Dendritic polymer macromolecular carriers for drug

466
Dendritic polymer macromolecular carriers for drug delivery
Anil K Patri, István J Majoros and James R Baker Jr*
Dendrimers are synthetic, highly branched, mono-disperse
macromolecules of nanometer dimensions. Started in the
mid-1980s, the research investigations into the synthetic
methodology, physical and chemical properties of these
macromolecules are increasing exponentially with growing
interest in this field. Potential applications for dendrimers are
now forthcoming. Properties associated with these dendrimers
such as uniform size, water solubility, modifiable surface
functionality and available internal cavities make them attractive
for biological and drug-delivery applications.
Addresses
Center for Biologic Nanotechnology, Department of Internal Medicine,
9220C MSRB III, University of Michigan, 1150 West Medical Center
Drive, Ann Arbor, Michigan 48109-0648, USA
www.nano.med.umich.edu
*e-mail: jbakerjr@umich.edu
Current Opinion in Chemical Biology 2002, 6:466–471
1367-5931/02/$ — see front matter
© 2002 Elsevier Science Ltd. All rights reserved.
DOI 10.1016/S1367-5931(02)00347-2
Abbreviations
EDC
1-[3(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
FITC
fluorescein isothiocyanate
hFR
high-affinity folate receptor
PAMAM polyamidoamine
PEG
polyethylene glycol
PSMA
prostate-specific membrane antigen
Introduction
A macromolecular drug-delivery system is a complex material
in which a drug is attached to a carrier molecule such as a
synthetic polymer, antibody, hormone or liposome. As the
absorption and distribution of the drug in such a system
depend on the properties of the macromolecular carrier,
parameters such as site specificity, protection from degradation and minimization of side effects can be altered by
modifying the properties of the carrier. An ideal drug
carrier must be biochemically inert and non-toxic, while
protecting the drug until it reaches the desired site of
action, with the carrier then releasing the drug. Many polymeric drug-delivery systems have been developed over the
years and have been extensively reviewed [1]. By contrast,
the use of dendrimers [2••,3••], which possess many of the
above-mentioned properties for an ideal drug-carrier
system, has not been highlighted. We review the current
trends in the drug-delivery systems using dendrimers.
Dendrimers in drug delivery
Dendrimers are synthetic, highly branched, spherical,
mono-disperse macromolecules of nanometer dimensions,
prepared by the iterative synthetic methodology. Since the
pioneering work of Tomalia et al. [4] and Newkome et al.
[5] on dendrimer synthesis in the early 1980s, several
research groups have contributed both synthetic methodology
and specific applications for this field. There is a continuing
effort to improve the efficiency and lessen the cost of
synthesizing these macromolecules. Further investigations
also are examining the specific physical and chemical
properties of dendrimers and, although there are many
factors that remain unknown, potential applications for
dendrimers are now forthcoming. These macromolecules
have uniform size and are mono-dispersed. They also have
modifiable surface functionality as well as internal cavities
[6]. These characteristics, along with water solubility, are
some of the features that make them attractive for biological
and drug-delivery applications [7,8]. In fact, much of the
current work in this field is focused on the characteristics
of dendrimer-based devices in vivo.
Polymeric micelles provide a model of sorts for dendrimermediated drug delivery. In polymeric micelles, the drug
molecules can be trapped in the inner hydrophobic core
while the outer shell is hydrophilic and soluble in aqueous
media. However, below a critical micelle concentration, the
polymeric aggregates dissociate into free chains, leading to
the sudden release of the drug. Newkome et al. [9] have
synthesized a dendritic unimolecular micelle (Figure 1a)
containing hydrophobic interior and hydrophilic surface
functionality to overcome this problem. Unlike polymeric
micelles, these unimolecular micelles do not dissociate as
they are covalently bound. The internal hydrophobic cavities of this unimolecular micelle were shown to solubilize
various hydrophobic guest molecules. Newkome’s group
has also prepared a series of dendritic molecules possessing
internal heterocyclic loci [10] capable of specific binding of
guest molecules (Figure 1b) and dendrimers with terminal
tryptophan units [11]. This provides a basis for dendrimers
as drug carriers.
Specific types of dendrimers for drug delivery
Perhaps the family of dendrimers most investigated for
drug delivery is the polyamidoamine (PAMAM) dendrimer
(Figure 1c). The divergent synthesis of PAMAM dendrimers starts with an amine functional core unit that is
reacted with methyl acrylate by Michael addition reaction.
This results in the formation of two new branches per
amine group with ester-terminated dendrimer, which is
called ‘half-generation’ dendrimer. Subsequent amidation
of the methyl ester with ethylene diamine gives a ‘fullgeneration’ amine-terminated dendrimer. Repetition of
Michael addition and amidation steps gives the next-higher ‘generation’ dendrimer with increase in the molecular
weight, number of terminal functional groups and size.
PAMAM dendrimers are biocompatable, nonimmunogenic, water-soluble and possess terminal- modifiable
amine functional groups for binding various targeting or
guest molecules. The internal cavities of PAMAM
Dendritic polymer macromolecular carriers for drug delivery Patri, Majoros and Baker
467
Figure 1
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(d)
Current Opinion in Chemical Biology
Different families of dendrimers. (a) Unimolecular micelle. (b) Newkome’s dendrimer with internal binding units. (c) PAMAM dendrimer.
(d) POPAM dendrimer.
dendrimers can host metals or guest molecules because of
the unique functional architecture, which contains tertiary
amines and amide linkages. Twyman et al. [12] have
converted the ester-terminated half-generation PAMAM
dendrimers to a more water-soluble hydroxyl surface by
reacting with tris. They have investigated complexing
these novel dendrimers with small hydrophobic guest
molecules, which then become highly soluble in phosphatebuffered dendrimer solution at pH 7.0. The complexes are
not stable in acid and precipitate at pH 2, presumably
468
Next-generation therapeutics
Figure 2
(a)
(b)
(c)
(FA)
Imaging
(FA)
(CO2H)
G5
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O
Targeting device
Gx
O-C-Drug
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(FA)
(FA)
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(CO2H)
G5
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G5
(CO2H)
(FA)
(CO2H)
(FA)
Current Opinion in Chemical Biology
Dendritic nanodevices for therapeutic applications. (a) Surface-modified PAMAM dendrimer for targeting, imaging and drug delivery.
(b) Antibody–dendrimer conjugate. (c) Tecto(dendrimer). FA, folate.
because of the protonation of the internal tertiary amines,
which releases the guest molecules.
Gadolinium is an FDA-approved contrast agent for MRI.
It provides greater contrast between normal tissue and
abnormal tissue in the brain and body. It is safer than the
iodine-type contrast used in CT scans, is non-radioactive
and is rapidly cleared by kidneys. An early attempt to use
dendrimers in vivo was efforts in the development of
target-specific MRI contrast agents by Wiener et al. [13].
These investigators produced gadolinium complexes of
folate-conjugated PAMAM dendrimers for targeting
tumour cells expressing high-affinity folate receptor
(hFR). These conjugates increased the longitudinal
relaxation rate of tumour cells expressing the hFR, and
subsequently the investigators demonstrated the specific
targeting ability of folate–PAMAM dendrimer MRI
contrast agents to ovarian tumour xenografts [14•]. Because
of the increased amount of gadolinium-ion delivery
per receptor using the dendrimer complex, the investigators
have shown a 33% increase by contrast enhancement
compared with that of a non-specific agent. More recent
studies have been conducted by our group with non-ionic
(surface amines capped with acetic anhydride) folateconjugated PAMAM dendrimers labeled with fluorescein
isothiocyanate (FITC) for targeting tumour cells expressing
hFR [15••]. Methotrexate and Taxol drug conjugates
of these folate/FITC-conjugated PAMAM dendrimers
(Figure 2a) are being investigated for their in vitro and
in vivo cytotoxicity and specificity of drug targeting.
Another approach to hFR targeting involves folic acid
surface modification on polyarylether dendrons and
dendrimers [16]. Folic acid is conjugated to the surface
hydrazides by active ester formation and EDC coupling
strategy. A similar reaction sequence was used to prepare a
second-generation dendron-methotrexate conjugate. Unlike
the folate–PAMAM dendrimer conjugates, which are water
soluble, the folate–dendron conjugates prepared by convergent polyether linkages show turbidity near pH 7.4 [16].
Unfortunately, attempts to improve water solubility by the
attachment of a polyethylene glycol (PEG) chain to the free
hydroxyl group of these dendrons decreased the binding of
folic acid and increased polydispersity.
Approaches to engineer dendrimers with the
ability to release drugs
To improve biocompatibility and solubility, PAMAM
dendrimers with PEG grafts on the surface have been
synthesized, and the encapsulation of anticancer drugs,
including adriamycin and methotrexate, using these structures has been attempted [17]. The ability to encapsulate
the drugs in the dendritic core increases with increased
generation and chain length of the attached PEG grafts.
Though the drugs are released slowly from the matrix in
low ionic strength aqueous solution, they are readily
released in isotonic solutions. This suggests the need
for further control of the drug release mechanism in
these molecules.
The pH-dependent change in the hydrodynamic radii of
acid-terminated dendrimers has been investigated as a
potential controlled-release system for encapsulated drugs
from the interior hydrophobic areas of the dendrimer [18].
Using this principle, Paleos and co-workers [19] have
investigated the pH-dependent inclusion and release of
pyrene in quarternized poly(propylene imine) dendrimers
(Figure 1d). The terminal quarternary ammonium salt not
only enhances the water solubility of the dendrimer, but
possess bactericidal, antifungal and antimicrobial properties.
Pyrene is released when the internal tertiary amines
get protonated between pH 4–2. This release within a
Dendritic polymer macromolecular carriers for drug delivery Patri, Majoros and Baker
narrower pH region suggests these materials are potential
candidates for pH-sensitive controlled-release drugdelivery applications.
Fréchet and co-workers [20,21] have prepared novel
polyaryl ether dendrimers containing dual functionality on
the surface by using a convergent synthetic strategy. One
type of functionality is used to attach PEG units on the
surface to render water solubility to the assembly, whereas
the other functionality is utilized to attach hydrophobic
drug molecules. They have conjugated cholesterol,
pheynylalanine and tryptophan by carbonate, ester and
carbamate linkages, respectively, and also synthesized a
series of dendritic unimolecular micelles with a hydrophobic
polyether core surrounded by a hydrophilic PEG shell for
drug encapsulation [21]. A third-generation micelle with
24 surface chains has been shown to entrap the model drug
indomethacin, loading up to an 11 wt% (approximately
9–10 drug molecules) per micelle. The in vitro drugrelease characteristics of these micelles were investigated
and found to be slow and sustained, as compared with that
of a cellulose membrane control. Together, these studies
suggest that the physico-chemical structure of the
dendrimer may allow for the loading and controlled release
of drugs.
Additional unique dendrimer-based
macromolecules with delivery capability:
immunoconjugates
Antibodies are useful in targeted drug therapy because of
the inherent specificity of the antibody–antigen interaction
(Figure 2b). Modification of the antibody molecule with
drugs often diminishes or eliminates its biological activity
and reduces the targeting potential. An attractive approach
to increase drug loading while retaining specificity is to
link the antibody to another macromolecule, containing
the drug, at a single site. Several research groups have
taken this approach and employed dendrimers that carry
imaging or therapeutic agents. Roberts et al. [22] have
utilized dendrimers as linkers to covalently couple porphyrin
to chelated copper ions. The resulting antibody PAMAM
dendrimer conjugates retained 90% of the immunoreactivity
of the unmodified antibody. They have also investigated
the site of attachment of porphyrin in the conjugate and
observed 100% of the conjugate bound to the heavy chain
of the antibody. This is in contrast to a random-labeling
technique in which only 69% of porphyrin was attached to
the heavy chain and 31% to the light chain in the vicinity
of antigen recognition. These radiolabeled antibody–dendrimer conjugates have potential application in cancer
imaging and therapy. Barth and co-workers have prepared
boronated starburst dendrimer–monoclonal-antibody
immunoconjugates [23] for boron neutron capture therapy
[24] (BNCT). They have compared the in vivo distribution
pattern of 125I-labeled and boronated MoAb–dendrimer
conjugates and reported that the dendrimers have a
propensity to localize in the liver and spleen. Studies with
non-boronated dendrimers revealed that this was directly
469
related to the molecular weight and number of terminal
amino groups. The zero-generation starburst dendrimer
with three terminal amino groups had the lowest hepatic
and splenic uptake, with 1% and 0.01% respectively, of the
injected dose of radioactivity at 72 h. Higher-generation
(G2–G4) dendrimers have five times more hepatic
uptake than the zero-generation dendrimer. PAMAM
dendrimer–antibody conjugates have also been used to
enhance the sensitivity of immunoassays [25,26], radioimmunotherapy [27] and imaging with minimal loss of
immunoreactivity. A fifth-generation PAMAM dendrimer
labeled with FITC, capped with acetic anhydride to
neutralize surface amines and minimize non-specific
interaction with the cell surface, was conjugated [28] to
anti-PSMA (prostate-specific membrane antigen) antibody
for targeting prostate cancer. This conjugate has been
shown to successfully target PSMA-positive LNCaP cell
line with minimal loss of immunoreactivity, compared with
the control without the receptor. Further investigation for
the drug-delivery and radioisotope studies are underway at
our laboratories.
Dendrimers clustered around a central core molecule, also
described as tectodendrimers, are prepared using dendrimers as core and shell reagents [29••]. This type of
cluster reagent (Figure 2c) has been prepared with fluorescein
in the core reagent for detection, and folate moieties in the
shell reagent for targeting. This minimizes the solubility
problems encountered in previous studies with aromatic
FITC moieties on the surface of the dendrimer while
maximizing the surface availability of the targeting agent.
This molecule has successfully targeted hFR cell lines and
appears potentially more efficient than a single dendrimer
having both agents on the surface of the polymer.
Specific studies on the safety and efficiency of
dendrimer-mediated drug delivery
The true utility determination of drug-delivery agents
requires testing in appropriate animal models. Recent
studies have begun this difficult process. Duncan and coworkers [30••] have investigated the relationship between
structure and biocompatibility of PAMAM, poly(propyleneimine), poly(ethylene oxide) grafted carbosilane
dendrimers with cationic (NH2-terminated) and anionic
(COONa-terminated) dendrimers in vitro. They have
reported that, regardless of structure, cationic dendrimers
were generally haemolytic and cytotoxic at even relatively
low concentrations. In the case of PAMAM dendrimers,
haemolysis is generation dependent (generations 1–4) with
it increased in higher generations. Conversely, dendrimers
with carboxylate-terminal groups were neither haemolytic
nor did they cause cytotoxicity of a panel of cell lines
studied in vitro. They have further observed that PAMAM
dendrimers of equivalent surface functionality were slightly
less toxic than DAB (polypropylenimine) dendrimers
with the same number of surface groups. They have also
investigated the biodistribution of 125I-labelled PAMAM
dendrimers in vivo and reported that cationic dendrimers
470
Next-generation therapeutics
were cleared rapidly from the circulation after intravenous
and intraperitoneal administration. Anionic PAMAM
dendrimers showed longer circulation times with generation-dependent clearance rates, the lower generations
circulating longer.
Using an everted rat intestinal sac system, Duncan and coworkers [31] have studied the effect of PAMAM dendrimer
size, charge and concentration on uptake and transport
across adult rat intestine in vitro. The results obtained from
this study show that 125I-labeled anionic dendrimers have
rapid serosal transfer rates and low tissue deposition. The
size or conformation sensitivity of the transport mechanism
was indicated as a generation 5.5 dendrimer displaying
higher tissue accumulation compared with that of either a
generation 2.5 or 3.5 polymer. In contrast to this, cationic
PAMAM dendrimers were associated with lower transport
rates as the negatively charged cell membranes appeared
to interact with the cationic dendrimer surface.
Ghandehari et al. [32] have investigated the influence of
increase in size and molecular weight of fluorescentlabeled PAMAM dendrimers on the extravasation across
microvascular endothelium and compared these molecules
with corresponding linear poly(ethylene glycol) of similar
molecular weight. They have observed an exponential
increase in the extravasation time with an increase in the
molecular weight and size of PAMAM dendrimers, from
generation zero through generation four, which increased
from 143.9 s to 422.7 s. It appeared that as the molecular
diameter and size of the PAMAM dendrimer increases
with generation, the exerted viscous drag on the polymer
together with its degree of exclusion from the endothelial
pores increases, and hence the observed increase in the
extravasation time. Compared with PAMAM dendrimers,
PEG molecules with a similar molecular weight took a
longer time to extravasate across the endothelium into the
interstitial tissue. For example, a 6.0 kDa PEG had a higher extravasation time of 453.9 s compared with that of the
similar molecular weight third-generation (molecular
weight 6909) with 203.8 s. It is proposed that this is the
result of a larger hydrodynamic volume on the hydrated
PEG chain because of the coiled conformation. The
permeability of a series of PAMAM dendrimers across
MDCK (Madin–Darby canine kidney) cell line also has
been investigated [33]. The investigators labeled G0–G4
PAMAMs with FITC; and determined the permeability
order was G4>> G1 ≈ G0 > G3 > G2. This suggested that
although dendrimers traverse the vascular endothelium,
there might be a size threshold for this migration.
Conclusions
Although dendrimer drug-delivery is in its infancy, it offers
several attractive features. It provides a uniform platform
for drug attachment that has the ability to bind and
release drugs through several mechanisms. Although toxicity
problems may exist, modification of the structure should
resolve these issues. Further work is needed to define the
structure of the polymer and the relationship between the
polymer and drug molecules for this technology to succeed
in drug delivery.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• of special interest
•• of outstanding interest
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•• Chichester, UK: Wiley; 2002.
Please refer to these recently published books (see also [3••]), edited/written
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this field.
3.
••
Newkome GR, Moorefield CN, Vögtle F: Dendrimers and Dendrons:
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See annotation to [2••].
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•
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Magn Reson Mater Phys Biol Med 2001, 12:104-113.
Wiener’s group is the first to use the folate-conjugated PAMAM dendrimers for
specific targeting to use in MRI contrast agents. This paper describes the use
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471
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This paper describes the in vitro and in vivo biodistribution studies of
PAMAM dendrimers. It is essential to understand the effect of size, surface
charge and functionality of dendrimers in vivo to ascertain their biocompatibility and toxicity for drug-delivery applications.
24. Soloway AH, Tjarks W, Barnum BA, Rong F-G, Barth RF, Codogni IM,
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