Biomedical Polymers

Drug delivery and molecular imaging

Zheng-Rong Lu,  Assistant Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, USA.

Furong Ye,  Graduate Student, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, USA.

During the last two decades, significant advances have been made in the development of biocompatible polymers as the platform for drug delivery and molecular imaging.

During the last two decades, significant advances have been made in the development of biocompatible polymers as the platform for drug delivery and molecular imaging. The idea of using synthetic and natural biocompatible polymers as a platform to improve pharmacokinetics and delivery efficacy of small molecular therapeutic drugs is not new. Biomedical polymers have been widely used as carriers for drugs for example, polymer-drug conjugates, polymeric micelles, polymer protein conjugates and polyplexes have been designed for the delivery of chemotherapeutics, proteins and gene therapeutics. The conjugation of drugs to polymers can increase solubility and stability of the drugs while reducing their systemic toxicity. The coupling of drugs to water soluble biomedical polymers has the principal effect of limiting cellular uptake by pinocytosis, and therefore altering drug pharmacokinetics at the whole organism and cellular level. The polymer drug conjugates can passively accumulate within solid tumour tissues due to the hyperpermeability of tumour blood vessels and poor lymphatic drainage of tumour tissues, a phenomenon termed as “Enhanced Permeability and Retention (EPR) effect”. Also, polymers can be designed to be multi-functional and can be modified by using targeting-moieties to enhance drug targeting to specific tumour sites.

With the incorporation of imaging agents into biomedical polymers, polymeric drug delivery can also be applied in the design of novel contrast agents or probes for molecular imaging. Unlike traditional diagnostic imaging, molecular imaging has a potential to help imaging various targets or pathways. Imaging modalities that have been applied in human subjects for in vivo evaluation include Ultrasound, Optical Imaging, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI). The incorporation of imaging agents into biocompatible polymers alters their pharmacokinetics, prolongs the retention of the agents in the tissue of interest, improves their specificity, and has a potential to help improve the accuracy of clinical diagnosis. Applications for different imaging modalities include MRI, SPECT, PET, Ultrasound and Optical Imaging.

In fact, the applications of biomedical polymers for drug delivery and molecular imaging are not mutually exclusive. The concept of drug delivery can be combined with molecular imaging to design more effective and specific imaging agents; after labelling the polymeric drug delivery systems with appropriate imaging probes, non-invasive visualisation of the delivery system reveals the complicated mechanisms of in vivo drug delivery and its correlation to pharmacodynamics. The combination of drug delivery and molecular imaging on the same polymer platform will result in more effective image-guided therapies. The earlier a disease can be diagnosed and a therapeutic drug can be delivered, the better the chance that the disease can be cured quickly. This is the rationale for the combination of polymer platform in drug delivery and molecular imaging.

The study of biomedical polymers in drug delivery and molecular imaging is becoming more and more comprehensive. Already, numerous studies have been undertaken on the application of biomedical polymers in optical imaging and MRI, including development of bioactivatable polymeric fluorescence probes, novel biodegradable macromolecular MRI contrast agents, non-invasive visualisation of in vivo drug delivery of polymeric conjugates with contrast-enhanced MRI, bifunctional polymeric conjugates for image-guided interventional procedures and so on. Molecular imaging with macromolecular imaging probes is effective to non-invasively and accurately assess therapeutic efficacy of new therapeutics in both pre-clinical and clinical drug development.

For example, MRI is an imaging modality that measures the difference in the longitudinal or transverse relaxation rates (1/T1 or 1/T2) of water protons in different tissues. Unlike other imaging modalities, MRI provides very high spatial resolution and is very adept at morphological imaging and functional imaging. High-resolution 3D MR imaging becomes particularly relevant when examining heterogeneous structures such as cancer tissues. Clinically approved MRI contrast agents are mostly low molecular weight Gd(III) chelates, including Gd-DOTA, Gd-DTPA and their derivatives. These agents are tissue non-specific and have a transient blood retention time, which lead to short imaging time windows and low signal intensity in the images. Therefore, macromolecular contrast agents have been developed to improve the pharmacokinetic profile of the contrast agents by covalently conjugating them to biomedical polymers including polyamino acids, polysaccharides and proteins. On the other hand, slow excretion of polymers brings in potential toxicity issues because Gd(III) ions are highly toxic and long-term tissue retention of macromolecular MRI contrast agents may result in release of toxic Gd(III) ions due to metabolism. To alleviate the safety concerns related to macromolecular Gd(III) contrast agents, novel designs like polydisulfide Gd(III) complexes and polymer Gd(III) chelate conjugates with disulfide spacers have been introduced. Tissue specific targeted MRI contrast agents could also be developed by incorporating a targeting moiety into the polymer backbone.

With MRI, treatment efficacy can be evaluated over extended periods of time, inter-individual variability is reduced, and therefore statistical significance may be obtained with much smaller groups. Hence, non-invasive visualisation of polymer-drug conjugates’ delivery on in vivo has been applied after labelling the conjugates with imaging probes. Although the MR signal intensity is not linearly correlated to the Gd(III) concentration in the tissues, it provides qualitative or semi-quantitative information about the structural effect of polymeric conjugates on in vivo drug delivery. MR images revealed a size-dependent, dynamic and heterogeneous distribution of the conjugates in organs and tumour tissues and the number of animals used in the study is greatly reduced. Currently, traditional biopsy-based pharmacokinetics studies are still needed for validating the imaging approaches. The two readouts from biopsy and MRI are complementary. Combining sensitive molecular imaging approaches such as PET or optical imaging with MR imaging allows the accurate and assimilated study of the pharmacokinetics / pharmacodynamics of a polymeric drug delivery system.

Polymers have also been used for image guidance and treatment assessment during interventional procedures. Both imaging agents and anti-cancer drugs can be loaded onto the same polymer platform to prepare bifunctional agents for image-guided therapy. The combination of contrast enhanced MRI with photodynamic therapy would provide accurate localisation of interstitial lesions, guiding specific light irradiation to the tumour tissue in photodynamic therapy. This has been demonstrated by using a bifunctional polymer conjugate containing an MRI contrast agent Gd-(DO3A) and a photosensitizer mesochlorin e6 (Mce6), poly-(L-glutamic acid)-(Gd-DO3A)-(Mce6) conjugate.

Biomedical polymers are able to favourably modify the pharmacokinetics of therapeutics and imaging probes and improve their efficacy in therapy or disease characterisation. Biomedical polymers based nanomedicine has a significant advantage over that based inorganic nanomaterials in terms of versatility and safety. Application of biomedical polymers in drug delivery, molecular imaging and nanomedicine will generate new and more efficacious therapeutics and imaging probes to improve human health, which will also create tremendous opportunities to pharmaceutical and biotechnology industry. Currently, several polymer drug conjugates and polymeric imaging agents are in clinical trials in the U.S. and Europe, and one is already being used in Japan.

In summary, the application of biomedical polymers benefits from their large sizes and unique pharmacokinetic properties. It has the potential to have an important impact on the way in which drugs are delivered. The impact will be the establishment of powerful diagnostic and therapeutic tools for pharmaceutical industry in the development of effective drug delivery systems and imaging probes, and non-invasive approaches for pre-clinical and clinical drug development.

References:

1. Haag R. and Kratz F., Polymer therapeutics: concepts and applications, Angew. Chem. Int. Ed. 2006(45): 1198
2. Maeda H., Seymour L.M. and Miyamoto Y., Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjugate Chem, 1992(3): 351
3. Kopecek J., Kopeckova P., Minko T. and Lu Z.-R., HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action, Eur. J. Pharm. Biopharm. 2000(50): 61
4. Kakizawa Y., Kataoka K., Block copolymer micelles for delivery of gene and related compounds, Adv. Drug Deliv. Rev. 2002(54): 203
5. Lavasanifar A., Samuel J., Kwon G.S., Poly (ethylene oxide)-block-poly (L-amino acid) micelles for drug delivery, Adv. Drug Deliv. Rev. 2002(54): 169
6. Harris J.M. and Chess R.B., Effect of pegylation on pharmaceuticals. Nature Rev. Drug Discov. 2003(2): 214
7. Veronese F.M. and Harris J.M., Special issue: peptide and protein PEGylation. Adv. Drug Deliv. Systems 2002(54): 453
8. Duncan R., Kopeckova P., Strohalm J., Hume I., Cable H.C., Pohl J., Lloyd J.B. and Kopecek J., Anticancer agents coupled to [N-(2-hydroxypropyl)methacrylamide] copolymers. 1. Evaluation of daunomycin and puromycin conjugates in vitro. Br. J. Cancer, 1987(55): 165
9. Maeda H., Seymour L.M. and Miyamoto Y., Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjugate Chem. 1992(3): 351
10. Rihova B., Kopeckova P., Strohalm J., Rossmann P., Vetvicka V., Kopecek J., Antibody directed affinity therapy applied to the immune system: in vivo effectiveness and limited toxicity of daunomycin conjugates to HPMA copolymers and targeting antibody. Clin. Immunol. Immunopathol. 1988(46): 100
11. Lu Z.-R., Kopeckova P., Kopecek J., Polymerizable Fab antibody fragments for targeting of anticancer drugs. Nat. Biotechnol. 1999(7): 1101
12. Croy S. R., Kwon G.S., Polymeric micells for drug delivery, Curr. Pharm. Des. 2006(12): 4669-4684
13. Torchilin V.P., Micellar nanocarriers: pharmaceutical perspectives, Pharm. Res. 2007 (24): 1-16
14. Haider M., Hatefi A., Ghandehari H., Recombinant polymers for cancer gene therapy: a minireview, J. Control. Release 2005(109): 108-119
15. Kopecek J., Kopeckova P., Minko T. and Lu Z-R. Water soluble polymers in tumor targeted delivery, J. control. Release 2001(74): 147-158
16. Mohs A.M., Lu Z.R., Gadolinium(III)-based blood-pool contrast agents for magnetic resonance imaging: status and clinical potential, Expert Opin. Drug Deliv. 2007(4): 149-164
17. Mitra A., Coleman T., Borgman M., Nan A., Ghandehari H., Line B.R., Polymeric conjugates of mono- and bi-cyclic alphavbeta3 binding peptides for tumor targeting, J. Control. Release 2006(114): 175-183
18. Chen X., Hou Y., Tohme M., Park R., Khankaldyyan V., GonzalesGomez I. Bading J.R., Laug W.E., Conti P.S., Pegylated Arg-Gly-Asp peptide: 64Gu labeling and PET imaging of brain tumor alphavbeta3-integrin expression, J. Nucl. Med. 2004(45): 1776-1783
19. Straub J.A., Chickering D.E., Churh C.C., Shah B., Hanlon T., Bernstein H., Porous PLGA microparticles: AI-700, an intravenously administered ultrasound contrast agent for use in echocardiography, J. Control. Release 2005(108): 21-32
20. Kang H.W., Weissleder R., Bogdanov A. Jr., Targeting of MPEG-protected polyamino acid carrier to human E-selectin in vitro, Amino Acids 2002(23): 301-30
21. Lu Z.R., Application of biomedical imaging in drug discovery and development, Pharm. Res. 2007 (electronic publication ahead of print)
22. Rudin M., Weissleder R., Molecular imaging in drug discovery and development, Nat. Rev. Drug Discov. 2003(2): 123-131
23. Liang Z.P., Lauterbur P.C., Principles of Magnetic Resonance imaging, IEEE Press, New York, NY, 2000
24. Schuhmann-giampieri G., Schmitt-Willich H., Frezel T., Press W.R., Wienmann H.J., In vivo and in vitro evaluation of Gd-DTPA-polylysine as a macromolecular contrast agent for magnetic resonance imaging, invest. Radiol. 1991(26): 969-974
25. Meyer D., Schaffer M., Chambon C., Beaute S., Paramagnetic dextrans as magnetic resonance blodd pool tracers, Invest. Radiol. 1994(29 suppl2): S90-S92
26. ogan M.D., Schmiedl U., Moselely M.E., Grodd W., Paajanen H., Brasch R.C., Albumin labeled with Gd-DTPA an intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization, Invest. Radiol. 1987(22): 665-671
27. Zong Y., Wang X., Goodrich K.C., Mohs A.M., Parker D.L., Lu Z.R., Contrast-enhanced MRI with new biodegradable macromolecular Gd(III) complexes in tumor-bearing mice. Magn Reson Med. 2005(53):835-42
28. Zong Y., Guo J., Ke T., Mohs A.M., Parker D.L., Lu Z.R. Effect of size and charge on pharmacokinetics and in vivo MRI contrast enhancement of biodegradable polydisulfide Gd(III) complexes, J. Control. Release 2006(112): 350-356
29. Ke T., Feng Y., Guo J., Parker D.L., Lu Z.R., Biodegradable cystamine spacer facilitates the clearance of Gd(III) chelates in poly(glutamic acid) Gd-DO3A conjugates for contrast-enhanced MR imaging. Magn Reson Imaging. 2006(24):931-40.
30. Ye F., Ke T., Jeong E.K., Wang X., Sun Y., Johnson M., Lu Z.R., Non-invasive visualization of in vivo drug delivery of poly(L-glutamic acid) using contrast-enhanced MRI, Mol. Pharmacol. 2006(3): 507-515
31. Wang Y., Ye F., Jeong E.K., Sun Y., Parker D.L., Lu Z.R., Non-invasive visualization of pharmacokinetics, biodistribution and tumor targeting of poly[N-(2-hydroxypropyl)methacrylamide] in mice using contrast enhanced MRI. Pharm. Res. 2007(24): 1208-1216
32. Vaidya A., Sun Y., Ke T., Jeong E.K., Lu Z.R., Contrast enhanced MRI-guided photodynamic therapy for site-specific cancer treatment, Magn. Reson. Med. 2006(56): 761-767

Author Bio

Zheng-Rong Lu
Furong Ye
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