-185. doi:10.1016/j.cardiores.2007.03.028

[51]   A. T. Raiche and D. A. Puleo, “In Vitro EFfects of Combined and Sequential Delivery of Two Bone Growth Factors,” Biomaterials, Vol. 25, No. 4, 2004, pp. 677-685. doi:10.1016/S0142-9612(03)00564-7

[52]   R. R. Chen, E. A. Silva, W. W. Yuen and D. J. Mooney, “Spatio-Temporal VEGF and PDGF Delivery Patterns Blood Vessel Formation and Maturation,” Pharmaceutical Research, Vol. 24, No. 2, 2007, pp. 258-264. doi:10.1007/s11095-006-9173-4

[53]   C. Strobel, N. Bormann, A. Kadow-Romacker, G. Schmi- dmaier and B. Wildemann, “Sequential Release Kinetics of Two (Gentamicin and BMP-2) or Three (Gentamicin, IGF-I and BMP-2) Substances from a One-Component Polymeric Coating on Implants,” Journal of Controlled Release, Vol. 156, No. 1, 2011, pp. 37-45. doi:10.1016/j.jconrel.2011.07.006

[54]   F. B. Basmanav, G. T. Kose and V. Hasirci, “Sequential Growth Factor Delivery from Complexed microspheres for Bone Tissue Engineering,” Biomaterials, Vol. 29, No. 31, 2008, pp. 4195-4204. doi:10.1016/j.biomaterials.2008.07.017

[55]   P. Yilgor, K. Tuzlakoglu, R. L. Reis, N. Hasirci and V. Hasirci, “Incorporation of a Sequential BMP-2/BMP-7 Delivery System into Chitosan-Based Scaffolds for Bone Tissue Engineering,” Biomaterials, Vol. 30, No. 21, 2009, pp. 3551-3559. doi:10.1016/j.biomaterials.2009.03.024

[56]   Q. Sun, et al., “Sustained Release of Multiple Growth Factors from Injectable Polymeric System as a Novel Therapeutic Approach towards Angiogenesis,” Pharmaceutical Research, Vol. 27, No. 2, 2010, pp. 264-271. doi:10.1007/s11095-009-0014-0

[57]   J. A. MacDiarmid, et al., “Sequential Treatment of Drug- Resistant Tumors with Targeted Minicells Containing siRNA or a Cytotoxic Drug,” Nature biotechnology, Vol. 27, No. 7, 2009, pp. 643-651. doi:10.1038/nbt.1547

[58]   J. Jiangm, et al., “Sequential Treatment of Drug-Resistant Tumors with RGD-Modified Liposomes Containing siRNA or Doxorubicin,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 76, No. 2, 2010, pp. 170-178. doi:10.1016/j.ejpb.2010.06.011

[59]   P. Yilgor, N. Hasirci and V. Hasirci, “Sequential BMP-2/ BMP-7 Delivery from Polyester Nanocapsules,” Journal of Biomedical Materials Research Part A, Vol. 93, No. 2, 2010, pp. 528-536. doi:10.1002/jbm.a.32520

[60]   J. E. Tengood, K. M. Kovach, P. E. Vescovi, A. J. Russell and S. R. Little, “Sequential Delivery of Vascular Endothelial Growth Factor and Sphingosine 1-Phosphate for Angiogenesis,” Biomaterials, Vol. 31, No. 30, 2010, pp. 7805-7812. doi:10.1016/j.biomaterials.2010.07.010

[61]   W. Xia, J. Chang, J. Lin and J. Zhu, “The pH-Controlled Dual-Drug Release from Mesoporous Bioactive Glass/ Polypeptide Graft Copolymer Nanomicelle Composites,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 69, No. 2, 2008, pp. 546-552. doi:10.1016/j.ejpb.2007.11.018

[62]   L. Wei, C. Cai, J. Lin and T. Chen, “Dual-Drug Delivery System Based on Hydrogel/Micelle Composites,” Bio-materials, Vol. 30, No. 13, 2009, pp. 2606-2613. doi:10.1016/j.biomaterials.2009.01.006

[63]   T. Okuda, K. Tominaga and S. Kidoaki, “Time-Programmed Dual Release Formulation by Multilayered Drug-Loaded Nanofiber Meshes,” Journal of Controlled Release, Vol. 143, No. 2, 2010, pp. 258-264. doi:10.1016/j.jconrel.2009.12.029

[64]   A. S. Barbas, J. Mi, B. M. Clary and R. R. White, “Aptamer Applications for Targeted Cancer Therapy,” Future Oncology, Vol. 6, No. 7, 2010, pp. 1117-1126. doi:10.2217/fon.10.67

[65]   X.-B. Xiong and A. Lavasanifar, “Traceable Multifunctional Micellar Nanocarriers for Cancer-Targeted Co-Delivery of MDR-1 siRNA and Doxorubicin,” ACS Nano, Vol. 5, No. 6, 2011, pp. 5202-5213. doi:10.1021/nn2013707

[66]   A. Singh, F. Dilnawaz, S. Mewar, U. Sharma, N. R. Jagannathan and S. K. Sahoo, “Composite Polymeric Magnetic Nanoparticles for Co-Delivery of Hydrophobic and Hydrophilic Anticancer Drugs and MRI Imaging for Cancer Therapy,” ACS Applied Materials & Interfaces, Vol. 3, No. 3, 2011, pp. 842-856. doi:10.1021/am101196v

[67]   C.-C. Huang, W. Huang and C.-S. Yeh, “Shell-by-Shell Synthesis of Multi-Shelled Mesoporous Silica Nanospheres for Optical Imaging and Drug Delivery,” Biomaterials, Vol. 32, No. 2, 2011, pp. 556-564. doi: 0.1016/j.biomaterials.2010.08.114