Pediatr Drugs 2008; 10 (6): 351-355 1174-5878/08/0006-0351/$48.00/0

COMMENTARY

© 2008 Adis Data Information BV. All rights reserved.

Drug Delivery Systems in Children Stephen Lowis Department of Paediatric and Adolescent Oncology, Bristol Royal Hospital for Children, Bristol, UK

The efficacy of a given drug is dependent upon the reliability of delivery to its site of action; the drug must reach its target to have an effect. At the simplest level, the preparation of a drug, its route of administration, and its disposition according to pharmacokinetic properties define its delivery; these factors are particularly important in pediatric practice. For the last 20 years, modification of drug disposition has been possible, and a number of specific delivery systems have appeared with this in mind. Examples include polymeric carriers, reservoirs and matrix devices, liposomal preparations, and modification of molecules to influence their antigenicity. Selective targeting of carrier molecules, to deliver a chosen drug to its site of action, has been attempted. All of these strategies aim to improve activity or reduce toxicity. Routes of Administration Intravenous administration is impractical for most drugs outside the hospital setting and, if possible, other routes are usually to be preferred. Central and peripheral venous administration achieves the most reliable drug exposure but has many disadvantages, particularly for children. The necessity for venepuncture, associated pain, risk of extravasation, and even inappropriate cannulation of arteries are major drawbacks, and significant behavioral problems are common for children needing repeated venous access. There may be a greater risk of acute drug reactions with intravenous administration, although administration can be reliably discontinued if a problem arises. Central venous long lines are used for many children with chronic conditions requiring regular intravenous access. Singleand double-lumen long lines and portacaths are essential in the management of many children with cystic fibrosis, or hematologic and oncologic problems. They overcome many of the difficulties with long-term access, but are associated with significant infection risks in their own right, and often lead to deep venous thrombosis.[1] Intramuscular injection is sometimes used if intravenous access cannot be achieved, and is the preferred route for some agents such as immunoglobulin for passive immunization. In the UK,

leukemia therapy with asparaginase is administered intramuscularly because of a continued belief that allergic reactions to the drug are less likely to occur; intravenous administration of this drug is accepted as standard in most other countries.[2,3] Intramuscular administration often achieves a high bioavailability, but bioavailability cannot be assumed to be complete for all patients.[4] Intramuscular injection is particularly difficult in children, for whom the pain of administration may cause severe problems; in general, this route is rarely used if alternatives exist. Subcutaneous administration is used most commonly for prophylactic or therapeutic heparin, some chemotherapy agents (such as cytarabine), and stem cell growth factors (such as granulocyte colony-stimulating factor). Bioavailability may not be complete because of incomplete absorption from the subcutaneous compartment, sequestration or local degradation and removal, but for some drugs, subcutaneous administration is the preferred and most effective route of administration. Topical administration is effective for local delivery to skin, such as in the treatment of eczema or psoriasis. Dosing by creams may be imprecise, but for most patients systemic absorption is not significant. However, this may not be the case for the very young and, in particular, for preterm infants. Preterm infants have a high surface area to bodyweight ratio, have thin skin, and may absorb significant proportions of the drug by this route.[5-7] Intradermal administration, which usually requires injection, may be achieved using technology that relies upon compressed air delivery. Advantages of this approach are pain reduction, more effective delivery to the target area, and (for vaccines) improved immunologic response.[8] A similar approach has been used to deliver local anesthetic agents prior to painful procedures.[9] Transdermal administration has been proven to be effective and reliable in patients needing a continuous drug supply over several days. Opiate analgesics, antiemetics, steroid hormones, and nicotine are well suited to this method.[10,11] Patches release drugs by diffusion, the rate of which is limited by the available surface area. This may cause difficulties for children for whom the appropriate dose is below the minimum patch size.

352

Lowis

The disadvantages of this method are that there is a significant time lag before the drug achieves clinically relevant concentrations, and it is suitable for small molecules (relative molecular mass <500) and potent drugs, for which small amounts achieve the desired therapeutic effect. Local skin irritation may be a problem, but in general, this route allows good compliance and delivery with a reliable rate to the systemic circulation. Nevertheless, this route has been of particular value for children with hypersecretion and drooling, and in the control of pain in palliative care.[12-14] Iontophoretic administration has been developed for local cutaneous administration of anesthetic agents, and also as a means of enhancing transdermal delivery for systemic agents such as fentanyl.[15] Ocular administration of methylprednisolone is enhanced by iontophoresis.[16] Iontophoresis has not been widely used, although individual iontophoretic packs have recently been developed for elimination of pain control with venepuncture. Intrathecal and intraventricular administration may be appropriate for a small number of patients, for example those receiving treatment for malignant CNS disease or patients who have ventricular infections after neurosurgery. Patients undergoing treatment for acute lymphoblastic leukemia receive many intrathecal injections in the course of their therapy. There is some evidence that intraventricular administration is more effective than intrathecal in reducing the risk of disease recurrence in patients with leukemia;[17-19] this may be expected, given the normal flow of cerebrospinal fluid from the ventricles to the rest of the CNS, but routine administration by this route has not been adopted. Intrathecal administration requires substantial patient compliance; for this reason, most children will be anaesthetized or have sedation before any attempted intrathecal therapy. A recently developed preparation of cytarabine may offer improvements to intrathecal therapy. Depocyte 1 (Napp Pharmaceuticals Ltd, Cambridge, UK), which is licensed for the treatment of lymphomatous meningitis, comprises cytarabine held within lipid vesicles. The active drug is released slowly and, as a consequence, distribution throughout the entire CNS is significantly improved.[20] Activity in patients with lymphomatous meningitis has been shown to be similar, but fewer intrathecal injections are required. Transmucosal administration has been used for many drugs for which a prompt response is required, where venous access is not available. Nasal, buccal, and rectal mucosae have been used in children, particularly with anticonvulsants (midazolam, diazepam, clonazepam, paraldehyde), antihypertensives (nifedipine), analgesia (morphine, fentanyl), and glucose gel. 1

Inhalational administration is used widely in respiratory disease and has been reviewed extensively elsewhere.[21-25] Examples of agents administered via the inhalation route are corticosteroids, bronchodilators, antibiotics, mucolytics, antivirals (ribavirin), and pneumocystis (pentamidine) therapy. The intention of inhalational therapy is to deliver the drug topically to the site of inflammation or infection to enhance the therapeutic index of these drugs. The delivery of the drug is affected by the drug itself, the device used, the patient’s ability to comply, and the electrostatic charge produced when the spray or powder is dispersed.[26,27] Differences in corticosteroid particle size may explain differences in drug requirements and differing systemic effects.[28] Even with a single device such as a nebulizer, the delivery of a nebulized drug is affected by the drug characteristics and the respiratory pattern.[29,30] Oral administration is the preferred method for most drugs. Apart from the chemical characteristics of a given drug, which determine solubility and absorption, its preparation and presentation, compliance rates, and the technical ability needed to comply with a given regimen have significant effects on delivery. Once daily dose regimens are associated with better compliance than twice-daily regimens, and these in turn have better compliance rates than multiple-dose regimens. Side effects, taste, and tablet size affect delivery greatly, particularly in children, and considerable research into the manufacture of orally administered medications is typical for all pharmaceutical studies. In addition, targeted education programs have been shown to improve compliance in specific disease groups such as cystic fibrosis and HIV.[31,32] The bioavailability of a given drug affects its efficacy. Poor absorption may render an active drug inactive, and marked variability in bioavailability affects the population therapeutic index. Absorption is affected by the chemical structure of a drug (particularly its ionization state at physiologic pH), its size (most absorbed drugs have a relative molecular mass <1000), its solubility (hence the availability of drug for absorption), and its partition coefficient. Chemical stability affects absorption, particularly where a low gastric pH causes hydrolysis, as with many penicillins. Excipients, which enhance dissolution of active drug, affect absorption and may also influence other pharmacokinetic parameters. Cremaphor EL® (BASF Corporation, Florham Park, NJ, USA) markedly affected the pharmacokinetics of paclitaxel, resulting in reduced clearance at higher doses.[33] Other excipients include DMSO (dimethylsulfoxide), ethanol, solutol (a mixture of mono- and diesters with polyethylene glycol), and propylene

The use of trade names is for product identification purposes only and does not imply endorsement

© 2008 Adis Data Information BV. All rights reserved.

Pediatr Drugs 2008; 10 (6)

Drug Delivery Systems in Children

glycol. The effects are usually not as great as for Cremaphor EL®, but occasionally may be of clinical significance.[34] Ciclosporin is a cyclic peptide compound that has a low bioavailability but, more importantly, markedly variable absorption both between and within individuals.[35] Therapeutic monitoring is difficult. Neoral® (Novartis Pharmaceuticals Corporation, NJ, USA), an emulsified preparation, has significantly greater absorption, less variability, and is associated with an improved therapeutic effect.[36,37] Drug Delivery Vehicles The disposition (ADME; administration, distribution, metabolism, and elimination) of a drug affects its pharmacodynamic effects and, for many drugs, the schedule adopted will influence clinical effectiveness and toxicity. In recent years, there has been increasing interest in formulations that influence delivery. Sustained- or slow-release preparations of oral medications have been in wide use for many years, and offer the potential of improved compliance associated with less frequent dosing (for example, in asthma,[38,39] epilepsy,[40] and attention deficit hyperactivity disorder[41]). Slow-release vehicles usually rely upon diffusion of water into the preparation, displacing a supply of the drug. This can be achieved at the macroscopic level (and is commonly used to enhance delivery to the lower gastrointestinal tract), and now also at the microscopic level by several means. Liposomal encapsulation involves the entrapment of soluble drug within lipid vesicles. It has been explored for several drugs, but has found clinical use for the delivery of anthracyclines (DaunoXome®; Diaos, Paris, France and Caelyx®; Schering Plough, Kenilworth, NJ, USA) and of amphotericin (Ambisome®; Gilead Sciences, Foster City, CA, USA). DaunoXome® for example, comprises an anthracycline (daunorubicin) in a vesicle of disteroyl-phosphatidyl-choline (DSPC) and cholesterol. Caelyx® has a similar structure, but uses doxorubicin which has been pegylated to further modify its pharmacokinetic parameters. Ambisome® is a liposomal preparation in which a unilamellar vesicle contains amphotericin molecules within the membrane.[42] Vesicles are chosen with a specific diameter, and function as a slow-release compartment, modifying exposure significantly. Furthermore, tissue distribution of liposomes differs significantly from that of the native drug, and this may allow improvement in the therapeutic index. DaunoXome® vesicles, for example, are cleared slowly from the plasma by the reticulo-endothelial system, and release of daunorubicin continues in a sustained manner. Preclinical studies indicate increased tissue concentrations of daunorubicin in tumor, brain, liver, spleen, and intestine following administration of DaunoXome®, but a reduced concentration in © 2008 Adis Data Information BV. All rights reserved.

353

cardiac tissue.[43,44] The absence of a lymphatic system in tumor tissue may further enhance drug retention, with greater therapeutic effect. Polymeric hydrogels may offer an alternative method of controlled release, with the possibility of regulated release according to need. Hydrogels are cross-linked polymeric substances that are able to absorb at least 20% of their weight in water. If the gel is pre-loaded with an active agent, the process of water absorption causes loss of drug through displacement and distortion of the gel structure. Synthesis of these hydrogels is relatively cheap, and release is predictable according to defined mathematical models. It is important to consider the ability of a drug to diffuse, the pore size within the matrix, the degree of cross-linking seen, and the degree of swelling in designing such matrices. These factors are of particular relevance when an additional component, allowing a predictable response of the gel, is incorporated. For example, copreparation of a hydrogel with glucose oxidase and insulin has been shown to deliver insulin according to blood glucose concentrations; glucose enters the gel and is converted to gluconic acid where it causes the local pH to fall, causing distortion and release of insulin from the matrix.[45] Other examples include hydrogels that are able to respond to magnetic fields, ultrasound, urea, and pH.[46] Polymeric delivery vehicles are of particular value where very prolonged delivery is needed in relatively inaccessible sites. Examples include non-biodegradable implants for insertion into the posterior chamber of the eye. Vitrasert® (Bausch & Lomb Surgical, Inc., Irvine, CA, USA) comprises an ethylene vinyl acetate (EVA) and polyvinyl alcohol (PVA) polymer that releases ganciclovir, and is effective in the treatment of cytomegalovirus retinitis over a period of 8 months.[47] Retisert® (Bausch & Lomb Surgical, Inc., Irvine, CA, USA) is a PVA-silicone implant that releases fluocinolone acetonide (corticosteroid) in patients with uveitis.[48] Branching polymeric molecules, which are uncommon in nature (including only glycogen, amylopectin, and proteoglycan), have been developed as potential carrier molecules for a variety of agents. Poly(amidoamine) [PAMAM] compounds tend to form repeating, spherical structures known as dendrimers; production is straightforward, relying on favorable chemical and hydrophilic/ phobic interactions.[49] The dendrimers themselves tend to have well defined diameters, depending upon the number of ‘shells’ polymerized, and a variety of sized particles may, therefore, be developed. PAMAM is further able to associate stably with other macromolecules, such as DNA, and may, therefore, have value as a delivery vehicle or as a stabilization agent for DNA-based drugs and vaccines. Finally, many such dendrimers have a hollow core, and may act as micelles or other delivery mechanisms for less stable drugs. Pediatr Drugs 2008; 10 (6)

354

Lowis

Many drugs achieve entry into the cell because they have extensive hydrophobic domains, and can therefore diffuse across the lipid bilayer, or can enter the cell using active or passive transport mechanisms. Since many new biologically active agents are large, hydrophilic molecules (such as DNA or proteins), mechanisms that assist entry are likely to become increasingly important. Examples include cell-penetrating polypeptide sequences such as SynB vectors; these are derived from an antimicrobial polypeptide, which forms pores in the lipid matrix of cell membranes.[50] These vectors have been demonstrated to enhance intracellular delivery of exogenous proteins and peptides.[51] Potential benefits include the improvement of vaccine response and, for delivery of agents to the CNS, overcoming the blood-brain barrier. Conjugation of drugs to other polypeptides may offer significant benefits, with better targeting to organs of interest. For example, a conjugate of doxorubicin with another cell-penetrating polypeptide, pAntp43–58 (Penetratin™; UMR CNRS 8542, Paris, France), was able to cause a 5-fold greater accumulation of doxorubicin in brain tissue than native doxorubicin.[52] Conclusions Drug delivery is a major factor in the safe and effective use of all medications and is of particular relevance to children. Recent technologic innovations offer a chance to modify the disposition of many agents and may allow the use of more sophisticated agents, that otherwise would not reach their active site. However, it is wise to remember the simpler elements of the therapeutic chain – presentation, taste, acceptability, and the administration regimen – to ensure that all drugs are used to greatest effect. Acknowledgments No sources of funding were used to assist in the preparation of this article. The author has no conflicts of interest that are directly relevant to the content of this article.

References 1. Nowak-Gottl U, Heinecke A, von Kries R, et al. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res 2001 Aug 1; 103 (3): 165-72 2. Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 2007; 109: 896-904 3. Rodriguez T, Baumgarten E, Fengler R, et al. Long-term infusion of L-asparaginase: an alternative to intramuscular injection? [in German]. Klin Padiatr 1995; 109 (4): 207-10 4. Tuttle CB. Intramuscular injections and bioavailability. Am J Hosp Pharm 1977 Sep; 34 (9): 965-8 5. Ellison JA, Patel L, Ray DW, et al. Hypothalamic-pituitary-adrenal function and glucocorticoid sensitivity in atopic dermatitis. Pediatrics 2000 Apr; 105 (4 Pt 1): 794-9 © 2008 Adis Data Information BV. All rights reserved.

6. Ozon A, Cetinkaya S, Alikasifoglu A, et al. Inappropriate use of potent topical glucocorticoids in infants. J Pediatr Endocrinol Metab 2007 Feb; 20 (2): 219-25 7. Guven A, Gulumser O, Ozgen T. Cushing’s syndrome and adrenocortical insufficiency caused by topical steroids: misuse or abuse? J Pediatr Endocrinol Metab 2007 Nov; 20 (11): 1173-82 8. Osorio JE, Zuleger CL, Burger M, et al. Immune responses to hepatitis B surface antigen following epidermal powder immunization. Immunol Cell Biol 2003 Feb; 81 (1): 52-8 9. Wolf AR, Stoddart PA, Murphy PJ, et al. Rapid skin anaesthesia using high velocity lignocaine particles: a prospective placebo controlled trial. Arch Dis Child 2002 Apr; 86 (4): 309-12 10. Burkman RT. Transdermal hormonal contraception: benefits and risks. Am J Obstet Gynecol 2007; 134: e1-6 11. Hunt A, Goldman A, Devine T, et al. Transdermal fentanyl for pain relief in a paediatric palliative care population. Palliat Med 2001; 15: 405-12 12. Horimoto Y, Tomie H, Hanzawa K, et al. Scopolamine patch reduces postoperative emesis in paediatric patients following strabismus surgery. Can J Anaesth 1991; 38: 441-4 13. Zernikow B, Michel E, Anderson B. Transdermal fentanyl in childhood and adolescence: a comprehensive literature review. J Pain 2007; 8: 187-207 14. Collins JJ, Dunkel IJ, Gupta SK, et al. Transdermal fentanyl in children with cancer pain: feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 1999; 134: 319-23 15. Power I. Fentanyl HCl iontophoretic transdermal system (ITS): clinical application of iontophoretic technology in the management of acute postoperative pain. Br J Anaesth 2007 Jan; 98 (1): 4-11 16. Halhal M, Renard G, Courtois Y, et al. Iontophoresis: from the lab to the bed side. Exp Eye Res 2004 Mar; 78 (3): 751-7 17. Fujimoto T. Pharmacokinetics of intrathecal chemotherapy and clinical problems [in Japanese]. Gan To Kagaku Ryoho 1984 Aug; 11 (8): 1536-42 18. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975 Jul 24; 293 (4): 161-6 19. Bleyer WA, Poplack DG. Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: prolonged remission with the Ommaya reservoir. Med Pediatr Oncol 1979; 6 (3): 207-13 20. Phuphanich S, Maria B, Braeckman R, et al. A pharmacokinetic study of intra-CSF administered encapsulated cytarabine (DepoCyt) for the treatment of neoplastic meningitis in patients with leukemia, lymphoma, or solid tumors as part of a phase III study. J Neurooncol 2007 Jan; 81 (2): 201-8 21. Biggart E, Bush A. Antiasthmatic drug delivery in children. Paediatr Drugs 2002; 4 (2): 85-93 22. Sermet-Gaudelus I, Le Cocguic Y, Ferroni A, et al. Nebulized antibiotics in cystic fibrosis. Paediatr Drugs 2002; 4 (7): 455-67 23. Cheer SM, Warner GT, Easthope SE. Formoterol delivered by Turbuhaler: in pediatric asthma. Paediatr Drugs 2003; 5 (1): 63-8 discussion 9 24. De Benedictis FM, Selvaggio D. Use of inhaler devices in pediatric asthma. Paediatr Drugs 2003; 5 (9): 629-38 25. Gulliver T, Morton R, Eid N. Inhaled corticosteroids in children with asthma: pharmacologic determinants of safety and efficacy and other clinical considerations. Paediatr Drugs 2007; 9 (3): 185-94 26. Mitchell JP, Coppolo DP, Nagel MW. Electrostatics and inhaled medications: influence on delivery via pressurized metered-dose inhalers and add-on devices. Respir Care 2007 Mar; 52 (3): 283-300 27. Wildhaber JH, Waterer GW, Hall GL, et al. Reducing electrostatic charge on spacer devices and bronchodilator response. Br J Clin Pharmacol 2000 Sep; 50 (3): 277-80 28. Vaghi A, Berg E, Liljedahl S, et al. In vitro comparison of nebulised budesonide (Pulmicort respules) and beclomethasone dipropionate (Clenil per aerosol). Pulm Pharmacol Ther 2005; 18 (2): 151-3 29. Barry PW, O’Callaghan C. The output of budesonide from spacer devices assessed under simulated breathing conditions. J Allergy Clin Immunol 1999 Dec; 104 (6): 1205-10 30. O’Callaghan C, White J, Jackson J, et al. Delivery of nebulized budesonide is affected by nebulizer type and breathing pattern. J Pharm Pharmacol 2005 Jun; 57 (6): 787-90 Pediatr Drugs 2008; 10 (6)

Drug Delivery Systems in Children

31. Zindani GN, Streetman DD, Streetman DS, et al. Adherence to treatment in children and adolescent patients with cystic fibrosis. J Adolesc Health 2006; 38: 13-7 32. Garvie PA, Lensing S, Rai SN. Efficacy of a pill-swallowing training intervention to improve antiretroviral medication adherence in pediatric patients with HIV/ AIDS. Pediatrics 2007; 119: e893-9

355

44. Forssen EA, Coulter DM, Proffitt RT. Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res 1992 Jun 15; 52 (12): 3255-61 45. Brown LR, Edelman ER, Fischel-Ghodsian F, et al. Characterization of glucosemediated insulin release from implantable polymers. J Pharm Sci 1996 Dec; 85 (12): 1341-5

33. Sparreboom A, van Tellingen O, Nooijen WJ, et al. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res 1996 May 1; 56 (9): 2112-5

46. Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive

34. Buggins TR, Dickinson PA, Taylor G. The effects of pharmaceutical excipients on drug disposition. Adv Drug Deliv Rev 2007 Dec 22; 59 (15): 1482-503

47. Bourges JL, Bloquel C, Thomas A, et al. Intraocular implants for extended drug

35. Fanta S, Jonsson S, Backman JT, et al. Developmental pharmacokinetics of ciclosporin: a population pharmacokinetic study in paediatric renal transplant candidates. Br J Clin Pharmacol 2007 Dec; 64 (6): 772-84 36. Pollard SG. Pharmacologic monitoring and outcomes of cyclosporine. Transplant Proc 2004 Mar; 36 (2 Suppl.): 404S-7S

drug delivery. Drug Discov Today 2002 May 15; 7 (10): 569-79 delivery: therapeutic applications. Adv Drug Deliv Rev 2006 Nov 15; 58 (11): 1182-202 48. Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 2006 Jun; 113 (6): 1020-7

37. Kahan BD. Therapeutic drug monitoring of cyclosporine: 20 years of progress. Transplant Proc 2004 Mar; 36 (2 Suppl.): 378S-91S

49. Wolinsky JB, Grinstaff MW. Therapeutic and diagnostic applications of den-

38. Dubus JC, Anhoj J. A review of once-daily delivery of anti-asthmatic drugs in children. Pediatr Allergy Immunol 2003; 14: 4-9

50. Drin G, Rousselle C, Scherrmann JM, et al. Peptide delivery to the brain via

39. Lonnerholm G, Foucard T, Lindstrom B. Treatment of chronic asthma in children with a sustained-release preparation of theophylline in addition to beta 2-stimulating agents. Eur J Respir DisSuppl 1980; 109: 95-7 40. Genton P. Progress in pharmaceutical development presentation with improved pharmacokinetics: a new formulation for valproate. Acta Neurol Scand Suppl 2005; 182: 26-32 41. Daviss WB, Bentivoglio P, Racusin R, et al. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Pshychiatry 2001; 40: 307-14 42. Adler-Moore J, Proffitt RT. AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. J Antimicrob Chemother 2002; 49 Suppl. 1: 21-30 43. Forssen EA, Ross ME. DaunoXome treatment of solid tumours: preclinical and clinical investigations. J Liposome Research 1994; 4: 481

© 2008 Adis Data Information BV. All rights reserved.

drimers for cancer treatment. Adv Drug Deliv Rev 2008; 60: 1037-55 adsorptive-mediated endocytosis: advances with SynB vectors. AAPS PharmSci 2002; 4: E26 51. Day FH, Zhang Y, Clair P, et al. Induction of antigen-specific CTL responses using antigens conjugated to short peptide vectors. J Immunol 2003 Feb 1; 170 (3): 1498-503 52. Rousselle C, Clair P, Lefauconnier JM, et al. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol Pharmacol 2000 Apr; 57 (4): 679-86

Correspondence: Dr Stephen Lowis, Department of Paediatric and Adolescent Oncology, Bristol Royal Hospital for Children, Bristol, UK. E-mail: [email protected]

Pediatr Drugs 2008; 10 (6)