Recent Advances in Dendrimer Research for Cardiovascular

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Recent advances in dendrimer research for cardiovascular diseases Maomao Yu, Xu Jie, Lu Xu, Cong Chen, Wanli Shen, Yini Cao, Guan Lian, and Rong QI Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.5b00979 • Publication Date (Web): 27 Aug 2015 Downloaded from http://pubs.acs.org on September 1, 2015

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Biomacromolecules

Recent advances in dendrimer research for cardiovascular diseases

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Maomao Yu †

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Xu Jie ‡

Lu Xu †

Cong Chen †

Guan Lian ‡

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Wanli Shen ‡

Yini Cao †

Rong Qi †‡*

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†

Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China

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‡

School of Pharmacy, Shihezi University, Shihezi 832000, China

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* Corresponding author

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Mailing address: Rong Qi, 38 Xueyuan Road, Peking University Institute of Cardiovascular

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Science, Peking University Health Science Center, Beijing 100191, China.

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Tel: (+) 8610-8280-5164

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E-mail: [email protected]

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ACS Paragon Plus Environment

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Abstract:

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Dendrimers, as a type of artificially synthesized polymers, have been increasingly

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attracting attention in many research fields, including the material and medical sciences,

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due to their unique characteristics that include their highly branched and well-defined

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molecular architecture, multivalency and tunable chemical compositions. These advantages

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make dendrimers potential carriers for the delivery of therapeutic and diagnostic agents.

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Herein, we review the recent advances in dendrimer research for the prevention and

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treatment of cardiovascular diseases, with special focus on their applications as carriers for

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drug and gene delivery, as contrast agents and as potential new drugs.

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Keywords: dendrimers; cardiovascular diseases; gene and drug delivery; contrast agents;

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potential drugs

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Introduction

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Dendrimers are a class of spherical polymers with multiple branches and topological

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features. Their unique properties are attracting increasing interest among scientists in many

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relevant fields1, 2. The term dendrimer comes from the Greek word dendron (meaning trees)

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and was chosen to name the polymers due to their structural shape. A typical dendrimer is

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composed of three different parts, which confer many fascinating advantages:3 a focal core

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of either a single atom or an atomic group, building blocks composed of repeating units

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emanating from the core like branches, and multiple peripheral functional groups (Fig. 1).

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In contrast to other linear, cross-linked and branched polymers, dendrimers exhibit many

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attractive characteristics determined by their controllable preparation, such as a

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multi-branched three dimensional structure with a defined molecular weight, a much lower

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polydispersity and a higher functionality, which distinguish dendrimers from other

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polymers and give them many promising applications in various fields, including material

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science and medical science. For example, the repeating units of dendrimers provide a

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flexible space created within the voids of dendritic building blocks that can encapsulate

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various small guest molecules such as drugs4. A large number of peripheral functional

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groups of dendrimers can interact with the external environment, thereby defining their

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macroscopic properties5. The step-by-step synthesis of dendrimers allows them

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site-selective modification and functionalization of the terminal groups. Specifically,

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targeted molecules could be covalently or non-covalently conjugated to dendrimers to form

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targeted delivery systems.

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Figure 1. Structure of dendrimers. 3


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As promising non-viral gene delivery carriers, dendrimers have many apparent

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advantages, such as their high solubility, enhanced stability, non-immunogenicity, and

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mediating and enhancing the delivery of diverse nucleic acids including DNAs and RNAs,

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over other viral vectors (e.g., retroviral and adenoviral vectors) and non-viral carriers (e.g.,

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plasmids and liposomes)6. In 1993, Haensler and Szoka first reported poly(amidoamine)

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(PAMAM) dendrimer-based gene transfection7. Today gene transfer reagents such as

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PolyFect and SuperFect, which are based on activated dendrimers and optimized for DNA

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transfection, are already commercially available.

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Dendrimers are also used to deliver drugs either by encapsulating drugs in their interior

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void spaces or by conjugating drugs to their surface functional groups. By constructing

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dendrimer-based

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bioavailabilities of the drugs can potentially be improved, and their side effects could be

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ameliorated to some extent. Compared to liposomes, an another widely used carrier,

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dendrimers have higher drug delivery efficiencies and lower drug leakage percentages6,

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which make them effective in the trans-dermal, oral and ocular delivery of drugs with

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improved pharmacokinetic profiles of the loaded drugs8,9. As for oral delivery, researchers

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concluded that PAMAM dendrimer could efficiently help the loaded drugs traverse

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epithelial monolayers via both paracellular and transcellular pathways10.

drug

delivery

systems,

the

solubilities,

oral absorptions and

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In addition to gene and drug delivery, the unique structural properties of dendrimers

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allow them to be used as templates or stabilizers to synthesize dendrimer-entrapped

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contrast agents in CT or MR imaging applications for disease diagnosis11. Contrast agents

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modified by dendrimers have extended imaging times, increased biocompatibilities and

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improved imaging specificities. In addition, to our surprise, dendrimers themselves are

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found to be bioactive and can be used as potential drugs in diverse medical fields.

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In recent years, the conjugation of dendrimers with multiple copies of targeting ligands

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such as antibodies and active moieties including drugs and dyes has provided a popular

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method for exploiting novel materials useful for both the diagnosis and treatment of

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disease12-14. Dendrimer conjugates supply the possibility to vary the active size and

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functionality on the scaffold and therefore tune the solubility, toxicity, and biodistribution15,

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which gives dendrimers many advantages including an enhanced targeting ability, 4


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increased and varied bioactivity, the ability to report the location of action, and optimal

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impact at the target when applied as scaffolds in drug and gene delivery as well as contrast

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agent design. However, most of the conjugation designs for dendrimers would encounter

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the following inherent challenge common to theranostics as well as dendrimers: the

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heterogeneity introduced by the attachment of functional ligands to dendrimer scaffolds16,

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which means that it is difficult to control the ligand/nanoparticle ratio. The heterogeneity

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may decrease the specificity and targeting ability, cause uncertain therapeutic effects and

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influence the biodistribution, thus hindering the application of dendrimer conjugates in the

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diagnosis and treatment of diseases17, 18. The major approaches to overcome problems with

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heterogeneity in multivalent conjugates include high density conjugates, the exhaustive

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conversion of small numbers of terminal reaction sites, high ligand densities and so on,

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which could be used to minimize the production of complex mixtures and a wide array of

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products during the synthesis of dendrimer conjugates16.

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Cardiovascular diseases (CVDs) are the leading cause of death worldwide, particularly

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in ageing populations, and their incidence is still on the rise. As multi-functional polymers,

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dendrimers have been popularly studied for their potential to be utilized for the diagnosis,

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prevention and treatment of CVDs. The objective of this paper is to review the recent

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advances of dendrimer research in cardiovascular diseases, with a special focus placed on

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dendrimers and their conjugates used as drug and gene delivery carriers, contrast agents

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and potential drugs.

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Recent advances of dendrimers in gene delivery

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In terms of etiology, the current paradigm is that CVDs are associated with the

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dysfunction of certain mutable genes. Silencing “bad” genes using RNA interference

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technology and upregulating “good” genes are effective tools to correct or compensate for

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functions of the mutable genes, and these two methods are generally called gene therapy19.

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Increasing efforts have been put into exploring new and effective strategies of gene therapy

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for CVDs. Dendrimers, as popular gene carriers, are promising agents for application in the

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gene therapy of CVDs. Specifically, dendrimers having primary amine end groups can

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interact with and compact DNA plasmids or siRNA by electrostatic interactions, thus

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forming nano-composites favoring the cell uptake process and releasing DNA or siRNA 5


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into the cells to complete the following transcription and translation 20.

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Myocardial infarction (MI) is a class of CVDs that accounts for 1 in every 6 deaths in

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the US alone with a total of approximately 1.5 million deaths annually21, 22. Those who

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survive the initial insult and are characterized by the regional loss of myocardium and

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function, and they have a high probability of developing heart failure in subsequent years.

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Vascular endothelial growth factor (VEGF) is a crucial factor to promote angiogenesis and

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increase the blood supply in an ischemic heart. Upregulation of VEGF expression in a local

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ischemic area of the heart through angiogenic gene therapy may be an effective way to

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improve heart function and reduce left ventricular dilation following acute myocardial

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ischemia and infarction.23 However, exorbitant expression of VEGF may lead to severe

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side effects including the development of vascular tumors, which may also cause heart

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failure24, thus limiting the efficacy and safety of gene therapy in the myocardium.

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Therefore, the key factor for success in clinical angiogenic gene therapy is to establish a

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safe and highly effective delivery system to target the VEGF gene, which requires

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hypoxia-regulated VEGF expression, the protection of VEGF from degradation, the

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limitation of rapid renal clearance and the improvement of intracellular delivery with

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minimal side-effects.

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Dendrimers as gene delivery carriers have already been studied in the treatment of MI.

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Won et al. developed a new post-translationally regulated hypoxia-responsible VEGF

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plasmid, PAM-ABP/VEGF (ABP = arginine-grafted bio-reducible poly (disulfide amine)),

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in which PAM-ABP was a dendrimer-type bio-reducible polymer used as a VEGF carrier.

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PAM-ABP, which demonstrated superior condensing ability for plasmid VEGF through the

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formation of compacted and nanosized polyplexes, could enhance cellular uptake and be

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less susceptible to reducing agents. Therefore, it resulted in a greater transfection efficiency

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compared to ABP alone

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new dendrimeric VEGF plasmid protected rat cardiomyocytes against apoptosis, preserved

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their left ventricular (LV) function and prevented LV from remodeling more effectively27.

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. Compared to a hypoxia-inducible RTP-VEGF plasmid26, this

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Hyperbranched-PAMAM (h-PAMAM) dendrimer, an analog of PAMAM dendrimer in

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structure, shows an excellent DNA protection ability, low cytotoxicity and high gene

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transfection efficiency28. Zhu et al. adopted h-PAMAM dendrimer as a carrier to deliver 6


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hypoxia-regulated human VEGF-165 plasmids into skeletal myoblasts (SkMs) to

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controllably express the VEGF gene. Then, these gene-manipulated SkMs were

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transplanted into infarct myocardium for cardiac repair in a MI model29. The

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H-PAMAM-based VEGF gene delivery system exhibited a high transfection efficiency and

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minor cytotoxicity in primary SkMs. The transfected SkMs could constantly express the

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VEGF gene for 18 days under in vitro hypoxia conditions. As for in vivo circumstances, the

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intramyocardial transplantation of transfected SkMs significantly reduced the number of

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apoptotic myocardiocytes, improved the survival of grafted cells, decreased the infarct size

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and interstitial fibrosis, and increased the blood vessel density, which inhibited left

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ventricle remodeling and improved heart function during the late phase following

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infarction.

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To overexpress VEGF in a manner similar to the manipulation mentioned in SkMs29,

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Paul et al. developed a new gene delivery system consisting of human adipose tissue

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derived stem cells (h-ASCs) that were genetically modified with the self-assembled

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nanocomplex of recombinant baculovirus and PAMAM dendrimer (Bac-PAMAM)30. In

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vitro results confirmed that this system could efficiently transduce h-ASCs and express

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functionally active VEGF. In vivo results on chronically infarcted rat hearts confirmed

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higher myocardial VEGF gene expression with significantly enhanced neovasculature after

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treating rats with h-ASCs-VEGF. In addition, the ejection fraction in the hearts of

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h-ASCs-VEGF-treated rats also significantly improved. The reason why baculoviruses and

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PAMAM dendrimer were used together as a VEGF delivery system may be that adeno- and

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retro-viral vectors could work in coordination with polymers through a non-covalent

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complexation as superior gene delivery vectors31,

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interactions between the viral surface and mammalian cell membranes enhance the cellular

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entry of the polyplexes33. On the other hand, the PAMAM dendrimer itself functions as a

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highly efficient cationic carrier for gene delivery.

27

32

. On the one hand, electrostatic

CVDs are controlled and influenced by numerous factors in the “cardiovascular

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continuum”34,

35

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renin-angiotensin-aldosterone system (RAAS), involved in the pathogenesis of CVDs. RAAS

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activation following a cardiovascular ischemic injury is supposed to promote blood pressure

. Apart from VEGF, there is another important hormone system, the

7


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recovery, but its continuous stimulation can cause vasoconstriction, vascular and cardiac

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hypotrophy, and fibrosis36. Angiotensin II (Ang II), an end product of RAAS, regulates most

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of the effects of RAAS. Overexpression of Ang II can cause adverse cardiac remodeling,

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progressive ventricular dysfunction and finally heart failure37. Therefore, the inhibition of

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Ang II activation may be feasible for the prevention and treatment of CVDs. Ang II type 1

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receptor (AT1R), a major receptor that mediates most adverse effects of Ang II38, could be a

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potential silencing target to attenuate the worse cardiac function after heart injury. Liu et al.

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employed PAMAM dendrimer as a carrier for AT1R siRNA to silence AT1R expression in a

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rat ischemia-reperfusion (I/R) model19. In this study, they developed a non-cytotoxic and

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efficient “tadpole” siRNA delivery system composed of a cationic generation 4 (G4)

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PAMAM dendrimer penetrating peptide (CPP) and oligo arginine (R9) cross-linked by

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polyethylene glycol (PEG). The remarkableness of this delivery system was that PAMAM

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moieties regulated siRNA complexation and endosome escape, CPP improved cell

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internalization, and PEG segments with disulfide linkages in the three parts enhanced the

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biocompatibility of the system. Loading AT1R siRNA in this dendrimer-based delivery

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system had better downregulation effects on AT1R expression in vitro in cardiomyocytes

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than ATIR siRNA alone. Moreover, in vivo siRNA delivery by this system prevented an

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increase in AT1R expression and recovered cardiac function after I/R injury more

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significantly than groups treated with saline or dendrimers alone.

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Figure 2. Schematic diagram of gene therapy of MI delivered by dendrimer-based delivery 8


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system.

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The adhesion molecules P- and E-selectin express on activated endothelial cells, and they

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can be the targets of gene therapy for inflammatory diseases such as the majority of types of

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CVDs. Theoharis et al. investigated the potential targeting of a PAMAM dendrimer-based

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P/E-selectin expression system using a monoclonal antibody to recognize the targeted

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molecules39. Specifically, they used biotin and avidin to cross-link anti-E/P-selectin

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monoclonal antibodies to pre-form Superfect (PAMAM dendrimer)-DNA complexes, which

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were then used to transfect reporter genes into CHO cells, cytokine-activated primary human

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saphenous vein endothelial cells (HSVEC) and whole vein segments to express E/P-selectin.

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The results showed that this dendrimer-based targeting system increased the transfection

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efficiency of the reporter genes. Hopefully, this gene therapy technique not only shows great

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potential in the treatment of CVDs but can also target other diseased cells or tissues by using

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different antibodies.

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Although dendrimers have great advantages as non-viral gene delivery carriers as

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mentioned above, cationic dendrimers are associated with cytotoxicity, hemolysis and liver

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toxicity40,

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characteristics as gene delivery carriers, we conjugated PEG (molecular weight = 5,000) to

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G5 and G6 PAMAM dendrimers42. Compared with the unconjugated dendrimers, PEG

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conjugation significantly decreased the in vitro and in vivo cytotoxicities as well as the

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hemolysis of G5 and G6 dendrimers, especially at higher PEG molar ratios. Among all of the

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PEGylated PAMAM dendrimers, 8% PEG-conjugated G5 and G6 dendrimers resulted in the

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most efficient muscular gene expression in neonatal mice as well as in 293A cells. In addition,

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these PEG-conjugated G5 and G6 PAMAM dendrimers could protect siRNA from being

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digested by RNase and exhibited high transfection efficiencies of FITC-labeled siRNA in the

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primary vascular smooth muscle cells (VSMC) and mouse peritoneal macrophages. In vivo

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results showed that the intramuscular delivery of GFP-siRNA using PEG-conjugated

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dendrimers significantly suppressed GFP expression in both transiently adenovirus infected

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C57BL/6 mice and GFP transgenic mice43.

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, which limits their applications in vitro and in vivo. To improve their

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The exact mechanism of the internalization of dendrimer-gene polyplexes into cells still

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remains unclear and controversial. Most of the studies on dendrimer-gene polyplexes have 9


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reported that the internalization process is possibly mediated by several endocytosis

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pathways, including macropinocytosis, phagocytosis, clathrin-mediated endocytosis

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(CME)44 and caveolin-mediated endocytosis (CvME45. The ultimate fate of dendrimer-gene

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polyplexes is resolved by lysosomes, and then, DNA escapes from the complex and enters

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the nucleus to complete the following process of transcription and translation (Figure 3).

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However, recent studies have strongly suggested alternative pathways for similar polymer

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systems. Fichter et al. investigated the intracellular trafficking of linear polyethyleneimine

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(PEI) and Glycofect polyplexes through sorting organelles such as the Golgi and

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endoplasmic reticulum (ER) in H9c2(2-1) cells, and they showed that both PEI and

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Glycofect could promote an alternative active transport pathway involving inter-organelle

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transport via the Golgi and ER. Specifically, polyplexes tended to be sorted into the Golgi

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and likely underwent retrograde transport to the ER via coat protein complex I (COPI)

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vesicles while bypassing lysosomes in a manner similar to that of viruses after

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internalization initiated by the clathrin- and caveolae-mediated pathways shown in Fig. 346,

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which was also confirmed by other studies47. It has been reported in several studies that

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endosomes can fuse with acidic lysosomes where the cargo could be degraded48-50. Rehman

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et al. have investigated the interactions of polyplexes with HeLa cells by live cell imaging

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to clarify the internalization mechanism of polyplexes. The results presented direct

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evidence in support of the proton sponge effect, which directly mediated nucleic acid

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delivery by highly buffering polyplexes including dendrimer-gene polyplexes

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Grandinetti et al. examined the mechanism of the entry of polyplexes into the nucleus, and

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they found that polycations such as PEI may cause permeabilization of the nuclear

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membrane, thus allowing physical penetration and the entry of nanomedicine into the

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nucleus. However, this effect is certainly reliant on the chemical structure and molecular

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weight of the polymer-based vehicle52.

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51

.

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Figure 3. Internalization pathways of dendrimer-gene complex into cells and the following

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transcription and translation process.

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Our group has been long committed to figuring out the possible mechanisms of the

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internalization of dendrimer/gene polyplexes into cells. We explored the GM1/caveolin-1

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(GM1 = monosialotetrahexosylganglioside) lipid raft mediated endocytosis (GM1/CAV-1

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LRME) mechanism for G5 and G7 PAMAM dendrimer polyplexes employing Cos-7,

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293A, C6, HeLa, KB, and HepG2 cell lines, but we found that there was no evidence for

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GM1/CAV-1 LRME involvement in the internalization of G5 and G7 polyplexes into these

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cell lines45. Recently, we found that downregulation of syndecan-4 and upregulation of

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caveolin-1 significantly improved the internalization of G5 and G7 PEG-PAMAM

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dendrimer polyplexes into HepG2 cells; meanwhile, for C2C12 cells, the uptake of the

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PEG-PAMAM polyplexes was affected by Syn-4 but not CAV-1, and the upregulation of

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Syn-4 would contribute to gene delivery. (Figure 4)53. All of our results supplied guidelines

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on how to use strategies to improve the in vivo gene delivery efficiency of PAMAM

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dendrimers in clinical gene therapy.

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Figure 4. Different effects of syndecan-4 and caveolin-1 on the internalization of

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dendrimer-gene complex into cells. Reprinted from ref 53. Copyright 2014, with permission

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from Elsevier.

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Dendrimers can be combined with other gene delivery systems, such as virus and other

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polymers, to achieve a better transfection efficacy and higher biocompatibility. Moreover,

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dendrimers can be modified with targeted molecules, such as certain antibodies, to deliver

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genes to the targeted diseased tissues. With the development of synthetic chemistry and

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nanotechnology, more and more types of multi-functional and multi-target systems based on

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dendrimers will be applied as gene carriers in the prevention and treatment of CVDs with a

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good targeting ability and minimal side effects.

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Recent advances of dendrimers in drug delivery

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An ideal drug delivery carrier must be biochemically inert and non-toxic as well as

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protect the payload (drug) from dissociation until it reaches the target site. In fact, their

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unique molecular architecture and branched surface groups make dendrimers excellent

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nanoscale carriers for the efficient delivery of drugs and biological molecules, especially

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for solving solubility and absorption problems of drugs54. The original dendrimers

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(PAMAM, PPI, PEI and their derivatives) in later generations are rarely used directly in

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drug delivery systems due to their cytotoxicities55. Dendrimers commonly used in drug

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delivery are mainly modified in the following three ways: PEGylation; targeting groups,

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such as folic acid (FA) receptor; and stimuli-sensitive functional groups, such as those 12


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sensitive to pH stimuli. All of these modifications make dendrimers suitable for use as drug

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carriers, which is reflected in their lower toxicities, reduced immunogenicities, higher

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biocompatibilities and larger drug-loading capacities.

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Dendrimers could carry drugs in non-covalent and covalent manners. The non-covalent

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manner means drugs can be non-covalently encapsulated in the interior void spaces of the

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dendrimers through electrostatic, hydrophobic or hydrogen bonding interactions.

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Meanwhile, the covalent manner refers to the covalent conjugation of drugs to the terminal

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groups of dendrimers (Figure 5). In 1994, Meijer et al. reported that guest molecules such

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as dyes were captured within the internal cavities of the dendritic boxes when these boxes

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were constructed in the presence of guest molecules, which was confirmed by nuclear

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magnetic resonance-relaxation and optical data56. Thereafter, Meijer et al. investigated the

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multiple monovalent conjugation of dendritic host–guest complexes by X-ray

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crystallography and molecular dynamics simulations, and the results showed that the guest

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molecules can bind to the dendrimer in a variety of ways, including hydrogen bonds and

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acid–base interactions57. After internalization into cells, dendrimer-drug complexes would

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be digested by lysosomes, and the drug would be released (Figure 5).

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Figure 5. Different ways dendrimers carry drugs and internalization process of

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dendrimer-drug complex.

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Simvastatin (SMV) is a specific inhibitor of HMG CoA reductase and an effective 13


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cholesterol-lowering drug with few adverse effects and drug interactions58, 59. SMV is

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generally used in the clinical setting to treat hypercholesterolemia and reduce coronary

3

events through mechanisms of antioxidant, anti-inflammatory and anti-proliferative

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effects60. However, SMV is a water insoluble drug and has irregular intestinal absorption,

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which make its oral bioavailability less than 5%54. Therefore, there is the need for a

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delivery system that not only delivers the drug efficiently but also improves the

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pharmacokinetic properties of SMV.

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Kulhari et al. constructed three different PAMAM dendrimer (NH2, OH and PEG)-based

9

SMV nano-complexes for the in vitro enhancement of water solubility and controlled

10

release as well as the in vivo improvement of the oral absorption of SMV54. The

11

pharmacodynamic results showed that the increased percentage of plasma cholesterol was

12

lower with PAMAM dendrimer formulations compared to pure SMV. The reductions in

13

triglyceride and low density lipoprotein levels were also more prominent with the

14

dendrimer-SMV formulations. Moreover, dendrimer-SMV formulations showed better

15

pharmacokinetic performances than a pure SMV suspension, including a higher peak

16

plasma SMV concentration and a longer mean SMV residence time. Furthermore, SMV

17

absorption and elimination rates were significantly reduced, indicating the controlled

18

release of SMV from the dendrimer complexes. Qi et al. found that the formulation

19

composed of SMV and G5-NH2 PAMAM dendrimers could significantly improve the

20

solubility and transepithelial transport of SMV, thereby causing the enhancement of the oral

21

bioavailability. According to the in vitro experiments, an increase in SMV/G5-NH2

22

transport on Caco-2 cells was modulated by the inhibitory effect on P-gp in addition to the

23

intercellular pathway of interrupting occluding-1 and opening the tight junction (TJ)61

24

(Figure 6). Based on these findings, PAMAM dendrimers may be used as potential carriers

25

for SMV delivery to increase its oral bioavailability. Probucol, similar to SMV, has a poor

26

water solubility (only 5 ng/mL in water) and a low oral absorption efficiency

27

(bioavailability only 2-8%)

28

dendrimers63.

62

, which could also be enhanced by being incorporated into

14


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Biomacromolecules

1 2

Figure 6. Effects of G5-NH2 on SMV water solubility (A), pharmacokinetics parameters

3

(B), transport across the Caco-2 cell monolayers (C) and possible molecular mechanism for

4

its transepithelial transport (D). Reproduced from ref 61. Copyright 2015, with permission

5

from Elsevier.

6

Nifedipine, another drug for the treatment of the CVDs, is a calcium channel blocking

7

drug, which is mainly administered to hypertension and angina patients. The major problem

8

associated with the formulation and effectiveness of nifedipine is that this drug has a poor

9

aqueous solubility, 5-6 µg/mL over a pH range of 4-13, which may account for its low and

10

irregular bioavailability in human bodies64,

65

11

generation (G0–G3) of PAMAM dendrimers with both amine and ester termination could

12

significantly increase the aqueous solubility of nifedipine at a pH of 7, and the

13

ester-terminated dendrimers were more efficient than the amine-terminated ones possessing

14

the same number of surface functional groups66. They concluded that this pH- and surface

15

functional group-dependent increase in the solubility of nifedipine caused by the

16

dendrimers was likely due to changes in the degree of protonation of the dendrimers. In

17

conclusion, PAMAM dendrimers could potentially be a solubilizer for nefidipine to

18

intensify its therapeutic effects in the treatment of CVDs.

. Devarakonda et al. found that early

19

In addition to VEGF and Ang II mentioned in the gene delivery section of this article,

20

adenosine could possibly be another potential target to treat MI. Adenosine is released in 15


Biomacromolecules

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1

large amounts during MI and plays a major role in the mediation of preconditioning and

2

other cardioprotective effects in most animal species including humans67-69. There are four

3

subtypes of adenosine receptors (ARs), but only three of them (A1, A2 and A3 ARs) are

4

functionally expressed in cardiomyocytes70. Researchers found that activation of

5

cardiomyocyte A1 and A3 ARs could effectively reduce infarct size and improve

6

contractile dysfunction in various animal models of I/R injury, and A2 AR agonists exhibit

7

cardioprotective functions via anti-inflammatory effects71.

8

PAMAM dendrimers can serve as biocompatible polymeric nanocarriers for bioactive

9

molecules of interest, such as nucleoside derivatives, which activate a certain type of ARs.

10

Through their attachment to dendrimers, the cardioprotective potencies or effectiveness of

11

these nucleoside ligands of ARs could be greatly improved. Keene et al. constructed a new

12

multivalent dendrimeric conjugate of an AR agonist and investigated the cardioprotective

13

effects of activated A3AR on HL-1 cardiomyocytes72. In this study, they synthesized a

14

conjugate of G5.5 PAMAM dendrimer with a N6-chain-functionalized adenosine agonist.

15

They found that this conjugate non-selectively activated the A3AR, inhibited

16

forskolin-stimulated cAMP formation, and protected HL-1 cells from apoptosis induced by

17

H2O2. Moreover, Chanyshev et al. investigated the effects of the three different conjugates

18

of PAMAM dendrimer and A3 AR agonists, named MRS5216, MRS5246 and MRS5539,

19

on cultured rat primary cardiac cells and isolated hearts73. The results showed that all three

20

conjugates protected ischemic rat cardiomyocytes from hypoxia injury and significantly

21

decreased the infarct size in the isolated rat hearts with improving rates of pressure product,

22

contraction and relaxation. Wan et al. also found that MRS5246 was effective in increasing

23

the recovery of function of isolated mouse hearts after 20 min of ischemia followed by 45

24

min of reperfusion, including a statistically significant improvement in the left ventricular

25

developed pressure (LVDP)74.

26

The unique structure of dendrimers gives them many fascinating advantages, which

27

make dendrimers the most promising drug delivery carriers applied in the prevention and

28

treatment of CVDs. By encapsulating drugs in or conjugating them to dendrimers, the

29

solubilities, biocompatibilities, bioavailabilities and pharmacokinetic profiles of the drugs

30

could be greatly improved, and therefore, they would be more effective and safe in clinical 16


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1

applications.

2

Recent advances of dendrimers in contrast agents

3

In the past few decades, imaging technology has been rapidly developed and provides

4

physiological and pathological information with high sensitivity and specificity for the

5

diagnosis of diseases75. The main imaging modalities include optical imaging, computed

6

tomography (CT), magnetic resonance (MR), position emission tomography (PET) and

7

single photon emission computed tomography (SPECT). For better and more specific

8

imaging, several requirements are proposed for contrast agents, which generally include a

9

long half-decay time, a relatively low renal toxicity and a high specificity. With the

10

development of nanotechnology, researchers are trying to apply nanoparticles (NPs) as

11

contrast agents76. These NP systems have many advantages over the conventional contrast

12

agents, such as a prolonged blood circulation time, facile surface functionalization, an

13

extended imaging time, the desired biocompatibility and enhanced imaging specificity77.

14

Dendrimers, as a popular nanomaterial, are broadly involved in the design and

15

exploitation of contrast agents. Specifically, literally atom-by-atom modifications on the

16

cores, interiors and surface groups of dendrimers permit rational manipulation of

17

dendrimer-based agents to optimize the physical characteristics, biodistribution,

18

receptor-mediated targeting and controlled release of payload contrast agents.

19

Modifications with targeted elements enable contrast agents to localize preferentially to

20

areas of interest or organs for target-specific imaging as well as excretion pathways that do

21

not interfere with the desired applications. Their unique structural properties allow

22

dendrimers to be used as templates or stabilizers to synthesize dendrimer-entrapped Au

23

NPs8,

24

Simultaneously, the surface periphery of dendrimers can be modified with Gd (III) chelator

25

to form Gd (III) complexes for the subsequent T1 MR imaging of tumors82. Thus, the

26

applications of dendrimers in contrast agents mainly involve combining dendrimers with

27

other contrast agents such as Cu, Ag and Au. These dendrimer-based contrast agent systems

28

were colloidally stable and non-cytotoxic. They also exhibited an extended blood

29

circulation time as well as a relatively short clearance time from organs. They displayed

30

both r1 relaxivity in the MR imaging mode and X-ray attenuation properties in the CT

78, 79

or dendrimer-stabilized Au or Ag NPs80,

81

for CT imaging applications.

17


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1

imaging mode.

2

To recognize cancer cells overexpressing FA receptors by synchrotron X-ray

3

fluorescence analysis, Zhang et al. prepared metal nanoclusters using a dendrimer modified

4

with folic acid (FA)83. They investigated the imaging properties of this dendrimer–folate–

5

copper conjugate in KB cells, and they found that the metal nanoclusters in the dendrimer

6

exhibited excellent folic acid receptor targeting properties. Moreover, Kojima et al. studied

7

the effect of PEGylation and generation on the relaxivity and pharmacokinetics of

8

dendrimer-based MRI contrast agents84, and they found that surface-PEGylated

9

Gd-PAMAM dendrimers had decreased plasma clearance and prolonged retention in the

10

blood pool. Moreover, later generation of dendrimers conjugated with PEG with a shorter

11

chain length led to a higher relaxivity, which might provide some advice for the choice of

12

dendrimers in the design of contrast agents.

13

Atherosclerosis (AS), a chronic inflammatory vascular disease, is a high-risk factor for

14

myocardial infarction and cerebrovascular events. Apart from drug therapy, researchers

15

increasingly realize the importance of molecular imaging in monitoring the progression of

16

AS, which can facilitate the diagnosis of AS and improve the management of patients85.

17

Macrophage accumulation and the ingestion of lipids into foam cells are substantially

18

important hallmarks in the pathogenesis of AS86. Thus, imaging systems detecting and

19

quantifying macrophage accumulation will provide diagnostic and prognostic information

20

for atherosclerotic plaque.

21

Macrophages piled in an AS lesion always express many biomarkers, such as p32

22

protein87, which could be a potential target for the non-invasive identification of AS

23

progression. Recently, Hamzah et al. demonstrated that LyP-1 was a promising peptide for

24

targeting p32, which is over-expressed on plaque-associated macrophages88, but the

25

inadequacy of this study was that the binding affinity of LyP-1 was relatively low in the

26

aorta. To improve the accumulation efficacy of LyP-1 targeting on AS, Seo et al. designed

27

and synthesized a dendrimer with multiple LyP-1 ligands on a solid phase using lysine as

28

a core structural element89, which was named as (LyP-1)4-dendrimer-64Cu. Then, the

29

(LyP-1)4-dendrimer-64Cu was intravenously injected into ApoE-/- atherosclerotic mice.

30

After two hours of circulation, PET-CT co-registered images demonstrated a greater 18


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1

uptake of the (LyP-1)4-dendrimer-64Cu than the (ARAL)4-dendrimer-64Cu, where ARAL is

2

another type of peptide like LyP-1 except for the ability to bind to p32 in the aortic root

3

and descending aorta. Ex vivo images and biodistribution acquired at three hours after

4

injection also demonstrate a significantly higher uptake of the (LyP-1)4-dendrimer-64Cu in

5

the aorta. Similarly, the subcutaneous injection of LyP-1 dendrimeric carriers resulted in

6

preferential accumulation in plaque-containing regions over 24 h. Taken together, these

7

results suggested that the (LyP-1)4-dendrimer can be applied as a nanocarrier of contrast

8

media for the in vivo PET imaging of plaque and that LyP-1 could be further exploited for

9

the delivery of therapeutics with other multivalent carriers or NPs. Given that

10

macrophages play an important role in development and progression of the major types of

11

CVDs90, we can apply this targeted imaging system to other types of CVDs (Figure 7).

12 13

Figure 7. Dendrimer based targeting contrast agents to recognize the activated

14

macrophages in AS.

15

In brief, dendrimer-based contrast agents are desirable components for molecular

16

imaging contrast media due to their ability to deliver an imaging payload with target

17

specificity. In the future, it would be expected that a greater number of and better imaging

18

agents other than metals could conjugate to dendrimers to obtain better image quality and

19

help diagnose more diseases.

20

Dendrimers as potential drugs

21

Over the past few years, dendrimers have been found to be bioactive and can be used as 19


Biomacromolecules

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Page 20 of 35

1

potential drugs in diverse medical fields. Karolczaka et al. found that G4 PAMAM

2

dendrimers could reduce hyperglycemia and restore impaired blood brain barrier (BBB) in

3

streptozotocin (STZ) diabetic rats91. They demonstrated, for the first time, that G4 PAMAM

4

protected the BBB against diabetes-induced functional disturbances. Although this research

5

focused on diabetes, it might provide useful ideas and methods for the application of

6

PAMAM dendrimers in restoring impaired BBB permeability in strokes, a type of CVD

7

and the third leading cause of death and disability in developed countries92. Labieniec et al.

8

assessed the effects of G4 PAMAM on the heart and liver mitochondria in diabetic rats93.

9

They investigated the liver, myocardium and plasma of diabetic rats treated with G4

10

PAMAM by using statistical scale biochemical parameters including creatinine, CoQ9,

11

CoQ10, albumin, urea, total cholesterol, HbA1 and tocopherol. The results showed that G4

12

PAMAM alleviated long-term markers of hyperglycemia and reduced blood and tissue

13

lipophilic antioxidants in diabetic rats but did not restore heart or liver mitochondrial

14

function. This series of research on diabetes gives us many clues about dendrimers as drug

15

or gene delivery carriers in hyperglycemia and diabetes therapy.

16

Dendrimers have been reported to have anti-inflammatory activities. Tomalia, who

17

reported the synthesis of PAMAM dendrimers for the first time, unexpectedly found

18

unmodified PAMAM dendrimers bearing simple surface functional groups (e.g., -NH2 and

19

-OH) had in vivo anti-inflammatory activities on three different inflammatory disease

20

models, which were the carrageenan-induced paw edema model, cotton pellet granuloma

21

model and adjuvant-induced arthritis model94. Myriam et al. used two different

22

experimental arthritis models, IL-1ra−/− mice and mice that had undergone K/BxN serum

23

transfer, to assess the therapeutic potentials of azabisphosphonate (ABP)–capped

24

dendrimers in the treatment of rheumatoid arthritis (RA)95. The results showed that

25

dendrimer

26

anti-inflammatory activation to attenuate RA severity, reduced the levels of inflammatory

27

cytokines, and protected cartilage and bone from destruction and erosion. Marchand et al.

28

also found that non-symmetrical azadiphosphonate-capped dendrimers with various

29

substituents on their nitrogen atoms (methyl, allyl or butyl) were able to activate human

30

monocytes in the short term96, which agrees well with the studies on dendrimer ABP95.

ABP

selectively

targeted

monocytes

and

20


directed

them

toward

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1

Tang et al. investigated the anti-inflammatory effects of two types of PAMAMs including

2

G4.5-COOH and G5-OH on pancreas injury in a caerulein-induced acute pancreatitis (AP)

3

mouse model. They showed that both dendrimers significantly ameliorated the severity of

4

pancreas injury through downregulating the expression of pro-inflammatory cytokines97.

5

Furthermore, Dai et al. found that the G4 PAMAM dendrimers (with no targeting ligands)

6

had an unusual neuroinflammation targeting ability and could localize in activated

7

microglia and astrocytes (cells responsible for neuroinflammation) in a rabbit cerebral

8

palsy model, which supplied useful strategies for the targeted delivery of therapeutics in

9

disorders such as cerebral palsy and other inflammatory cerebral diseases98. Although the

10

above findings on the anti-inflammatory activity of dendrimers were confirmed in various

11

diseases other than CVDs, they may still be used against CVD inflammatory diseases such

12

as AS.

13

Not only do the dendrimers themselves have attractive biomedical activities, but their

14

derivatives also present some types of bioactivities. Esteban et al.99 synthesized two types

15

of G4 PAMAM dendrimer derivatives, G4-arginine-Tos (Tos = tocopherol succinate) and

16

G4-lysine-Cbz (Cbz = carbamazepine), and evaluated their effects on interactions with

17

serum metabolites, the viability of red blood cells and antithrombotic properties. They

18

found that both of the derivatives acted as potent inhibitors of platelet aggregation induced

19

by adenosine diphosphate (ADP). G4-arginine-Tos also showed inhibition of platelet

20

aggregation induced by collagen, thrombin receptor-activated peptide (TRAP-6) and

21

arachidonic acid. Moreover, G4-arginine-Tos presented the inhibition of platelet secretion

22

and thrombus formation under flow conditions. Therefore, G4-arginine-Tos derivatives

23

could be hopefully used as a potential antithrombotic drugs in the future. In other research,

24

Lee et al.100 reported two antioxidant dendrimers with surfaces rich in multiple phenolic

25

hydroxyl groups and benzylic hydrogens, which contributed to their potent free

26

radical-quenching properties. The biggest advantage of these two derivatives was that they

27

could minimize the pro-oxidant effects, which were the common problem of antioxidants.

28

To their delight, these two dendrimers exhibited potent radical scavenging properties.

29

Moreover, they also protected low-density lipoproteins, lysozymes and DNA from free

30

radical damage. 21


Biomacromolecules

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Page 22 of 35

1

The reason why dendrimers can be potential drugs may be due to their multiple

2

peripheral functional groups, especially at the cationic terminals101. For example,

3

Karolczak et al. thought that the hypoglycemic effect of PAMAM dendrimers in diabetes

4

was due to the modification of their surface free amino groups with excessive glucose

5

moieties91, which resulted in the reduction of the plasma glucose level and then attenuated

6

the impaired BBB permeability. More mechanisms behind the fascinating bioactivities of

7

dendrimers need to be discovered in the future. Of course, the in vivo applications of

8

dendrimers as potential drugs should be safe and biocompatible. Therefore, the

9

pharmacokinetic features and distributions of dendrimers in the human body after a long

10

continuous repetitive application need to be explored in detail102.

11

Table 1. Application lists of dendrimers and their derivatives as potential new drugs

Dendrimers

Bioactive effects

G4 PAMAM

hypoglycemic effect; restore the

streptozotocin(STZ)

multiple peripheral functional groups,

impaired BBB

diabetic rats

especially the cationic terminals of dendrimers

alleviation of long-term diabetic

streptozotocin(STZ)

markers; decrease of blood and

diabetic rats

G4 PAMAM

Animal models

Mechanism

Reference 91

93

—

tissue lipophilic antioxidants G4 PAMAM

anti-inflammatory activity

(-NH2, -OH)

paw edema model, cotton pellet

the nature of the dendrimer surface functional

granuloma model and arthritis

groups; inhibitory effects on the nitric oxide

model

production

94

(ABP)–capped

anti-inflammatory activity;

arthritis models: IL-1ra−/− mice

selectively target to monocytes and direct them

dendrimer

anti-osteoclastic activity

and mice undergone K/BxN

toward anti-inflammatory activation;

serum transfer

increase amounts of anti-inflammatory

95

cytokines G4 PAMAM

neuroinflammation targeting in

a rabbit cerebral palsy model

activated microglia and astrocytes

Dendrimers are taken up by the activated microglial

G4.5-COOH

protective effects against acute

caerulein-induced

and G5-OH

pancreatitis

model

AP

mouse

and

the

98

pro-inflammatory

97

astrocytes

in

periventricular regions decrease

PAMAM

cells

cytokines;

expression

of

inhibition

of

the

nuclear

translocation of NF-κB in macrophages G4-Arginine-To

potent inhibitors of platelet

platelet aggregation induced by

s

aggregation; inhibition of platelet

ADP, collagen, TRAP-6 and

secretion and thrombus formation

arachidonic acid

potent inhibitors of platelet

platelet aggregation induced by

aggregation

ADP

G4-Lysine-Cbz

surface-modifie

potent free radical-quenching

d dendrimers

property; minimize the

—

pro-oxidant effects 22


—

99

—

99

—

100

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Biomacromolecules

1 2

Conclusions and Future Perspectives

3

In the past few decades, dendrimers have played important roles as gene and drug

4

delivery carriers applied in the treatment of CVDs, especially in MI. Dendrimers can also

5

be used in diagnostic imaging by conjugating with other imaging agents, which is

6

meaningful for the early detection and prevention of CVDs. In addition to the traditional

7

use of dendrimers as scaffolds for drugs and genes, their own bioactivities are attracting

8

increasing attention in diverse fields, including in the treatment of CVDs. Dendrimers show

9

great potential in the application of CVD prevention and treatment as well as in other

10

realms of human diseases in the future.

11

The application of dendrimers in clinical treatment still faces great challenges. The key

12

problem is that the long-term pharmacokinetics and biodistribution of dendrimers in human

13

bodies are not very clear; thus the safety, biocompatibility and biodegradation of

14

dendrimers in human bodies still remain to be explored for their bioapplication. Moreover,

15

dendrimers could be conjugated with other targeting molecules such as antibodies to

16

improve their targeting ability and delivery efficiency, but the heterogeneity introduced by

17

the attachment of functional ligands to dendrimers should be emphasized and solved in

18

future research. Other delivery systems, such as viruses, liposomes and polymers, can be

19

combined with dendrimers to form multi-functional and multi-target delivery systems,

20

which could dramatically increase the delivery efficiency. However, their safety and

21

biocompatibility should also be carefully considered. Still, to our delight, more efforts from

22

researchers are directed at modifying and perfecting dendrimers for their clinical

23

applications. We would expect dendrimers to have a bright future not only in the diagnosis

24

and treatment of CVDs but also in other medical applications, thus bringing tremendous

25

benefits to patients and disease management.

26

Conflict of Interest:

27 28 29 30

We declare that we have no conflict of interest. Acknowledgement: We thank the National Natural Science Foundation of China (No. 81270368，81360054) for financial support. 23


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W.;

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D.;

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126x71mm (600 x 600 DPI)


Recent Advances in Dendrimer Research for Cardiovascular

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