Current Drug Delivery, Volume 1, No. 1, 2004
ATP-Containing Immunoliposomes Specific for
Cardiac Myosin Pp.1-7
Wei
Liang, Tatyana Levchenko, Ban-An Khaw and Vladimir Torchilin
[Abstract]
Biphasic Lipid Vesicles (BiphasixTM) Enhance
the Adjuvanticity of CpG Oligonucleotides Following Systemic and Mucosal
Administration Pp.9-15
Shawn
Babiuk, Maria E. Baca-Estrada, Dorothy M. Middleton, Rolf Hecker, Lorne A.
Babiuk and Marianna Foldvari
[Abstract]
Formulation and Characterisation of
Tetracycline-Containing Bioadhesive Polymer Networks Designed for the Treatment
of Periodontal Disease
Pp.17-25
David
S. Jones, Michelle S. Lawlor and A. David Woolfson
[Abstract]
The Role of ABC Transporters in Drug
Resistance, Metabolism and Toxicity Pp.27-42
Hristos
Glavinas, Peter Krajcsi, Judit Cserepes
and Balazs Sarkadi
[Abstract] [Full text article]
An MDR-EGFP Gene Fusion Allows for Direct
Cellular Localization, Function and Stability Assessment of P-Glycoprotein Pp.43-56
Jordi
Petriz, Michael M. Gottesman and Josep
M. Aran
[Abstract]
Pain Control Via Opioid Analgesic- Local
Anesthetic Loaded IPNs
Pp.57-64
Dilek
Sendil Keskin, Donald L.Wise and Vasif
Hasirci
[Abstract] [Full text article]
Development of Topically Effective Formulations
of Acetazolamide Using HP-β-CD-Polymer
Co-Complexes Pp.65-72
Indu Pal Kaur, Mona Kapil, R. Smitha and Deepika Aggarwal
[Abstract]
Challenges in Current Drug Delivery from the
Potential Application of Pharmacogenomics and Personalized Medicine in Clinical
Practice Pp.73-80
Ioannis S. Vizirianakis
[Abstract] [Full text article]
Physical Enhancement of Transdermal Drug
Application: Is Delivery Technology Keeping up with Pharmaceutical Development? Pp.81-92
S.E. Cross and M.S. Roberts
[Back to top] ATP-Containing Immunoliposomes Specific for
Cardiac Myosin
Wei Liang, Tatyana Levchenko, Ban-An Khaw and Vladimir
Torchilin
The application of
ATP-loaded liposomes has been shown effective against ischemic damage in
several tissues. In this study, we have prepared ATP-containing liposomes
capable of specific recognition of component (myosin) specific for ischemic
myocardium. ATP-containing immunoliposomes specific towards cardiac myosin were
obtained by the attachment of the monoclonal anti-cardiac myosin 2G4 antibody
to the surface of ATP-containing PEGylated liposomes prepared by the
freezing-thawing method. Since intracellular myosin is exposed only in the
areas containing ischemically compromised cells with damaged plasmic membranes,
such liposomes are expected to target these areas both in vitro and in vivo.
The attachment of the antibody did not provoke their ATP release from the
liposomes and only minimally influenced liposome size and size distribution.
Liposome-attached anti-myosin 2G4 antibody preserved its specific activity; and
anti-myosin antibody-bearing, ATP-loaded liposomes bound efficiently to the
monolayer of myosin in ELISA. The preparation of myosin-specific ATP-loaded
immunoliposomes represented an important step in the development of targeted
delivery systems capable of providing energy support to ischemic myocardium in
vivo.
[Back to top] Biphasic Lipid Vesicles (BiphasixTM) Enhance
the Adjuvanticity of CpG Oligonucleotides Following Systemic and Mucosal Administration
Shawn Babiuk, Maria E. Baca-Estrada, Dorothy M. Middleton,
Rolf Hecker, Lorne A. Babiuk and Marianna
Foldvari
CpG
oligonucleotides (ODNs) are potent mucosal and systemic adjuvants. For
practical applications however, improvements in delivery need to be developed.
A mouse model was used to determine if the biological activity of CpG ODNs
could be enhanced using a novel delivery system of biphasic lipid vesicles (BiphasixTM Vaccine-Targeting Adjuvant; VTA).
Immunization
studies were performed to evaluate the potential of VTA formulations to enhance
the immunoadjuvant activity of CpG ODNs following systemic or mucosal
administration with gD. Immune responses following immunization were assessed
by protection from HSV-1 viral challenge and characterization of serum
gD-specific antibody responses using ELISA.
VTA formulations
in combination with CpG and glycoprotein D (gD) were able to increase
gD-specific IgG in serum compared to gD alone, and protect from a lethal HSV-1
challenge following subcutaneous immunization. Following mucosal immunization,
VTA formulations in combination with CpG and antigen enhanced mucosal IgA
responses compared to CpG and antigen administered in PBS.
[Back to top] Formulation and Characterisation of
Tetracycline-Containing Bioadhesive Polymer Networks Designed for the Treatment
of Periodontal Disease
David S. Jones, Michelle S. Lawlor and A. David Woolfson
This study
described the drug release, rheological (dynamic and flow) and
textural/mechanical properties of a series of formulations composed of 15% w/w
polymethylvinylether-co-maleic anhydride (PMVE-MA), 0–9% w/w
polyvinylpyrrolidone (PVP) and containing 1–5% w/w tetracycline
hydrochloride, designed for the treatment of periodontal disease. All
formulations exhibited pseudoplastic flow with minimal thixotropy. Increasing
the concentration of PVP sequentially increased the zero-rate viscosity
(derived from the Cross model) and the hardness and compressibility of the
formulations (derived from texture profile analysis). These affects may be
accredited to increased polymer entanglement and, in light of the observed
synergy between the two polymers with respect to their textural and rheological
properties, interaction between PVP and PMVEMA. Increasing the concentration of
PVP increased the storage and loss moduli yet decreased the loss tangent of all
formulations, indicative of increased elastic behaviour. Synergy between the
two polymers with respect to their viscoelastic properties was observed.
Increased adhesiveness, associated with increased concentrations of PVP was
ascribed to the increasing bioadhesion and tack of the formulations. The effect
of increasing drug concentration on therheological and textural properties was
dependent on PVP concentration. At lower concentrations (0, 3% w/w) no effect
was observed whereas, in the presence of 9% w/w PVP, increasing drug
concentration increased formulation elasticity, zero rate viscosity, hardness
and compressibility. These observations were ascribed to the greater mass of
suspended drug in formulations containing the highest concentration of PVP.
Drug release from formulations containing 6 and 9% PVP (and 5% w/w drug) was
prolonged and swelling/diffusion controlled. Based on the drug release,
rheological and textural properties, it is suggested that the formulation
containing 15% w/w PMVE-MA, 6% w/w PVP and tetracycline hydrochloride (5% w/w)
may be useful for the treatment of periodontal disease.
[Back to top] The Role of ABC Transporters in Drug
Resistance, Metabolism and Toxicity
Hristos Glavinas, Peter Krajcsi, Judit Cserepes and Balazs Sarkadi
ATP Binding
Cassette (ABC) transporters form a special family of membrane proteins,
characterized by homologous ATP-binding, and large, multispanning transmembrane
domains. Several members of this family are primary active transporters, which
significantly modulate the absorption, metabolism, cellular effectivity and
toxicity of pharmacological agents. This review provides a general overview of
the human ABC transporters, their expression, localization and basic mechanism
of action. Then we shortly deal with the human ABC transporters as targets of
therapeutic interventions in medicine, including cancer drug resistance, lipid
and other metabolic disorders, and even gene therapy applications. We place a
special emphasis on the three major groups of ABC transporters involved in
cancer multidrug resistance (MDR). These are the classical P-glycoprotein
(MDR1, ABCB1), the multidrug resistance associated proteins (MRPs, in the ABCC
subfamily), and the ABCG2 protein, an ABC half-transporter. All these proteins
catalyze an ATP-dependent active transport of chemically unrelated compounds,
including anticancer drugs. MDR1 (P-glycoprotein) and ABCG2 preferentially
extrude large hydrophobic, positively charged molecules, while the members of
the MRP family can extrude both hydrophobic uncharged molecules and
water-soluble anionic compounds. Based on the physiological expression and role
of these transporters, we provide examples for their role in
Absorption-Distribution- Metabolism-Excretion (ADME) and toxicology, and
describe several basic assays which can be applied for screening drug
interactions with ABC transporters in the course of drug research and
development.
[Back to top]
An MDR-EGFP Gene Fusion Allows for Direct Cellular Localization,
Function and Stability Assessment of P-Glycoprotein
Jordi Petriz, Michael M. Gottesman and Josep M. Aran
In cancer and
AIDS, overexpression of the MDR1 gene has important implications in the design
of chemotherapy protocols because of the ability of its product, the
ATPdependent drug efflux pump P-glycoprotein (Pgp), to confer selective
advantage to tumor and HIV-infected cells in the form of multidrug resistance.
To study Pgp expression and physiology, we designed a translational fusion
between the MDR1 and enhanced green fluorescent protein (EGFP) genes. The
chimeric protein, Pgp-EGFP, was concentrated mainly in the plasma membrane and
in the Golgi when expressed in drug-sensitive KB- 3-1 cells. Doxorubicin,
daunorubicin and rhodamine-123 efflux assays confirmed function of the chimeric
pump. Also, at the single-cell level, an inverse relationship between Pgp-EGFP
expression and nuclear doxorubicin accumulation was demonstrated. Polarized Pgp
expression on the apical cell surface was confirmed by transfection of the
MDR-EGFP fusion gene into MDCK cells. However, after colchicine selection,
Pgp-EGFP was also detectable in the lateral domain of the transfected MDCK
monolayers. These results indicate that drug selection affects not only
expression, but cellular localization of Pgp. Furthermore, using a tet-based
inducible expression system for Pgp-EGFP, we confirmed the stable nature of Pgp
(t1/2 total Pgp-EGFP= 2.2 days), but revealed that surface-Pgp acquires extra
stability as an active pump (t1/2 surface Pgp-EGFP= 3.7 days).
[Back to top] Pain Control Via Opioid Analgesic- Local
Anesthetic Loaded IPNs
Dilek
Sendil Keskin, Donald L.Wise and Vasif
Hasirci
Relief of chronic
pain is an important clinical problem requiring special care and approaches.
The present study was designed for the construction of a controlled release
system for local application of analgesics (hydromorphone (HM), morphine (M),
and codeine (C)) and a local anesthetic, bupivacaine (BP). An interpenetrating
network (IPN) drug release system was prepared by using a biocompatible,
biodegradable copolyester, poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV)
and another biocompatible but synthetic, nondegradable polymer, poly (2- hydroxyethyl
methacrylate), (PHEMA). In situ release kinetics of the IPN system was first
order for BP but could not be fitted to any known equation for the other drugs.
Complete release from the IPNs occurred within a considerably short time (24 h
for 80 % of the drugs) most probably due to the significant hydrophilicity of
PHEMA. In order to slow down the release rate these IPNs were coated with PHBV.
Release from these coated IPNs (cIPN) resulted in rates that could be described
by Higuchi’s equations. In vivo measurement of antinociceptive efficacy
was carried out in rats with tail flick and paw-withdrawal tests after inducing
chronic pain created by sciatic nerve ligation at the right side. Control
groups received placebo implants. In vivo studies showed potent, prolonged (2-3
days) antinociception at the site of injury (right paw) for strong opioids (HM
and M) and about 2 days for the weak opioid (C) and local anesthetic (BP). In
all cases the release rate was found to be as important as the antinociceptive
potency. The weakest opioid analgesic of those evaluated (C) had a higher first
day antinociception than its stronger counterpart M, probably due to its higher
initial concentration that was expected from its faster release rate in the in
situ experiments.
[Back to top] Development of Topically Effective Formulations of Acetazolamide
Using HP-β-CD-Polymer Co-Complexes
Indu
Pal Kaur, Mona Kapil, R. Smitha and Deepika Aggarwal
The myriad of side
effects induced by acetazolamide (oral use), the introduction of newer topical
carbonic anhydrase inhibitors (CAI’s) and the advent of other antiglaucoma
medications has led to a decreased interest in acetazolamide. The use of
cyclodextrins to improve the solubility and bioavailability of poorly soluble
drugs has however, rekindled an interest in acetazolamide (ACZ), because its
poor solubility is one of the major factor responsible for its failure to show
topical effectiveness. Since water soluble polymers have been reported to
improve the complexing capabilities of b-cyclodextrins, in the present study
water soluble polymers like polyvinyl alcohol (PVA), polyvinylpyrrolidone
(PVP), hydroxypropymethylcellulose (HPMC) and the mucoadhesive polymer Carbopol
934P were incorporated into aqueous 10% w/v 2HP-b-CD solution to improve the
solubility of ACZ. The effect of these polymers on the corneal transport of 5
mg/ml (0.5% w/v) solution of ACZ in aqueous 10% 2HP-b-CD was evaluated. The
inclusion of these polymers significantly increased the solubility of ACZ from
3.43 mg/ml in aqueous 10% 2HP-b-CD to 5.1 mg/ml (48.6%) in 0.05% PVP; 6.80
mg/ml (98.3%) in 0.05% PVA; and 6.74 mg/ml (96.5%) in 0.2% Carbopol 934P. From
amongst the various polymers assessed in the study, PVA was deemed the best,
based on the premise of better apparent permeability coefficient (Papp) upon in
vitro corneal permeation studies. Inspite of a large enhancement in solubility
produced by Carbopol 934P, surprisingly, it could not efficiently increase the Papp.
[Back to top] Challenges in Current Drug Delivery from the Potential Application of
Pharmacogenomics and Personalized Medicine in Clinical Practice
Ioannis
S. Vizirianakis
The recent
technological achievements in biotechnology and recombinant DNA technology have
provided multiple new methods, molecular targets, and DNA-based diagnostics to
pharmaceutical research that can be utilized in assays for screening and
developing potential biotechnology-based drugs, as well as in biomedicine,
health and pharmaceutical care. Furthermore, such advances opened up new
opportunities by applying genetic information data in pharmacotherapy and drug
delivery, thus ensuring better drug efficacy and safety in clinical practice.
Now the concepts of personalized medicine and pharmacogenomics are likely
improving the area of pharmacodynamics and pharmacokinetics, since they favor
differentiation of the conventional clinical diagnosis and drug selection into
separate molecular subtypes of individuals belonging within a group of patients
suffering from the same disease. Genetic polymorphisms have already been
detected and analyzed in genes encoding drug-metabolizing enzymes, transporters
as well as targets (e.g. receptors). The potential of applying genotyping and
haplotyping analysis in future pharmaceutical care could eventually lead to
pharmacotyping, i.e. individualized drug delivery profiling based on
genetic-bioinformatic data in routine patient care. However, the steps towards
this direction of drug delivery in clinical practice still have a long way to
go to be fully achieved; until then, the critical evaluation of all available
clinical data including pharmacodynamic, pharmacokinetic and genomic must be
assessed for ensuring drug efficacy and safety. In this way, there has been
great progress in elucidating genetic determinants contributing to the observed
interindividual differences in drug disposition and effects, thus implementing
current drug delivery with molecular genetics and diagnostics.
[Back to top] Physical Enhancement of Transdermal Drug Application: Is Delivery
Technology Keeping up with Pharmaceutical Development?
S.E.
Cross and M.S. Roberts
Advances in molecular biology have given us a wide range of protein and peptide-based drugs that are unsuitable for oral delivery because of their high degree of first-pass metabolism. Though parenteral delivery is the obvious answer, for the successful development of commercial chronic and self-administration usage formulations it is not the ideal choice. Transdermal delivery is emerging as the biggest application target for these agents, however, the skin is extremely efficient at keeping out such large molecular weight compounds and therapeutic levels are never going to be realistically achieved by passive absorption. Physical enhancement mechanisms including: iontophoresis, electroporation, ultrasound, photomechanical waves, microneedles and jet-propelled particles are emerging as solutions to this topical delivery dilemma. Adding proteins and peptides to the list of other large molecular weight drugs with insufficient passive transdermal fluxes to be therapeutically useful, we have a collection of pharmacological agents waiting for efficient delivery methods to be introduced. This article reviews the current state of physical transdermal delivery technology, assesses the pros and cons of each technique and summarises the evidence-base of their drug delivery capabilities.