Skip to main content
Log in

Developing macromolecular therapeutics: the future drug-of-choice

  • Review Article
  • Published:
Frontiers of Chemical Engineering in China Aims and scope Submit manuscript

Abstract

Macromolecular drugs including peptides, proteins, antibodies, polysaccharides and nucleic acids have been widely used for therapy of major diseases such as carcinoma and AIDS as well as cardiovascular and neurodegenerative disorders among other medical conditions. Due to their unmatched properties of high selectivity and efficiency, macromolecular drugs have been recognized as the drug-of-choice of the future. Since worldwide progress on macromolecular therapeutics still remains in the infant stage and is therefore wide open for equal-ground competition, R&D related to macromolecular drugs should be considered as the main point of focus in China in setting up its strategic plans in pharmaceutical development. In this article, research strategies and drug delivery approaches that should be adopted to enhance the therapeutic effects of macromolecular drugs are reviewed. In addition, comments concerning how to implement such strategies to excel from competition in this challenging research field, such as the design of innovative and highly effective delivery systems of macromolecular drugs with self-owned intellectual property rights, are provided.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Delivery Rev, 2002, 54: 631–651

    Article  CAS  Google Scholar 

  2. Dreher M R, Liu W, Michelich C R, Dewhirst M W, Yuan F, Chilkoti A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst, 2006, 98: 335–344

    Article  CAS  Google Scholar 

  3. Maeda H, Seymour L W, Miyamoto Y. Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjugate Chem, 2002, 3: 351–362

    Article  Google Scholar 

  4. Takakura Y, Hashida M. Macromolecular drug carrier systems in cancer chemotherapy: macromolecular prodrugs. Crit Rev in Oncol Hematol, 1995, 18: 207–231

    Article  CAS  Google Scholar 

  5. Defoort J P, Nardelli B, Huang W, Ho D D, Tam J P. Macromolecular assemblage in the design of a synthetic AIDS vaccine. Proc Natl Acad Sci USA, 1992, 89: 3879–3883

    Article  CAS  Google Scholar 

  6. Hamajima K, Bukawa H, Fukushima J, Kawamoto S, Kaneko T, Sekigawa K I, Tanaka S I, Tsukuda M, Okuda K. A macromolecular multicomponent peptide vaccine prepared using the glutaraldehyde conjugation method with strong immunogenicity for HIV-1. Clin Immunol Immunopathol, 1995, 77: 374–379

    Article  CAS  Google Scholar 

  7. Greenberg S, Frishman W. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol, 1990, 30: 596–608

    CAS  Google Scholar 

  8. Torchilin V P. Targeting of drugs and drug carriers within the cardiovascular system. Adv Drug Delivery Rev, 1995, 17: 75–101

    Article  CAS  Google Scholar 

  9. Chang C-T L, Liou H-Y, Tang H L, Sung H Y. Activation, purification and properties of beta-amylase from sweet potatoes (Ipomoea batatas). Biotechnol Appl Biochem, 1996, 24: 13–18

    CAS  Google Scholar 

  10. Noda T, Furuta S, Suda I. Sweet potato [beta]-amylase immobilized on chitosan beads and its application in the semi-continuous production of maltose. Carbohydr Polym, 2001, 44: 189–195

    Article  CAS  Google Scholar 

  11. Buchner J, Pastan I, Brinkmann U. A method for increasing the yield of properly folded recombinant fusion proteins: single-chain immunotoxins from renaturation of bacterial inclusion bodies. Anal Biochem, 1992, 205: 263–270

    Article  CAS  Google Scholar 

  12. Chen C, Ridzon D A, Broomer A J, Zhou Z, Lee D H, Nguyen J T, Barbisin M, Xu N L, Mahuvakar V R, Andersen M R, Lao K Q, Livak K J, Guegler K J. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucl Acids Res, 2005, 33: e179

    Article  CAS  Google Scholar 

  13. Gibson U E, Heid C A, Williams P M. A novel method for real time quantitative RT-PCR. Genome Res, 1996, 6: 995–1001

    Article  CAS  Google Scholar 

  14. Siebert P D, Chenchik A, Kellogg D E, Lukyanov K A, Lukyanov S A. An improved PCR method for walking in uncloned genomic DNA. Nucl Acids Res, 1995, 23: 1087–1088

    Article  CAS  Google Scholar 

  15. Gerrard A J, Hudson D L, Brownlee G G, Watt F M. Towards gene therapy for haemophilia B using primary human keratinocytes. Nat Genet, 1993, 3: 180–183

    Article  CAS  Google Scholar 

  16. Pipe S W. Coagulation factors with improved properties for hemophilia gene therapy. Semin Thromb Hemost, 2004, 30: 227–237

    Article  CAS  Google Scholar 

  17. Suh J S, Lee J Y, Choi Y S, Yu F, Yang V, Lee S J, Chung C P, Park Y J. Efficient labeling of mesenchymal stem cells using cell permeable magnetic nanoparticles. Biochem Biophys Res Commun, 2009, 379: 669–675

    Article  CAS  Google Scholar 

  18. Allen T M, Cullis P R. Drug delivery systems: entering the mainstream. Science, 2004, 303: 1818–1822

    Article  CAS  Google Scholar 

  19. Creque H M, Langer R, Folkman J. One month of sustained release of insulin from a polymer implant. Diabetes, 1980, 29: 37–40

    Article  CAS  Google Scholar 

  20. Drummond D C, Meyer O, Hong K, Kirpotin D B, Papahadjopoulos D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev, 1999, 51: 691–744

    CAS  Google Scholar 

  21. Harrington K J, Lewanski C R, Stewart J S W. Liposomes as vehicles for targeted therapy of cancer. Part 1: Preclinical development. Clin Oncol, 2000, 12: 2–15

    CAS  Google Scholar 

  22. Lukyanov A N, Elbayoumi T A, Chakilam A R, Torchilin V P. Tumor-targeted liposomes: doxorubicin-loaded long-circulating liposomes modified with anti-cancer antibody. J Controlled Release, 2004, 100: 135–144

    Article  CAS  Google Scholar 

  23. Templeton N S, Lasic D D, Frederik P M, Strey H H, Roberts D D, Pavlakis G N. Improved DNA: liposome complexes for increased systemic delivery and gene expression. Nat Biotech, 1997, 15: 647–652

    Article  CAS  Google Scholar 

  24. Barichello J M, Morishita M, Takayama K, Nagai T. Encapsulation of hydrophilic and lipophilic drugs in PLGA nanoparticles by the nanoprecipitation method. Drug Dev Ind Pharm, 1999, 25: 471–476

    Article  CAS  Google Scholar 

  25. Deamer D W, Barchfeld G L. Encapsulation of macromolecules by lipid vesicles under simulated prebiotic conditions. J Mol Evol, 1982, 18: 203–206

    Article  CAS  Google Scholar 

  26. Grenha A, Seijo B, Remuñán-López C. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci, 25: 427–437

  27. Radtchenko I L, Sukhorukov G B, Möhwald H. Incorporation of macromolecules into polyelectrolyte micro- and nanocapsules via surface controlled precipitation on colloidal particles. Colloids SurfA, 2002, 202: 127–133

    Article  CAS  Google Scholar 

  28. Hariharan S, Bhardwaj V, Bala I, Sitterberg J, Bakowsky U, Ravi Kumar M. Design of estradiol loaded PLGA nanoparticulate formulations: a potential oral delivery system for hormone therapy. Pharm Res, 2006, 23: 184–195

    Article  CAS  Google Scholar 

  29. Carino G P, Jacob J S, Mathiowitz E. Nanosphere based oral insulin delivery. J Controlled Release, 2000, 65: 261–269

    Article  CAS  Google Scholar 

  30. Lowman A M, Morishita M, Kajita M, Nagai T, Peppas N A. Oral delivery of insulin using pH-responsive complexation gels. J Pharm Sci, 1999, 88: 933–937

    Article  CAS  Google Scholar 

  31. Liu X, Pettway G J, McCauley L K, Ma P X. Pulsatile release of parathyroid hormone from an implantable delivery system. Biomaterials, 2007, 28: 4124–4131

    Article  CAS  Google Scholar 

  32. Song H, Liang J F, Yang V C. A prodrug approach for delivery of t-PA: construction of the cationic t-PA prodrug by a recombinant method and preliminary in vitro evaluation of the construct. ASAIO J, 2000, 46: 663–668

    Article  CAS  Google Scholar 

  33. Duncan R. Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharmaceut Sci Tech Today, 1999, 2: 441–449

    Article  CAS  Google Scholar 

  34. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Advances in Enzyme Regulation, 2001, 41: 189–207

    Article  CAS  Google Scholar 

  35. Maeda H, Sawa T, Konno T. 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, 2001, 74: 47–61

    Article  CAS  Google Scholar 

  36. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. Journal of Controlled Release, 2000, 65: 271–284

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  38. Ahmad I, Longenecker M, Samuel J, Allen T M. Antibody-targeted delivery of doxorubicin entrapped in sterically stabilized liposomes can eradicate lung cancer in mice. Cancer Res, 1993, 53: 1484–1488

    CAS  Google Scholar 

  39. Baselga J, Norton L, Albanell J, Kim Y M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (herceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res, 1998, 58: 2825–2831

    CAS  Google Scholar 

  40. Tardi P, Boman N, Cullis P. Liposomal doxorubicin. Journal of Drug Targeting, 1996, 4: 129–140

    Article  CAS  Google Scholar 

  41. Yang H M, Reisfeld R A. Doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice. Proc Natl Acad Sci USA, 1988, 85: 1189–1193

    Article  CAS  Google Scholar 

  42. Davis TA, Grillo-Lopez A J, White C A, McLaughlin P, Czuczman M S, Link B K, Maloney D G, Weaver R L, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy in nonhodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol, 2000, 18: 3135–3143

    CAS  Google Scholar 

  43. Davis T A, White C A, Grillo-Lopez A J, Velasquez W S, Link B, Maloney D G, Dillman R O, Williams M E, Mohrbacher A, Weaver R, Dowden S, Levy R. Single-agent monoclonal antibody efficacy in bulky non-hodgkin’s lymphoma: results of a phase II trial of rituximab. J Clin Oncol, 1999, 17: 1851–1857

    CAS  Google Scholar 

  44. Jazirehi A R, Bonavida B. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin’s lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene, 2005, 24: 2121–2143

    Article  CAS  Google Scholar 

  45. Maloney D G, Grillo-Lopez A J, White C A, Bodkin D, Schilder R J, Neidhart J A, Janakiraman N, Foon K A, Liles T M, Dallaire B K, Wey K, Royston I, Davis T, Levy R. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood, 1997, 90: 2188–2195

    CAS  Google Scholar 

  46. Witzig T E, Flinn IW, Gordon L I, Emmanouilides C, Czuczman M S, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani P S, White C A. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol, 2002, 20: 3262–3269

    Article  CAS  Google Scholar 

  47. Gao X, Tao W, Lu W, Zhang Q, Zhang Y, Jiang X, Fu S. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intranasal administration. Biomaterials, 2006, 27: 3482–3490

    Article  CAS  Google Scholar 

  48. Lassalle V, Ferreira M L. PLA nano- and microparticles for drug delivery: an overview of the methods of preparation. Macromolecular Bioscience, 2007, 7: 767–783

    Article  CAS  Google Scholar 

  49. Munier S, Messai I, Delair T, Verrier B, Ataman-Önal Y. Cationic PLA nanoparticles for DNA delivery: comparison of three surface polycations for DNA binding, protection and transfection properties. Colloids and Surfaces B: Biointerfaces, 2005, 43: 163–173

    Article  CAS  Google Scholar 

  50. Elvassore N, Bertucco A, Caliceti P. Production of insulin-loaded poly(ethylene glycol)/poly(1-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques. J Pharm Sci, 2001, 90: 1628–1636

    Article  CAS  Google Scholar 

  51. Janes K A, Calvo P, Alonso M J. Polysaccharide colloidal particles as delivery systems for macromolecules. Adv Drug Delivery Rev, 2001, 47: 83–97

    Article  CAS  Google Scholar 

  52. Chertok B, David A E, Moffat B A, Yang V C. Substantiating in vivo magnetic brain tumor targeting of cationic iron oxide nanocarriers via adsorptive surface masking. Biomaterials, 2009, 30: 6780–6787

    Article  CAS  Google Scholar 

  53. Huang M, Qiao Z, Miao F, Jia N, Shen H. Biofunctional magnetic nanoparticles as contrast agents for magnetic resonance imaging of pancreas cancer. Microchimica Acta, 2009, 167: 27–34

    Article  CAS  Google Scholar 

  54. Zhao M, Kircher M F, Josephson L, Weissleder R. Differential conjugation of tat peptide to superparamagnetic nanoparticles and its effect on cellular uptake. Bioconjugate Chemistry, 2002, 13: 840–844

    Article  CAS  Google Scholar 

  55. Needham D, Dewhirst M W. The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors. Adv Drug Delivery Rev, 2001, 53: 285–305

    Article  CAS  Google Scholar 

  56. Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug Delivery Rev, 2001, 53: 321–339

    Article  CAS  Google Scholar 

  57. Morçöl T, Nagappan P, Nerenbaum L, Mitchell A, Bell S J D. Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. International Journal of Pharmaceutics, 2004, 277: 91–97

    Article  CAS  Google Scholar 

  58. Agnihotri S A, Mallikarjuna N N, Aminabhavi T M. Recent advances on chitosan-based micro- and nanoparticles in drug delivery. Journal of Controlled Release, 2004, 100: 5–28

    Article  CAS  Google Scholar 

  59. Ceh B, Winterhalter M, Frederik P M, Vallner J J, Lasic D D. Stealth® liposomes: from theory to product. Adv Drug Delivery Rev, 1997, 24: 165–177

    Article  CAS  Google Scholar 

  60. Moghimi S M, Szebeni J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Progress in Lipid Research, 2003, 42: 463–478

    Article  CAS  Google Scholar 

  61. Gupta B, Levchenko T S, Torchilin V P. Intracellular delivery of large molecules and small particles by cell-penetrating proteins and peptides. Adv Drug Delivery Rev, 2005, 57: 637–651

    Article  CAS  Google Scholar 

  62. Patel L, Zaro J, Shen W C. Cell penetrating peptides: intracellular pathways and pharmaceutical perspectives. Pharmaceutical Research, 2007, 24: 1977–1992

    Article  CAS  Google Scholar 

  63. Snyder E, Dowdy S. Cell penetrating peptides in drug delivery. Pharmaceutical Research, 2004, 21: 389–393

    Article  CAS  Google Scholar 

  64. Tréhin R, Merkle H P. Chances and pitfalls of cell penetrating peptides for cellular drug delivery. European Journal of Pharmaceutics and Biopharmaceutics, 2004, 58: 209–223

    Article  CAS  Google Scholar 

  65. Fawell S, Seery J, Daikh Y, Moore C, Chen L L, Pepinsky B, Barsoum J. Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci USA, 1994, 91: 664–668

    Article  CAS  Google Scholar 

  66. Frankel A D, Pabo C O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell, 1988, 55: 1189–1193

    Article  CAS  Google Scholar 

  67. Green M, Loewenstein P M. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat transactivator protein. Cell, 1988, 55: 1179–1188

    Article  CAS  Google Scholar 

  68. Derossi D, Joliot A H, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. Journal of Biological Chemistry, 1994, 269: 10444–10450

    CAS  Google Scholar 

  69. Phelan A, Elliott G, O’Hare P. Intercellular delivery of functional p53 by the herpesvirus protein VP22. Nat Biotech, 1998, 16: 440–443

    Article  CAS  Google Scholar 

  70. Byun Y, Chang L C, Lee L M, Han I S, Singh V K, Yang V C. Low molecular weight protamine: a potent but nontoxic antagonist to heparin/low molecular weight protamine. ASAIO Journal, 2000, 46: 435–439

    Article  CAS  Google Scholar 

  71. Byun Y, Singh V K, Yang V C. Low molecular weight protamine: a potential nontoxic heparin antagonist. Thrombosis Research, 1999, 94: 53–61

    Article  CAS  Google Scholar 

  72. Chang L C, Lee H F, Yang Z, Yang V. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (I): Preparation and characterization. The AAPS Journal, 2001, 3: 7–14

    Google Scholar 

  73. Chang L C, Liang J, Lee H F, Lee L, Yang V. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): In vitro evaluation of efficacy and toxicity. The AAPS Journal, 2001, 3: 15–23

    Google Scholar 

  74. Chang L C, Wrobleski S, Wakefield T, Lee L, Yang V. Low molecular weight protamine as nontoxic heparin/low molecular weight heparin antidote (III): Preliminary in vivo evaluation of efficacy and toxicity using a canine model. The AAPS Journal, 2001, 3: 24–31

    Google Scholar 

  75. Liang J F, Zhen L, Chang L C, Yang V C. A less toxic heparin antagonist—low molecular weight protamine. Biochemistry (Moscow), 2003, 68: 116–120

    Article  CAS  Google Scholar 

  76. Park Y J, Chang L C, Liang J F, Moon C, Chung C P, Yang V C. Nontoxic membrane translocation peptide from protamine, low molecular weight protamine (LMWP), for enhanced intracellular protein delivery: in vitro and in vivo study. FASEB J, 2005, 19: 1555–1557

    CAS  Google Scholar 

  77. Park Y J, Liang J F, Ko K S, Kim S W, Yang V C. Low molecular weight protamine as an efficient and nontoxic gene carrier: in vitro study. The Journal of Gene Medicine, 2003, 5: 700–711

    Article  CAS  Google Scholar 

  78. Schwarze S R, Ho A, Vocero-Akbani A, Dowdy S F. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science, 1999, 285: 1569–1572

    Article  CAS  Google Scholar 

  79. Kwon Y M, Li Y, Naik S, Liang J F, Huang Y, Park Y J, Yang V C. The ATTEMPTS delivery systems for macromolecular drugs. Expert Opinion on Drug Delivery, 2008, 5: 1255–1266

    Article  CAS  Google Scholar 

  80. Li Y T, Kwon YM, Spangrude G J, Liang J F, Chung H S, Park Y J, Yang V C. Preliminary in vivo evaluation of the protein transduction domain-modified ATTEMPTS approach in enhancing asparaginase therapy. Journal of Biomedical Materials Research Part A, 2009, 91A: 209–220

    Article  CAS  Google Scholar 

  81. Liang J F, Li Y T, Song H, Park Y J, Naik S S, Yang V C. ATTEMPTS: a heparin/protamine-based delivery system for enzyme drugs. Journal of Controlled Release, 2002, 78: 67–79

    Article  CAS  Google Scholar 

  82. Park Y J, Liang J F, Song H, Li Y T, Naik S, Yang V C. ATTEMPTS: a heparin/protamine-based triggered release system for the delivery of enzyme drugs without associated side-effects. Adv Drug Delivery Rev, 2003, 55: 251–265

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jingkang Wang or Victor C. Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, H., Dong, W., Gong, J. et al. Developing macromolecular therapeutics: the future drug-of-choice. Front. Chem. Eng. China 4, 10–17 (2010). https://doi.org/10.1007/s11705-009-0291-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11705-009-0291-5

Keywords

Navigation