Polymers for CNS drug delivery

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-05-01-2007, Volume 19, Issue 5

There is a tremendous need to enhance delivery of potential therapeutics to the brain for treatment of central nervous system (CNS) disorders. The blood brain barrier (BBB) restricts and controls the exchange of compounds between the CNS and the blood, which requires discovery of new modalities allowing for effective drug delivery to the CNS. Polymer nanotechnology has now become one of the most attractive areas of pharmaceutical research. This review focuses on the current progress in polymeric nanoparticles, where the specific arrangement of the polymeric matter at the nanoscale is utilized to design drug delivery systems that provide safe and efficient transport of CNS drugs across the BBB.

The blood brain barrier (BBB) is one of the most challenging barriers in the body, significantly restricting the entry of compounds to the brain from the periphery.1 This includes many low molecular weight drugs as well as biomacromolecules, such as DNA and proteins, which can be used for treatment of neurological diseases — particularly in the early stages of the disease when the BBB remains intact. Tight extracellular junctions in brain microvessel endothelial cells, relatively low pinocytic activity, enzymatic barrier and expression of various efflux protein systems transporting many small molecule compounds back into the bloodstream make the brain inaccessible to the majority of substances circulated in the blood.

These features require the discovery of new modalities allowing for effective drug delivery to the central nervous system (CNS), which is of great need and importance for treatment of neurological diseases.

Advantages of polymer drug delivery systems

There are several fundamental properties of polymers that are useful in solving drug delivery problems. They can be:

  • Designed to be intrinsically multifunctional and can be combined either covalently or noncovalently with drugs to overcome multiple problems such as solubility, stability and permeability.

  • Easily modified with various targeting vectors to direct drugs to specific sites in the body.

  • Designed to be environmentally responsive materials, allowing for the controlled and sustained release of a drug at its site of action.

  • Biologically active, a property that can be exploited to modify the activity of various endogenous drug transport systems within the body to improve delivery and, therefore, drug performance.

A great number of polymer therapeutics is presently on the market or undergoing clinical evaluation. Recently, a new generation of polymer therapeutics has emerged that uses nanoscale materials and devices for the delivery of drugs, genes and imaging molecules.2–5 These materials include polymer micelles, polymer-DNA complexes (polyplexes), liposomes and other nanostructured materials for medical use (nanomedicines).

Polymer nanocarriers for drug delivery

Liposomes. The use of liposomes for drug delivery across the brain capillaries has been extensively reported. 6–9 In general, encapsulation of a drug into liposomes prolongs the time of drug circulation in the blood stream, reduces adverse side effects and enhances therapeutic effects of CNS agents.

An interesting approach was utilized for thermosensitive liposomes loaded with an antineoplastic agent, adriamycin, for treatment of malignant gliomas.7 These carriers released their contents when the tumour core was heated to 40 °C by the brain heating system. Elevated accumulation of the drug in the brain of the heated animals resulted in significantly longer overall survival time compared with the nonheated animals.

Unfortunately, conventional liposomes are normally cleared rapidly from circulation by the reticuloendothelial system. Water-soluble polymers (such as polyethylene glycol [PEG]) attach to the surface of long-circulating liposomes (stealth liposomes) and reduce the adhesion of opsonic plasma proteins, which induces recognition and rapid removal of liposomes from the circulation by the mononuclear phagocyte system in the liver and spleen.10

In particular, commercial pegylated liposomal-encapsulated Dox (Doxil [Ortho Biotech, NJ, USA]) has already been approved for use in the treatment of recurrent ovarian cancer and AIDS-related Kaposi's sarcoma.11 Novel, highly stable nanoparticle/liposomes containing anticancer drug CPT-11, prolonged drug tissue retention and enhanced antitumour effect in the intracranial U87 glioma xenograft model (Figure 1).12 Long-circulating PEG-liposomes were also used to deliver high doses of glucocorticosteroids to the CNS to treat multiple sclerosis.13

Attachment of immunoreactive moieties to PEG-modified liposomes can target them to the BBB. Thus, efficient delivery of PEG-liposomes conjugated with transferrin (Tf) to the post-ischemic cerebral endothelium was achieved in rats.14 Tf receptor was also utilized as a target in pegylated immuno-liposomes conjugated with monoclonal antibodies, OX26.15

Figure 1

The b-galactosidase gene, doxorubicin, digoxin, biotinylated oligonucleotides, striatal tyrosine hydroxylase plasmid and neurotrophin peptides have been successfully delivered to the brain when encapsulated into these liposomes.9,15–20 Another example of brain targeting vector is reported by Coloma et al.;21 a chimeric monoclonal antibody to the human insulin receptor, 83-14 MAb, was replaced by human antibody sequence. This vector was also used for targeting liposomes with b-galactosidase or luciferase gene to the brain.

(PEG)ylated (stealth) BBB-targeted immunoliposomes directed against human gliofibrillary acidic protein (GFAP) have been obtained by coupling the thiolated monoclonal antiGFAP antibodies.8 Being incapable of penetrating the unimpaired BBB, it has been suggested that these immunoliposomes could deliver drugs to glial brain tumours (that continue to express GFAP) or to other pathological loci in the brain with a partially disintegrated BBB.8

Another vector moiety to the BBB was proposed by Zhang et al.22 An endogenetic bioactive peptide, RMP-7 (cereport), which is known to open tight junctions in the BBB binding selectively to B2 receptors, has linked to conventional liposomes.

Overall, liposomes have been extensively studied for CNS drug delivery showing increased drug efficacy and reduced drug toxicity.

Nanoparticles. This is a submicron drug carrier system, constituted by a solid core with insoluble and biodegradable polymer. These systems are attractive because their methods of preparation are generally simple and easy to scale-up. Similar to liposomes, the surface of such carriers are often modified by PEG brush (PEGylation) to increase the stability of nanoparticles in dispersion and extend their circulation time in the body.23

Poly(butyl)cyanoacrylate (PBCA) nanoparticles have been successfully used to deliver a wide range of drugs to the CNS, which were either incorporated into the particle structure or absorbed onto the surface.24 Analgetics (dalargin and loperamide), antineoplastic agent (doxorubicin), the NMDA receptor antagonist MRZ 2/576 and peptides (dalargin and kytorphin) have been successfully delivered to the CNS in these constructs.24 Another chelator, D-penicillamine, was formulated with nanoparticles and studied for therapy of Alzheimer's Disease and other CNS diseases.25

Nanospheres. These are hollow nanosized particles that can be prepared by microemulsion polymerization or covering the surfaces of colloidal templates with thin layers of the desired material followed by selective removal of the templates. Transport of carboxylated polystyrene nanospheres (20 nm) across the BBB was studied in vivo following cerebral ischemia and reperfusion.26 It was demonstrated that cerebral ischemia and reperfusion induced transient increase in fluorescence intensity, indicating accumulation of nanocarriers in the brain as a result of the opening of the tight junctions between endothelial cells.27

A new family of carrier systems, Nanogel, from the University of Nebraska Medical Center (USA), was recently developed for targeted delivery of drugs and biomacromolecules to the brain.28–30 Nanogel represents a nanoscale size polymer network of cross-linked ionic polyethyleneimine (PEI) and nonionic PEG chains (PEG-cl-PEI). A study tested Nanogel for the receptor-mediated delivery of oligonucleotides across brain microvascular endothelial cells monolayers.28 Specifically, the surface of the Nanogel particles was modified by either transferrin or insulin using avidin-biotin coupling chemistry.

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Both peptides were shown to increase transcellular permeability of the Nanogel and enhance delivery of ODNs across BMVEC monolayers (Figure 2). Finally, large amounts of the 5'-triphosphate antiviral nucleoside analogue, 3'-azido-2',3'-dideoxythymidine (AZT), were encapsulated into the Nanogel particles.29,30

Figure 2

Nanosuspensions. These systems represent crystalline particles of a solid drug, which are often stabilized by nonionic PEG-containing surfactants. Block copolymers such as Tween 80 and poloxamer 188 are used as stabilizers of nanosuspensions.31 The high drug load of the nanoparticles provides prolonged drug release in vitro and in vivo. It has been suggested that surface modification of nanosuspensions with Tween 80 will target them to the brain.32

Polymeric micelles. These are created from amphiphilic polymers that spontaneously form nanosized aggregates when the individual polymer chains (unimers) are directly dissolved in aqueous solution (dissolution method) above a threshold concentration (critical micelle concentration [CMC]) and solution temperature (critical micelle temperature [CMT]).2

These micro- and nanocontainers can incorporate hydrophobic and amphiphilic drugs, and serve as carriers for drug delivery (micellar nanocontainers).33,34 Polymeric micelles have been evaluated in multiple pharmaceutical applications as drug and gene delivery systems, as well as carriers for various diagnostic imaging agents.35–39

One of the early studies of targeted drug delivery to the brain used Pluronic from BASF Corp. (USA), block copolymers micelles as carriers for CNS drugs.40,41 These micelles were conjugated with either polyclonal antibodies against brain a2-glycoprotein (Ab-a2-gp) or insulin targeting to the receptors at the lumenal side of BMVEC. Vectorization of the drug-loaded micelles with Ab-a2-gp leaded to a much more pronounced (up to 500-fold) neuroleptic effects. Subsequent studies demonstrated that the vectorized micelles undergo receptor-mediated transport in BMVEC.42

Polymeric micelles formed by Pluronics, PEG-phospholipid conjugates, PEG-b-polyesters, or PEG-b-poly(L-amino acid)s were proposed for drug delivery of poorly water-soluble compounds, such as amphotericin B, propofol, paclitaxel and photosensitizers.43,44

A novel type of functional nanosystem polymer micelles with cross-linked ionic cores was developed using block ionomer complexes as a micellar template.45 The ionic character of the core allows the encapsulation of charged therapeutic or diagnostic molecules, while the cross-linking of the core will suppress dissociation of the micelle upon dilution. Overall, this strategy has potential in developing novel modalities for delivery of various drugs to the brain, including selected anticancer agents to treat metastatic brain tumours, as well as HIV protease inhibitors to eradicate HIV virus in the brain.

Nanofibres and nanotubes. Continuous fibres with nanoscale diameters have fascinating potential biotechnology applications as drug delivery systems; for example, for sustained drug release from implants, as channels for tiny volumes of chemicals in nanofluidic reactor devices, or as 'hypodermic needles' for injecting molecules one at a time.

Very few cases of nanofibres have been developed for CNS drug delivery. A new approach for manufacturing drug-loaded conducting polymer nanofibres using the electrospinning of a biodegradable polymer, poly(lactide-co-glycolide [PLGA]), has been reported.46 An anti-inflammatory agent, dexamethasone, was incorporated followed by electrochemical deposition of a conducting polymer, poly(3,4-ethylenedioxythiophene).

Permeability enhancers for CNS drug delivery

There are a number of efflux mechanisms within the CNS that influence drug concentrations in the brain. Much attention has been focused on the so-called multidrug efflux transporters P-glycoprotein (Pgp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); and the multispecific organic anion transporter (MOAT) that belong to the ABC cassette (ATP-binding cassette) family. As a consequence, the therapeutic value of many promising drugs is diminished.

An emerging strategy for enhanced BBB penetration of drugs is co-administration of competitive or noncompetitive inhibitors of the efflux transporter together with the desired CNS drug. A very potent class of inhibitors (nonionic polymer surfactants such as Pluronics, BRIJs, MYRJs, Tritons, Tweens and Chremophor) was identified as a promising agent for drug formulations. Studies in polarized brain microvessel endothelial cell (BMVEC) monolayers provided compelling evidence that selected Pluronic block copolymers can inhibit drug efflux transport systems.42,47

Table 1 Effect of P85 on drug transport across BBMEC monolayers.

Specifically, in primary cultured BMVEC monolayers, used as an in vitro model of BBB, the inhibition of drug efflux systems P-glycoprotein and Multidrug-Resistant Protein was associated with an increased accumulation and permeability of a broad spectrum of drugs in the BBB, including low molecular drugs (Table 1) and peptides.42,48 Brain delivery of a Pgp substrate, digoxin, administered intravenously in the wild-type mice expressing functional Pgp was greatly enhanced in the presence of Pluronic P85. Therefore, this formulation has a great potential for CNS drug delivery to the brain.

Key Points

Conclusions

Tremendous efforts during the last several decades have resulted in the development of many CNS drugs delivery systems creating a feeling of unlimited potential. The wide variety of strategies reflects the inherent difficulty in transport of therapeutic and imaging agents across the BBB. In fact, the effective combination of several approaches, such as encapsulation of drugs into nanoparticles conjugated with vector moieties and biologically active polymers that inhibit drug efflux transporters in the BBB, may give the most promising therapeutic outcomes.

Acknowledgments

This study was supported by National Institutes of Health grants NS36229, CA89225, CA116591, NS051335, United States National Science Foundation DMR0513699.

Elena V. Batrakova is assistant professor of pharmaceutical sciences at the University of Nebraska Medical Center.

Batrakova's aim is to extend and intensify research in developing new drug delivery polymer-based systems for chemotherapy and CNS disorders. Another part of her research is associated with applications of polymers in drug delivery across the BBB.

Alexander V. Kabanov is Parke-Davis Professor of pharmaceutical sciences and College of Pharmacy and director of the Center for Drug Delivery and Nanomedicine at the University of Nebraska Medical Center.

Kabanov has made substantial contributions in the fields of micellar enzymology, block polyelectrolyte complexes, nanomedicine, and drug and gene delivery. He was one of the first to use synthetic polycations and polymeric micelles for DNA and drug delivery (1989); amphiphilic block copolymers to overcome multidrug resistance in cancer (1994); co-invented nanogels for the delivery of nucleic acids (1999); discovered effects of polymer excipients on pharmacogenomic responses —"polymer genomics" (2002).

References

1. W. Pardridge, NeuroRx.,2, 3–14 (2005).

2. A. Kabanov et al.,Macromolecules,28, 2303–2314 (1995).

3. D. Missirlis, N. Tirelli and J.A. Hubbell, Langmuir,21, 2605–2613 (2005).

4. A.V. Kabanov and E.V. Batrakova, Curr. Pharmaceut. Des,. 10, 1355–1363 (2004).

5. S. Nayak and L.A. Lyon, Angew. Chem. Int. Ed. Engl., 44, 7686–7708 (2005).

6. F. Umezawa and Y. Eto, Biochem. Biophys. Res. Comm.,153, 1038–1044 (1988).

7. H. Aoki et al.,Int. J. Hyperther., 20, 595–605 (2004).

8. V.P. Chekhonin et al.,Drug Deliv.,12, 1–6 (2005).

9. W.M. Pardridge, NeuroRx., 2, 129–138 (2005).

10. M.Voinea and M. Simionescu, J. Cell Mol. Med.,6, 465–474 (2002).

11. A. Gabizon, H. Shmeeda and Y. Barenholz, Clin. Pharmacokinet.,42, 419–436 (2003).

12. C.O. Noble et al.,Cancer Res.,66, 2801–2806 (2006).

13. J. Schmidt et al., Brain,126, 1895–1904 (2003).

14. N. Omori et al.,Neurol Res.,25, 275–279 (2003).

15. N. Shi et al., Proc. Natl. Acad. Sci. USA,98, 12754–12759 (2001).

16. J. Huwyler, D. Wu and W.M. Pardridge, Proc. Natl. Acad. Sci. USA,93, 14164–14169 (1996).

17. J. Huwyler. J. Drug Target, 10, 73–79 (2002).

18. D. Wu et al., J. Drug Target,10, 239–245 (2002).

19. D. Wu., J. Pharmacol Exp. Ther.,276, 206–211 (1996).

20. S. Gosk et al., J. Cereb. Blood Flow Metab., 24, 1193–1204 (2004).

21. M.J. Coloma et al., Pharmaceut. Res.,17, 266–274 (2000).

22. X. Zhang et al., Drug Deliv.,11, 301–309 (2004).

23. P. Calvo et al.,Eur. J. Neurosci., 15, 1317–1326 (2002).

24. S.C. Steiniger et al., Int. J. Cancer,109, 759–767 (2004).

25. Z. Cui et al., Eur. J. Pharm. Biopharm.,59, 263–272 (2005).

26. C. Yang et al., Anal. Chem.,76, 4465–4471 (2004).

27. J. Kreuter, Adv. Drug Deliv. Rev.,47, 65–81 (2001).

28. S.V. Vinogradov et al., Bioconjugate Chem.15, 50–60 (2004).

29. S.V. Vinogradov, E. Kohli and A.D. Zeman, Mol. Pharm.,2, 449–461 (2005).

30. S.V. Vinogradov et al., J. Contr. Rel.,107, 143–157 (2005).

31. C. Jacobs, O. Kayser and R.H. Muller, Int. J. Pharm., 196, 161–164 (2000).

32. R.H. Muller and C.M. Keck, J. Nanosci. Nanotechnol.,4, 471–483 (2004).

33. K. Kataoka, A. Harada and Y. Nagasaki, Adv. Drug Deliv. Rev.,47, 113–131 (2001).

34. H.M. Aliabadi and A. Lavasanifar, Expert Opin. Drug Deliv., 3, 139-162 (2006).

35. A. Kabanov et al., FEBS Lett.,258, 343–345 (1989).

36. A. Kabanov, E. Batrakova and V. Alakhov, J. Contr. Rel.,82, 189–212 (2002).

37. T.K. Bronich et al., J. Am. Chem. Soc.,127, 8236–8237 (2005).

38. H. Yan and K. Tsujii, Colloids Surf. B. Biointerfaces,46, 142–146 (2005).

39. V.P. Torchilin, Adv. Drug Deliv. Rev.,54, 235–252 (2002).

40. A.V. Kabanov et al., FEBS Lett.,258, 343–345 (1989).

41. A. Kabanov et al., J. Contr. Rel.,22, 141–158 (1992).

42. E. Batrakova et al., Pharmaceut. Res.,15, 1525–1532 (1998).

43. M. Adams and G.S. Kwon, J. Pharm. Pharmaceut. Sci., 7, 1–6 (2004).

44. R. Vakil and G.S. Kwon, J. Contr. Rel.,101, 386–389 (2005).

45. T.K. Bronich et al., J. Am. Chem. Soc., 127, 8236–8237 (2005).

46. M. Abidian and D. Martin, MRS Symposium M1 San Francisco (CA, USA, 2005).

47. E.V. Batrakova, et al.,Pharmaceut. Res.,20, 1581–1590 (2003).

48. K.A. Witt et al., J. Pharmacol. Exp. Ther.,303, 760–767 (2002).