D.A. Tomalia, L.A. Reyna and S. Svenson- Dendrimers as multi-purpose nanodevices for oncology drug...

8/3/2019 D.A. Tomalia, L.A. Reyna and S. Svenson- Dendrimers as multi-purpose nanodevices for oncology drug delivery an

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Cellular Delivery of Therapeutic Macromolecules 61

Dendrimers as multi-purpose nanodevices foroncology drug delivery and diagnostic imagingD.A. Tomalia*1, L.A. Reyna* and S. Svenson**Dendritic Nanotechnologies Inc., 2625 Denison Drive, Mt. Pleasant, MI 48858, U.S.A., and Department of Chemistry, Central Michigan University,

Mt. Pleasant, MI 48859, U.S.A.

AbstractDendrimers are routinely synthesized as tuneable nanostructures that may be designed and regulated

as a function of their size, shape, surface chemistry and interior void space. They are obtained with

structural control approaching that of traditional biomacromolecules such as DNA/RNA or proteins and are

distinguished by their precise nanoscale scaffolding and nanocontainer properties. As such, these important

properties are expected to play an important role in the emerging field of nanomedicine. This review will

describe progress on the use of these features for both targeted diagnostic imaging and drug-delivery

applications. Recent efforts have focused on the synthesis and pre-clinical evaluation of a multipurpose

STARBURSTR

PAMAM (polyamidoamine) dendrimer prototype that exhibits properties suitable for use as:

(i) targeted, diagnostic MRI (magnetic resonance imaging)/NIR (near-IR) contrast agents, (ii) and/or forcontrolled delivery of cancer therapies. Special emphasis will be placed on the lead candidate, namely

[core: 1,4-diaminobutane; G (generation)= 4.5], [dendri-PAMAM(CO2Na)64]. This dendritic nanostructure

(i.e. 5.0 nm diameter) was selected on the basis of a very favourable biocompatibility profile [The

Nanotechnology Characterization Laboratory (NCL), an affiliate of the National Cancer Institute (NCI), has

completed extensive in vitro studies on the lead compound and have found it to be very benign, non-

immunogenic and highly biocompatible], the expectation that it will exhibit desirable mammalian kidney

excretion properties and demonstrated targeting features.

IntroductionThe extraordinary level of structural control that is possible

by either the Tomalia-type divergent synthesis or theFrechet-type convergent synthesis of dendrimers [13] rivals

that observed for precise biological nanostructures such as

DNA/RNA and proteins. In fact, owing to the widely

recognizedmimicry of protein sizes, shapes and functionality,

dendrimers are often referred to as artificial proteins [4,5].

Several critical properties that differentiate dendrimers from

proteins include: (i) their coreshell architecture, wherein the

core is concentrically surrounded by annular shells [i.e. gen-

erations (G)] of covalently linked branch cells that create an

interior upon which terminal surface groups(Z) are presented

and amplified according to the equation Z=NcNbG, whereNc is core multiplicity and Nb is branch cell multiplicity

(see Figure 1); (ii) a wide range of robust non-amino-

acid-derived dendrimer compositions; (iii) three-dimensional

shape presentations of surface functionality defined by the

shape/size of the core; (iv) a unique feature of developing

interior void space capable of hosting high multiples of

smaller guest molecules by surface-induced congestion; and

(v) their lack of immunogenicity. These features create a wide

variety of protein-like nanocontainer/scaffolding structures

Key words: dendrimer, diagnostic imaging, nanocontainer, nanomedicine, nanoscaffolding,

targeted delivery.

Abbreviations used: EPR, enhanced permeability retention; MRI, magnetic resonance imaging;

PAMAM, polyamidoamine; PEG, poly(ethylene glycol); P-gp, P-glycoprotein.1

To whom correspondence should be addressed (email [email protected]).

with demonstrated advantages compared with proteins in

nanomedical applications such as drug delivery [6], MRI

(magnetic resonance imaging) and DNA/RNA transfections[7]. This very active area has been reviewed recently [810].

Dendrimer properties of importanceto nanomedicineThe objective of nanomedicine is to control and manipulate

biomacromolecular constructs and supramolecular assem-

blies that are critical to living cells in order to improve the

quality of human health. By definition, these constructs and

assemblies are nanoscale and include entities such as proteins,

DNA/RNA, viruses, cellular lipid bilayers, cellular receptor

sites and antibody variable regions critical for immunology

and are involved in events of nanoscale proportions. Theemergence of such nanotherapeutics/diagnostics will allow

a deeper understanding of human longevity and human ills

that include cancer, cardiovascular disease, genetic disorders

and trauma. A technology platform that provides a wide

range of synthetic nanostructures that may be controlled

as a function of size, shape and surface chemistry and scale

to these nanobiological dimensions will be a critical first

step in developing appropriate tools and a scientific basis

for understanding nanomedicine. Many of the properties

of these critical parameters are offered by dendrimers and

include the following. (i) Monodisperse, nanoscale sizes

that scale with important bio-building block dimensions

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62 Biochemical Society Transactions (2007) Volume 35, part 1

Figure 1 Dendrimer topology

(a) Illustration of general dendrimer architectural topology with the three architectural components: (i) core, (ii) interior,

and (iii) terminal surface groups (Z). (b) Passive size-mediated targeting: dendrimer-based diagnostic imaging and

therapy delivery nanodevices involving [A] imaging moieties, [B] small-molecule therapy components, and (Z) low-toxicity

terminal surface groups. (c) Active receptor-mediated targeting: dendrimer-based diagnostic imaging and therapy delivery

nanodevices involving [A] imaging moieties, [B] small-molecule therapy components, [C] receptor-mediated targeting

groups, and (Z) low-toxicity surface groups.

(i.e. protein, cellular lipid bilayer, virus and DNA/RNA),

as a function of generation level. (ii) Mathematicallydefined numbers of terminal surface groups (Z) suitable for

bioconjugation of drugs, signalling groups, targeting moieties

or biocompatibility groups that amplify as a function of

generation level according to the equation Z=NbNcG.

(iii) Dendrimer surfaces may be functionally designed to

enhance or resist trans-cellular, epithelial or vascular bioper-

meability. (iv) Well-defined interior void space within the

dendrimer suitable for encapsulation (i.e. interior isolation) of

small-molecule drugs,metals or signalling groups[i.e. MRIor

NIR (near-IR)]. Incarceration in this void space reduces drug

toxicity and allows controlled release. The interior is defined

by the size and nature of the core (i.e. hydrophobic compared

with hydrophilic), as well as surface congestion, whichincreases with generation level. (v) Positive biocompatibility

patterns are associated with lower generation [i.e. G= 15

for PAMAM (polyamidoamine) dendrimers], anionic or

neutral polar terminal surface groups compared with higher

generation neutral apolar and cationic surface groups.

(vi) Non/low-immunogenicity properties for most dendri-

mers functionalized with small-molecule or PEGylated

{PEG [poly(ethylene glycol)]-modified} surface groups.

(vii) The ability to statistically modify and optimize the

number/ratio of dendrimer surface groups that influence

biodistribution, receptor-mediated targeting, therapy dosage

or controlled release of drugs from the dendrimer interior.

(viii) The ability to tune dendrimer mammalian excretion

mode (i.e. urinary compared with bile) as a function ofnanoscale diameter (i.e. generation level).

Critical parameters for designing multi-purpose dendrimer-based diagnosticimaging/therapy nanodevicesBased on the published literature and unpublished work from

our group, it is widely recognized that dendrimers may be

used in twomajormodalities forthe detectionand therapeutic

treatment of cancer and other diseases, namely by (i) passive

targeting nanodimension mediated via EPR (enhanced

permeability retention) effect [11] involving primary tumour

vascularization or organ-specific targeting [12], and (ii) activetargeting receptor-mediated cell-specific targeting involving

receptor-specific targeting groups. The combinatorial design

of these nanodevices may be visualized utilizing the four

construction parameters, A, B, C and Z, as described in

Figure 1. The scope, use and performance of these parameters

will be selectively reviewed in the remainder of this account.

Dendrimers as nanoscale scaffoldingDendrimer surfaces provide an excellent platform for

the attachment and presentation of cell-specific targeting

groups, solubility modifiers, stealth moieties that reduce



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immunological interactions and imaging tags. The ability to

attach any or all of these molecules in a well-defined and

controllable manner on to a robust dendritic surface clearly

differentiates dendrimers from other vectors such as micelles,

liposomes, emulsion droplets or engineered particles. The use

of dendrimers as targeting vectors for diagnostic imaging,

drug delivery and gene transfection had been proposed in the

patent literature nearly a decade ago [13]. These applications

evolved from early observations by Tomalia et al. [14]. It

was noted that bioactive agents could be encapsulated into

the interior of the dendrimers [15], physically adsorbed or

chemically attached [16] on to the dendrimer surface, with

an option to tailor the properties of the vector to the specific

needs of the active material and its therapeutic applications.

Furthermore, the mathematically defined number density of

surface groups allows rational attachment of desired ratios of

drugs, targeting groups or functionality that may be required

to obtain optimum solution, stealth, targeting or release

properties with minimal dendrimer toxicity. Concurrently it

was observed that appropriate surface-modified dendrimersthemselves may act as nanodrugs against viruses, bacteria

or tumours. Based on their now recognized multivalency

properties, a dendrimer-derived microbicide (i.e. VivaGelR

,

Starpharma) for HIV or genital herpes is in its final stage

of approval by the U.S. FDA (Food and Drug Admini-

stration) (http://www.biotech-intelligence.com/html/html/

070156594d92398317df5fd4e6324ccf.html).

Historically, the first in vivo diagnostic imaging applic-

ations using dendrimer-based MRI contrast agents were

demonstrated in the early 1990s by Lauterbur and colleagues

[18]. In contrast with the commercial small-molecule agent

(Magnevist

R

, Schering, AG), the dendrimer-based reagentsexhibited blood pool properties and extraordinary relaxivity

values when chelated gadolinium groups (Magnevist R

) were

attached to PAMAM dendrimer surfaces. These generation-

dependent, dramatic enhancements of MRI contrast prop-

erties were some of the first examples of a dendritic

effect. These architecturally driven properties were unique

to dendrimers as a member of the fourth major polymer ar-

chitecture class(i.e. dendritic), after (i) linear, (ii) cross-linked,

and (iii) branched types [19], and have notbeen observed with

any of the other three traditional polymer architecture types.

Subsequently, the work by Kobayashi and Brechbiel [12]

extended this concept by demonstrating the efficacy of size-

mediated targeting, using the discrete dendrimer generationsizes for in vivo imaging of primary tumours via the EPR

effect designing organ-specific diagnostic imaging modalit-

ies and defining size-dependent mammalian excretion routes

(i.e. urinary compared with bile pathways). Each of these

passive targeting modalities was based on appropriate use

of dendrimer scaffolding dimensions for presenting the MRI

imaging moieties and is illustrated in Figure 2.

One of the most effective cell-specific targeting agents

presented by dendrimer scaffolding is folic acid. Membrane-

associated high-affinity folate receptors are folate-binding

proteins that are overexpressed on the surface of a variety

of cancer cells (e.g. ovarian). They have been found to

preferentially internalize dendrimers modified with folic acid

into receptor-bearing cells via receptor-mediated endocytosis

over normal cells. The first in vivo cell-specific active

targeting work with dendrimers was reported by Wiener

et al. [20] against breast cancer. Functionalizing dendritic

imaging agents with folic acid allowed them to be specifically

directed to overexpressed folic acid receptor sites found in

these cancer types. Folatedendrimer conjugates have been

shown to be well suited for targeted cancer-specific drug

delivery of cytotoxic substances [2123]. In a very recent

study, branched poly(L-glutamic acid) chains were organized

around PAMAM and poly(ethyleneimine) dendrimer cores

to create new biodegradable polymers with improved

biodistribution and targeting ability [24]. These constructs

were surface terminated with PEG chains to enhance their

biocompatibility, and folic acid to introduce cell-specific

targeting against the epidermal KB carcinoma cell line [24].

Carbohydrates constitute another important class of bio-

logical recognition moieties, displaying a wide variety of

spatial structures because of their branching possibilities andanomericity. To achieve sufficiently high binding affinities

between simple monosaccharide/oligosaccharide ligands and

cell membrane receptors, these ligands have to be presented

to the receptors in a multivalent or cluster fashion [25,26].

The highly functionalized surface of dendrimers provides

an excellent platform for such presentations. The design,

synthesis and biomedical use of glycodendrimers, as well as

their application in diagnostics andfor vaccinationshave been

reviewed thoroughly [2729].

As early as 1990, Tomalia, Roberts and colleagues demon-

strated conjugations of antibodies to PAMAM dendrimers

[16]. More recently, antibodies specific to CD14 and PSMA(prostate-specific membrane antigen) were conjugated to a

G= 5 PAMAM dendrimer bearing a fluorescein imaging tag.

Cell binding and internalization of the antibody-conjugated

dendrimersto antigen-expressing cellswere evaluated by flow

cytometry and confocal microscopy. It was found that the

conjugates bound specifically to the antigen-expressing cells

in a time- and dose-dependent fashion with an affinity similar

to that of the free antibody. Confocal microscopy indicated

that cellular internalization of the dendrimer conjugate did

occur [30].

Recently, it has been demonstrated that PAMAM dendri-

mers modified with VEGF (vascular endothelial growth

factor) could be targeted to overexpressed tumour neovas-culatures in breast carcinoma [31].

Dendrimers as nanoscale containersTomalia and colleagues first demonstrated that certain

carboxylated PAMAM dendrimers possess topologies and

dimensional features reminiscent of regular classical micelles

[14,15]. Subsequent studies clearly described the ability to hy-

drophobically modify PAMAM dendrimers (i.e. with hydro-

phobic groups) to mimic inverse micelles and demonstrated

the unlimited guest-host properties [8,32] that were possible

for these two types of so-called covalently fixed dendritic



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Figure 2 Dendrimer scaffolding dimensions (a) for presenting MRI imaging (b)

(a) Scaled spheroids illustrating the relative sizes (nm) for G= 18 PAMAM dendrimer series, wherein the (core:

1,2-diaminoethane; G= 18); [dendri-PAMAM(NH2)NcNbG] generational series is categorized into the observed periodic

properties of (i) flexible scaffolding (G= 13), (ii) nanocontainer properties (G= 46), and (iii) rigid surface scaffolding

(G= 7 and greater), due to enhanced surface congestion as a function of generation. Note, reversible entry and departure

of most guest molecules is possible for G= 46; however, the surface is too congested for entry into G= 7 and

greater. (b) MRI images of mice using MagnevistR

-modified PAMAM dendrimers, i.e. (core:1,2-diaminoethane; G= 18);

[dendri-PAMAM(NH2)NcNb G]; wherein, MagnevistR and G= 34 are excreted completely through the kidney, G= 5 is

excreted through both kidney and liver, and G= 69 are excreted exclusively through the liver. Note: G= 39 are excellent

blood pool agents relative to MagnevistR

(i.e. diethylenetriaminepenta-acetic acid) and G= 9 is very organ-specific for the

liver, presumably due to its large nanosize [12].

micelles. Theseresultingnanoscale container propertieswerereferred to as unimolecular encapsulations [33], and have

been utilized to encapsulate a wide variety of bioactive drugs,

vitamins, metal salts and diagnostic imaging moieties. Par-

ticular interest has been focused on tailoring encapsulation,

release and biopermeabilty features to utilize the passive and

active targeting properties of dendrimers for either (i) size-

mediated targeting (EPR effect), or (ii) receptor-mediated

targeting to desired disease sites (organs) or cells. Many of

these issues have been reviewed recently [6,9,10,34].

Cisplatin is effective in treating major cancers such as

ovarian, head, neck and lung cancers, as well as melanomas,

lymphomas, osteosarcomas, bladder, cervical, bronchogenic

and oropharyngeal carcinomas. Unfortunately, cisplatinhas many adverse side effects, the most important being

nephrotoxicity and cytotoxicity to non-cancerous tissue, due

to the non-selective interaction between cisplatin and DNA

[35]. Furthermore, thetherapeutic effect of cisplatin is limited

by its poor water solubility (1 mg/ml), low lipophilicity

and the development of resistance to cisplatin drugs.

Encapsulation of cisplatin within PAMAM dendrimers gives

complexes that exhibit lower toxicity, higher accumulation

in solid tumours and slower release compared with free

cisplatin[3639]. Furthermore, preliminary evidence suggests

that dendrimer complexes are able to bypass the P-gp (P-

glycoprotein) efflux transporter [40] which may contribute



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Figure 3 Generalized patterns for in vitro toxicity, in vivo toxicity, biopermeability and immunogenic properties as a function of

dendrimer surface functionality

Note: anionic and non-charged polar surfaces in this series exhibit the most biocompatible least toxic functionality,

wherein () indicates less of a specific property, whereas non-charged apolar and cationic surfaces exhibit higher

toxicity/immunogenic properties designated by (+). From [10]. Reproduced by permission of The Royal Society of Chemistry.

to drug resistance. Cisplatin is an anti-tumour drug that

exerts its effects by forming stable DNAcisplatin complexes

through intrastrand cross-links, resulting in an alteration of

the DNA structure that prevents replication and initiates

apoptosis. Largely pioneered by Duncan and colleagues

[3639], the tumour activity of the cisplatindendrimer

complexes was studied using B16F10 cells. These cells were

injected into C57 mice subcutaneously to provide a solid

tumour model. Compared with cisplatin alone, the cisplatindendrimer complex was found to accumulate preferentially

in the tumour site relatively quickly after the injection. This

presumably occurs due to the EPR effect. The tumour AUC

(area under the curve) for the complex was 5-fold higher than

that of free cisplatin, while that in the kidney only increased

2.4 times, and accumulation in the liver was reduced [3639].

Another recent study revealed a remarkable stability

of cisplatindendrimer complexes, with a 20% release of

cisplatin over the first 8 h, and an additional 60% release

within 150 h (G. Krippner and S. Svenson, unpublished

work). In vivo animal efficacy of the platinate was demon-

strated using B16F10 tumour cells that were implanted

subcutaneously into mice. The tumour was allowed to growfor 7 days before treatment with two doses of drug, on day 7

and day 14, providing equal capsulation (5 mg/kg) doses in

both the dendrimer capsulation complex and free cisplatin. A

tumour mass reduction of40% compared with that for the

free drug was found in this study.

The anticancer drugs adriamycin and methotrexate were

encapsulated into PAMAM dendrimers (i.e. G= 3 and 4)

which had been modified with PEG monomethyl ether

chains (i.e. 550 and 2000 Da respectively) attached to their

surfaces. The encapsulation efficiency was dependent on the

PEG chain length and the generation (size) of the dendrimer,

with the highest encapsulation efficiencies (on average, 6.5

adriamycin molecules and 26 methotrexate molecules per

dendrimer) found for the G= 4 PAMAM terminated with

PEG2000 chains. The drug release from this dendrimer was

sustained at low ionic strength, again reflecting PEG chain

length and dendrimer size, but fast in the isotonic solution

[42]. In a related study, it was reported that the surface cover-

age of PAMAM dendrimers with PEG2000 chains had little

influence on the encapsulation efficiency of methotrexate, but

affected the release rate [43]. A similar construct involvingPEG chains and PAMAM dendrimers was used to deliver

the anticancer drug 5-fluorouracil. Encapsulation of 5-

fluorouracil into G= 4 PAMAM dendrimers modified with

carboxymethyl PEG5000 surface chains revealed reasonable

drug loading, a reduced release rate and reduced haemolytic

toxicity compared with the non-PEGylated dendrimer

[44].

Routes of applicationDendrimeric vectors are most commonly used as parenteral

injections, either directly into the tumour tissue or intra-

venously for systemic delivery. However, oral drug deliverystudies using the human colon adenocarcinoma cell line,

Caco-2, have indicated that low-generation PAMAM

dendrimers cross cell membranes, presumably through a

combination of two processes, i.e. paracellular transport and

adsorptive endocytosis [45]. Remarkably, the P-gp efflux

transporter does not appear to affect dendrimers, therefore

drugdendrimer complexes are able to bypass the efflux

transporter [40].

Biocompatibility of dendrimersThe most important features required for the widespread

use of dendrimers in nanomedicine are that they exhibit



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low toxicity, acceptable excretionary pathways and are non-

immunogenic. To date, the cytotoxicity of dendrimers has

been studied primarily in vitro, although a few in vivo

mammalian studies have been performed on mice or rats [46].

However, advanced human clinicals are currently in progress

involving topical uses of an anionic surface functionalized

polylysine dendrimer (i.e.VivaGelR

) which is used for the

prevention of HIV and genital herpes [47,48]. In general,

the dendrimer surface functionality in combination with the

generation level (size) are the two most significant para-

meters affecting toxicity either in vitro or in vivo. The most

comprehensive reviewof these issuesmay be found in a recent

paper by Boas, Christensen and Heegaard [10], wherein, they

have attempted to categorize in vitro and in vivo toxicities

of dendrimers according to four general types of dendrimer

surface groups as shown in Figure 3.

ConclusionsThe extraordinarily high level of synthetic control over the

size, shape, surface functionality and interior void space

makes these nanostructures ideal vectors for both passive and

activedrugdelivery/diagnosticimagingapplications.Thebio-

active agents may be encapsulated into the interior of the

dendrimers, physically adsorbed or chemically attached on to

the dendrimer surface, with the option to tailor the properties

of the vector to the specific needs of the active material and

its therapeutic applications. Furthermore, the ability to select

nanoscale-sized vectors with mathematically determined

numbers of surface groups and well-defined interior void

space allows systematic size adjustments to determine excre-

tionary pathways while producing optimal ratios of target-ing moieties, therapy and surface groups required in

combination with desired solution behaviour, excretionary

pathway and acceptable toxicity margins. Finally, certain

anionic surface-modified dendrimers are proving to function

as safe andeffective topicalnanodrugs against HIVand genital

herpes. These dendrimer-based nanopharmaceutics are in the

final stages of human clinical testing in the U.S. FDA ap-

proval process ([47,48], and http://www.biotech-intelligence.

com/html/html/070156594d92398317df5fd4e6324ccf.html).

This brief review of dendrimer-based nanomedical applic-

ations clearly illustrates the potential of this new fourth

architectural class of polymers [19,49] and substantiates ahigh optimism for the future role of dendrimers in the

emerging field of nanomedicine [50].

We thank all contributors to this fascinating field of nanomedical

research, as well as the funding agencies that have supported this

work over the years. This includes the NCI (National Cancer Institute),

NIH (National Institutes of Health) and DARPA (Defense Advanced

Research Projects Agency). In particular, D.N.T. also acknowledges

funding by the U.S. ARL (Army Research Laboratory) (Contract #

W911NF-04-2-0030). We express sincere appreciation to Ms L.S.

Nixon for manuscript preparation.

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Received 22 August 2006


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