Targeting of Drugs: Anatomical and Physiological Considerations

217 Pages·1988·12.21 MB·English

by  Albert Geerts

Targeting of
Drugs
Anatomical and
Physiological
Considerations
Edited by
Gregory Gregoriadis
Royal Free Hospital School of Medicine
London, United Kingdom
and
George Poste
Smith Kline & French Laboratories
Philadelphia, Pennsylvania
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Study Institute on
Targeting of Drugs: Anatomical and Physiological Considerations,
held June 20-July 1, 1987,
In Cape Sounlon Beach, Greece
ISBN-13: 978-1-4684-5576-2 e-ISBN-13: 978-1-4684-5574-8
001: 10.1007/978-1-4684-5574-8
© 1988 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1988
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system,
or transmitted in any form or by any means, electronic, mechanical, photocopying,
microfilming, recording, or otherwise, without written permission from the Publisher
PREFACE
A major vehicle for the transition of carrier-mediated drug delivery
from a theoretical/experimental status to one with practical uses has been
the NATO Advanced Studies Institute series "Targeting of Drugs". Three
previous ASls of the series[1-3], also held in Cape Sounion, dealt with
carriers of natural and synthetic origin, their preparation and drug
incorporation as well as a wide range of applications.
This book contains the proceedings of the 4th NATO ASI "Targeting of
Drugs: Anatomical and Physiological Considerations" held in Cape Sounion,
Greece during 20 June - 1 July 1987. Historically, carrier systems have
been chosen on the basis of selective affinity for target sites. For
instance, monoclonal antibodies bind selectively to antigens on the surface
of cells and the same applies to ligands such as certain glycoproteins
which bind to cell receptors. Colloidal carriers on the other hand, are
"passively" targeted to the reticuloendothelial system. However, effective
drug delivery depends not only on demonstration of affinity of the carrier
system for its target but also, and perhaps crucially, on the way(s) by
which the carrier-drug entity interacts with the interposed biological
milieu. The book deals in depth with a number of biological milieus as
travelled space for carriers en route to their destination, difficulties
arising from unfavorable milieu-carrier interactions and ways to circumvent
such difficulties. It also identifies, when possible, situations where
proposed uses would or would not be realistic and provides perspectives for
future goals.
We express our appreciation to Dr A.C. Allison, Professor S.S. Davis,
and Professor K. Sikora for their valuable advice throughout the planning
stages of the ASI and to Dr G. Deliconstantinos who, as chairman of the
local committee, contributed most effectively to its success. We are also
grateful to Mrs A. Massaro for both the enthusiastic management of many of
the practical aspects of the Institute and editorial help. The ASI was
held under the sponsorship of NATO Scientific Affairs Division and co
sponsored and generously financed by Smith Kline and French Laboratories,
Philadelphia, USA. Financial assistance was also provided by Schering
(FRG), Ciba Geigy (UK), Hoffmann La Roche (Switzerland), Boeringer (FRG),
Armour (USA), Biophor (USA), Syntex (USA), Biogen (USA), Avanti (USA),
Pfizer (UK), and ICI (UK).
May 1988 Gregory Gregoriadis
George Poste
v
1. Targeting of Drugs (eds. Gregoriadis. G• • Senior. J. and Trouet. A.).
Plenum. 1982.
2. Receptor-Mediated Targeting of Drugs (eds. Gregoriadis. G• • Poste, G.,
Senior, J. and Trouet, A.), Plenum, 1984.
3. Targeting of Drugs with Synthetic Systems (eds. Gregoriadis, G.,
Senior. J. and Poste, G.), Plenum, 1986.
CONTENTS
The Structure of Different Types of Liver Cells in Relation
to Uptake and Exchange Processes
A. Geerts, L. Bouwens, R. de Zanger, H. van Bossuyt
and E. Wisse 1
The Lymphatic System in Drug Targeting: An Overview
J.G. Hall 15
The Hepatic Receptor for Asialoglycoproteins: Search for
a Function
C.J. Steer, P. Weiss, P.J. Wirth and G. Ashwell 29
The Galactose-Particle Receptor on Liver Macrophages:
Biological Function and Implications for Clearance
of Particulate Material
V. Kolb-Bachofen 45
Free Radicals in Health and Disease: Implications for
Drug Delivery and Targeting
C. Rice-Evans 53
Monoclonal Antibodies and Drug Targeting in Cancer
K. Sikora 69
Immunotoxins in Cancer Therapy
F.K. Jansen, C. Blazy, H.E. Blythman, B. Bourrie,
P. Carayon, P. Casellas, J.M. Derocq, D. Dussossoy,
P. Gros, O. Gros, G. Laurent, G. Richer and H. Vidal 81
Techniques for Ex-Vivo Bone Marrow Treatment with
Immunotoxins
J.M. Derocq, G. Laurent, P. Casellas, H. Blythman
and F.K. Jansen 93
The Potential of Memhrane-Actin8 Toxins for Targeted
Cancer Therapy
F.A. Drobniewski, P.E. Thorpe, P.M. Wallace
and E.J. Wawrzynczak 103
In Vivo Uptake and Processing of Liposomes by Parenchymal
and Non-parenchymal Liver Cells: Application to
Immunotherapeutic Treatment of Hepatic Metastases
G.L. Scherphof, T. Daemen, H. Derksen, G. Lazar,
H.H. Spanjer and F.H. Roerdink 109
Platelet Activating Factor. a Potent Mediator of Allergy.
as a Structural Component of Phosphatidylcholine
Vesicles
E. Skrika and C. Vakirtzi-Lemonias 121
Phospholipid Stereospecificity in Liposomal Modulation of
Nitrogen Mustard Action
C. Ritter. C. Prood and R.J. Rutman 137
Niosomes: A Putative Drug Carrier System
A.J. Baillie 143
The Immunoadjuvant Action of Liposomes: Optimization Studies
G. Gregoriadis. D. Davis and N. Garcon 153
Targeting of Antigens to Antigen-Presenting Cells and Their
Activation: A Requirement for Vaccine Development
A.C. Allison and N.E. Byars 167
Targeting Using Physical Approaches and Particulate Drug
Carriers: Interaction with the Biological Milieu
S.S. Davis and L. IlIum 177
Pragmatic Approaches to Delivery of Pep tides and Proteins
as Drugs
D.A. Eppstein 189
Reconstituted Influenza Virus Envelopes as a Potential
Carrier for Fusion-Mediated Microinjection of
Macromolecules into Living Cells
A. Loyter and M. Lapidot 203
Contributors 213
Index 217
viii
THE STRUCTURE OF DIFFERENT TYPES OF LIVER CELLS IN RELATION
TO UPTAKE AND EXCHANGE PROCESSES
Albert Geerts, Luc Bouwens, Ronald De Zanger,
Hans Van Bossuyt and Eddie Wisse
Laboratory for Cell Biology and Histology
Free University Brussels (V.U.B.)
1090 Brussels-Jette, Belgium.
INTRODUCTION
The structural unit of the liver is classically named the liver lobule
and is defined as a unit of parenchymal tissue characterized by peripheral
branches of the portal vein and hepatic artery, and by a centrilobular
branch of the hepatic vein, i.e. the central vein. The blood enters the
lobule via the portal tracts through sinusoidal inlets and, after inter
action with the parenchymal tissue during passage through the hepatic
sinusoids, leaves the lobule through the central veins [Wisse and De Leeuw,
1984].
The alternative model of the liver acinus [Rappaport, 1973] puts the
terminal portions of the portal tract in the middle and divides the paren
chyma in zone I (periportal zone), zone II (midacinar zone) and the periph
eral zone III. The peripheral tissue (zone III) of several adjacent acini
forms a star shaped area around the terminal hepatic venules. A simple
acinus contains at least two terminal branches of the hepatic vein at its
periphery. This alternative model takes the existence of important gradi
ents between zone I and zone III into account.
The liver parenchyma is composed of several cell types including
parenchymal and sinusoidal cells. The latter comprise endothelial,
Kupffer, fat-storing and pit-cells [Wisse, 1977]. The parenchymal cells
are not directly accessible for molecules or particles present in the
sinusoidal blood. The sinusoidal endothelial cells form the sinusoidal
lining which is interposed between the sinusoidal lumen and the underlying
space of Disse. The hepatic sinusoidal endothelium is of a unique type.
The endothelial cells possess numerous fenestrae or pores which lack a
diaphragm. The fenestrae are organized in groups called sieve plates.
Underneath the endothelial cells, fragments of basal lamina are present.
Kupffer and pit cells are often present on or, less frequently, in between
the sinusoidal endothelial cells.
The space of Disse is a subendothelial tissue space, bordered on the
luminal side by the endothelial lining and on the other side by the sinus
oidal surface of the parenchymal cells bearing numerous microvilli. Behind
the sinusoidal lining, in the space of Disse or in recesses between two
adjacent parenchymal cells, the fat-storing cells (Ito cells, stellate
cells, peri- or parasinusoidal cells, lipocytes) are found.
In this paper, we will discuss the structural characteristics of the
different liver cells in relation to the transport, exchange and uptake
phenomena which take place in the hepatic sinusoids and in the underlying
space of Disse.
ENDOTHELIAL CELLS
The Liver Sieve
Sinusoidal endothelial cells form a continuous, but fenestrated lining
of the hepatic sinusoids [Wisse, 1980J. Fig. 1 shows the endothelial
lining of a rat liver sinusoid as seen in the scanning electron microscope.
In rat liver, the fenestrae have an average diameter of 105 nm in the
centrilobular areas of the liver and of III nm in periportal areas when
measured on scanning electron micrographs after critical point drying of
the tissue. The shrinkage of the tissue due to critical point drying is
clearly shown by comparing the results obtained by scanning with the dia
meter of fenestrae measured by transmission electron microscopy: 150 to 175
nm [Wisse et aI, 1985J. The fenestrae lack a diaphragm and are grouped
together in so called sieve plates. In low pressure perfusion fixed liver,
only fenestrae occur. Gaps, defined as endothelial pores with a diameter
of at least twice the average diameter of the fenestrae, have been de
scribed to occur inter- and intracellularly [Wisse et aI, 1985J. Most
probably, these gaps form during the fixation procedure due to hypoxia or
pressure exceeding the physiological pressure.
The fenestrated endothelium filters chylomicrons and other particulate
material, upon passage through the sinusoids [De Zanger and Wisse. 1982;
Naito and Wisse, 1978; Wisse et aI, 1985J. In these studies, it has been
shown that chylomicrons up to the size of fenestrae are present in the
space of Disse whereas bigger ones are absent by apparent exclusion. The
sieving of chylomicrons, their cholesterol rich remnants and other lipo
proteins affects the rate of uptake of dietary fat from the circulation and
therefore may play an important role in various diseases such as hyper
lipidaemias and atherosclerosis [Fraser et aI, 1978; Fraser et al. 1986J.
Possibly, this sieving effect is also of importance in the selective uptake
by parenchymal cells of various particles injected in the systemic or
portal bloodstream.
Forced Sieving and Endothelial Massage
It has been established by morphometry, that the size distributions of
white and red blood cells overlap the size distributions of periportal, and
to a lesser extent of pericentral sinusoids [Wisse et aI, 1985J. The mean
diameters of red blood cells, white blood cells and sinusoids measured
after critical point drying in the scanning electron microscope are re
spectively 5.30 ~m, 4.90 ~m and 4.98 pm. This overlap implies that large
blood cells are unable to pass through the sinusoids, unless the cells or
the sinusoidal wall adapt their shape. By in vivo microscopy, it has been
established that red blood cells are very flexible and adapt easily to the
diameter of the hepatic sinusoids. White blood cells on the contrary, are
more rigid and obstruct regularly the sinusoids [Wisse and McCuskey, 1986J
From these observations, the concepts of "forced sieving" and "endothelial
massage" have evolved [Wisse et aI, 1985].
Forced sieving is supposed to occur when fast-moving globular bodies
such as red blood cells pass through the sinusoids. These bodies promote
2
Fig. 1. Scanning electron micrograph of the sinusoidal endothelium.
Numerous fenestrae, organized in sieve plates, are present. In
the space of Disse (SD), the microvilli of parenchymal cells are
visible.
the entrance of fluid or particles such as chylomicrons through the fen
estrae into the space of Disse.
Endothelial massage can occur when rigid white blood cells pass
through narrow sinusoids. By compresssing the space of Disse, a downstream
displacement of fluid present in the space of Disse would be induced. When
fenestrae are encountered the fluid is forced out of the space of Disse
into the sinusoid. When the white blood cell moves along, the microvilli
of the parenchymal cells and the endothelial cell processes come back into
position, and as a result new plasma will be sucked into the space of
Disse.
Endocytosis
Blouin and coworkers [Blouin et aI, 1977] have demonstrated that,
although sinusoidal endothelial cells represent only 2.8% of the paren
chymal volume, they contain 45% of the pinocytotic vesicles and 14.5% of
the lysosomes present in the hepatic parenchyma (Fig. 2). These obser
vations indicate that endothelial cells take part in the uptake of com
pounds from the sinusoidal blood. Indeed, endothelial cells take up var
ious test substances when injected into the bloodstream [Praaning-Van Dalen
et aI, 1981; Wisse, 1972]. Particulate material such as latex beads
[Praaning-Van Dalen et aI, 1982a; Steffan et aI, 1986], colloidal sulfur,
silver iodide and carbon [Praaning-Van Dalen et aI, 1982a], Thorotrast
[Wisse, 1972], Frog-virus [Steffan et aI, 1981], heat aggregated albumin
[Brouwer et aI, 1985], immune complexes [Van Der Laan-Klamer et aI, 1986],
ferritins [Ghitescu and Fixman, 1984] and lipoproteins [Praaning-Van Dalen
et aI, 1982b], as well as monodispersed molecules such as horseradish
peroxidase [Praaning-Van Dalen et aI, 1982a] are taken up by these cells.
By electron microscopy, two types of structures appear to mediate the
uptake of particles by endothelial cells: bristle coated micropinocytotic
3
Fig. 2. Transmission electron micrograph of an endothelial cell.
Numerous bristle coated micropinocytotic vesicles are present
(arrows). In one of the cell processes, fenestrae (F) are ap
parent. (L): lysosome. (C): centriole. Arrowheads: microtubules.
SD: space of Disse. (P): parenchymal cell.
vesicles and macropinocytotic vesicles [De Bruyn et aI, 1977; Wisse,· 1972].
According to the kinetics and other biochemical characteristics of the
uptake, three mechanisms are distinguished:
(i) fluid phase endocytosis,
(ii) adsorptive, receptor mediated, endocytosis and
(iii) adsorptive, non receptor mediated, endocytosis
125I-polyvinylpyrrolidone (PVP) is taken up by fluid phase endo
cytosis, i.e. by pinocytosis without prior adsorption of the compound to
the cell membrane [Praaning-Van Dalen et aI, 1981].
Several compounds are taken up through adsorptive, receptor mediated,
endocytosis. One group of receptors is related to the hepatic catabolism
of dietary fat: the remnant (apo E) receptor, the acetyl LDL (scavenger)
receptor and the liver lipase receptor [Praaning-Van Dalen et aI, 1982b].
The scavenger receptor is present exclusively on endothelial cells and
would remove all "old" (Le. chemically modified) LDL from serum
[Nagelkerke et aI, 1984]. Endothelial cells also bear the Fe receptor [Van
Der Laan-Klamer et aI, 1986]. It remains to be established, whether en
dothelial cells remove significant quantities of immune complexes in vivo.
Receptors for hyaluronic acid, chondroitin sulphate and collagen al (I)
chain were demonstrated on isolated endothelial cells in primary culture
[Smedsrod et aI, 1985a; Smedsrod et aI, 1985b; Smedsrod et aI, 1984]. If
these receptors were operative in vivo, they might be of considerable
importance in degrading excess connective tissue in the space of Disse.
Mannose!N-acetylglucosamine terminated and galactose terminated glyco
proteins are cleared from the blood by receptors present, through not
exclusively, on endothelial cells. The physiological significance of these
4