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Journal ArticleDOI

Peptide dendrimers: drug/gene delivery and other approaches

TL;DR: It is worth emphasizing that some peptide dendrimers show activity per se, with the use of targeting peptides or other specific groups that direct the drug/bioactive compounds to specific organs is an important trend in the search for better drug delivery systems.
Abstract: Dendrimers are versatile hyperbranched molecules, which have deserved attention especially for their potential in many applications, including biological. Peptide dendrimers comprise interesting cl...

Summary (2 min read)

INTRODUCTION

  • Peptide dendrimers are hyperbranched macromolecules built by covalent bonds, in which dendrons, core or surface functional groups are composed of peptides.
  • The second type, generally, the smallest molecules, comprises branches composed of polyamino acids.
  • Canadian Journal of Chemistry Draft 3 groups.
  • They have been employed in biological and biochemical fields, especially as immunogens.
  • 1,8 Based on the previous characteristics and considering the importance of peptide dendrimers, the main objective of this review was to explore their different biomedical applications in the last 10 years.

Drug delivery

  • Drug delivery has been a challenge towards improving bioavailability and, specially, increasing selectivity, which lowers toxicity.
  • Trying to find a suitable peptide dendrimer structure to assist this kind of drug delivery, Jiang and coworkers 25 (2016) developed a peptide dendrimer based on PAMAM PEGylated.
  • Thus, proper and specific drug delivery systems would be of utmost importance and peptide dendrimers are able to achieve that purpose.
  • 42 Among the different approaches, the pH-responsive bond has also been used to link the drug to the carrier.
  • The authors observed some advantages such as stability, low toxicity to normal cells, although moderate activity in tumors was demonstrated.

Diagnostic, biosensor and nanodiagnostics

  • MAP (Multiple Antigen Peptides) dendrimers presented better specificity to some antibodies than linear peptides in ELISA tests.
  • Moreover, it has been used in many immunoassays to identify antigen, such as HIV, malaria, BTV (blue tongue virus), infectious bronchitis and other pathogens 63 .
  • MAP dendrimers may have more than one different epitopes in the serodiagnosis of hepatitis C virus.
  • 64,65 Additionally, those dendrimers, acting as biosensors, could be used as probes to detect bioorganic compounds.

Immune response and vaccines

  • Peptide dendrimers can be used to detect antibodies or immune responses with good sensitivity, for instance, that from PPR (Peste des petits ruminant virus) virus.
  • 64,65 Roy and coworkers published the first paper regarding glycopeptide dendrimers, in 1993.
  • 62 The researchers reported the synthesis of a peptide dendrimer composed of lysine and sialic acid as coating antigen, which showed excellent antigenic inhibitory capacity.
  • Many other architectures of glycopeptide dendrimers, potentially used as vaccines, were described in an excellent review published by Roy, Shiao and Rittenhouse-Olson (2013).
  • 67 MAP, having better protection profile, are used to enhance the immune response and are more chemically stable depending on their constitution, which can be homotropic (multimer with one epitope) or heterotropic (multimer with different epitopes).

Antimicrobial and antiviral actions

  • Some peptide dendrimers are described in the literature for their efficient antimicrobial and antiviral properties.
  • Some dendrimers received a gH625 peptide (membranotropic peptide sequence), which interact with the membrane bilayer and possess some antiviral activity.
  • HSV virus presented a consistent reduction in replication and more than 80% of inhibition.
  • To test the antimicrobial activity, they used three bacterium species, namely P. aeruginosa, E. coli and B. subtilis.
  • The human pathogen Pseudomonas aeruginosa infects immune-compromised and cystic fibrosis-patients, causing lethal airway infections.

Enzymes

  • Peptide dendrimers can be applied as artificial enzymes, as esterase, for instance.
  • These dendrimers were designed employing proteinogenic R-amino acids with branches containing diamino acids, with molecular weights ranging from 3 to 5 kDa.
  • They were synthesized by solid-phase methodology, purified and dimerized by disulfide bond using cysteine residues.
  • Combinations of aspartate, histidine, and serine, amino acids usually present in esterases and lipases, were coupled.

CONCLUDING REMARKS

  • The use of peptide dendrimers for their potential applications must be encouraged.
  • The association of the former and the latter must be Page 20 of 25 https://mc06.manuscriptcentral.com/cjc-pubs.
  • Canadian Journal of Chemistry Draft 21 stimulated since it can generate better alternatives in terms of efficacy, synergism and selectivity of action.
  • The main application of peptide dendrimers was on drug delivery systems, especially in cancer, which continues to be a huge challenge for the therapeutics.
  • Compounds to bypass the problem of resistance are urgently needed.

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Draft
Peptide dendrimers: drug/gene delivery and other
approaches
Journal:
Canadian Journal of Chemistry
Manuscript ID
cjc-2017-0242.R1
Manuscript Type:
Mini Review
Date Submitted by the Author:
14-Jun-2017
Complete List of Authors:
Santos, Soraya; University of Sao Paulo, Pharmacy
Gonzaga, Rodrigo; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Silva, João Vitor; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Savino, Débora; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Prieto, Diego; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Shikay, Jennifer; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Silva, Renan; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Paulo, Lucas Henrique; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Ferreira, Elizabeth; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Vargas, Jeanine; Universidade de Sao Paulo Faculdade de Ciencias
Farmaceuticas, Pharmacy
Is the invited manuscript for
consideration in a Special
Issue?:
Dendimers
Keyword:
Dendrimer, Peptide dendimer, Drug delivery, Gene delivery
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Canadian Journal of Chemistry

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1
PEPTIDE DENDRIMERS: DRUG/GENE DELIVERY AND OTHER
APPROACHES
SANTOS, S.S., GONZAGA, R.V., SILVA, J.V., SAVINO, D.F., PRIETO, D.,
SHIKAY, J.M., SILVA, R.S.; PAULO, L.H.A.; FERREIRA, E.I., GIAROLLA, J*.
*Corresponding author: jeanineg@usp.br
Faculty of Pharmaceutical Sciences, University of Sao Paulo, Brazil
ABSTRACT
Dendrimers are versatile hyperbranched molecules, which have deserved attention,
especially for their potential in many applications, including biological. Peptide
dendrimers comprises interesting classes of dendrimers and their use has been
emphasized as drug/bioactive compound delivery system, mostly in the antineoplastic
area. The bioactive molecules can be covalently linked or entrapped inside the peptide
derivative. Self-assembled nanocarriers are a recent trend in the design of potential
delivery systems and pH-sensitive carriers, one of their methods, have been designed to
control their systems. In addition, the use of targeting peptides or other specific groups
that direct the drug/bioactive compounds to specific organs is an important trend in the
search for better drug delivery systems. Recent examples have been given in the
literature showing that gene delivery as other important peptide dendrimers
applications. It is worth emphazing that some peptide dendrimers show activity per se,
without bioactive compounds. Immune compounds and vaccines were shortly presented
herein, as well as uses of other peptide dendrimers briefly discussed in this review,
which encompasses around 10 years of work.
Keyword: dendrimer, peptide dendrimer, drug delivery, gene delivery.
INTRODUCTION
Peptide dendrimers are hyperbranched macromolecules built by covalent bonds,
in which dendrons, core or surface functional groups are composed of peptides. Their
molecular weight ranges from 2 kDa, small structures, to 100 kDa, large protein-like
structures, arranged in 2 to 32 generations. Two features contribute to the complexity of
peptide dendrimers: generation number and surface terminal groups. These molecules
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2
provide a great chemical diversity and different applications, especially in
biotechnological sciences. Some of them include drug and gene delivery, biomedical
diagnosis, vaccines for multiple diseases, protein mimetics, and enzyme catalysts.
1–5
The diversity of applications are due, mainly, to better stability of the structures and to
their similarity to biomacromolecules.
6
Generally, peptide dendrimers are classified according to the bond between the
peptide and the dendron as covalent and non-covalent structures and can be synthesized
as follows: convergent (most common) and divergent method. Their synthesis is usually
carried out through solid phase
7
, by means of adequate resins, employing specific
protecting groups.
Interesting reviews have been published reporting general synthetic methods
employed to obtain peptide and glycopeptide dendrimers, such as solid-phase synthesis
to chemoselective and orthogonal binding.
1,2,8,9
. Jan Jezek’s group also reported
interesting and relevant papers related to peptide and glycopeptide dendrimers.
10,11,12,13
The combination of dendrimers and bioactive peptides properties through the
letter may provide synergic action due to: (1) polyvalence, which can raise biological
effects of the conjugated-peptides; (2) interaction with many receptors at the same time;
(3) protein-like characteristics, mimicking biological structures, for instance artificial
proteins. Moreover, they allow endowing biocompatibility and biodegradability to the
final structure.
9
There are mainly three kinds of peptide dendrimers:
The first has its branches grafted or decorated with unnatural amino acids or
organic groups and its core and surface groups may be decorated with peptide/proteins.
They present high generations, usually being the largest compounds. In a review by
Wan and Alewwod
3
(2016), the synthesis and biological applications of those
dendrimers was highlighted. Examples given involve dendrimers with a polymeric core
(as Poly(amidoamine) PAMAM - dendrimer) and multiple peptide unities covalently
coupled as surface groups.
The second type, generally, the smallest molecules, comprises branches
composed of polyamino acids. Since 1980s, when the research with peptide dendrimers
started, poly-lysine dendrimer has been one of the most widely used.
3
The third type, developed by Tam
8
(1988),
behaves as multiple Antigen Peptide
(MAP), and it is constituted of amino acids in the core and peptide chains as the surface
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3
groups. They have been employed in biological and biochemical fields, especially as
immunogens.
1,8
Based on the previous characteristics and considering the importance of peptide
dendrimers, the main objective of this review was to explore their different biomedical
applications in the last 10 years. In this context, the design of new drug delivery
systems, gene delivery, and their activity as therapeutic agent, will be emphasized. In
addition, other biological uses will be presented and briefly discussed herein.
Drug delivery
Drug delivery has been a challenge towards improving bioavailability and,
specially, increasing selectivity, which lowers toxicity.
14
Drugs can be bound to the dendrimers, either leading to prodrugs or targeted
drugs
15
or be encapsulated in these nanostructures, through weak interactions.
16
It is
worth noting that several targeting strategies based on the fact that carbohydrates have
the ability to target active sites, have been explored. Mannose, for example, can be
recognized by macrophages and also neutralize cationic charges on dendrimer surface,
which increases toxicity
17
Other cells, as hepatocytes, show receptors sensitive to
galactose interaction, allowing liver selectivity for some drugs.
18
Encapsulated-dendrimers have attracted interest in recent years due to their
unique properties, such as well-defined size, globular shape, and internal empty space,
allowing encapsulate drugs through electrostatic, complex formation, van der Waals
forces and H-bonding interactions. Their properties permit increasing drug/bioactive
compound water solubility as well.
19
Poly(amidoamine) (PAMAM) has been employed
to encapsulate poorly soluble bioactive compounds, increasing solubility successfully,
enhancing their activity.
20
Many approaches have been used to achieve drug delivery. Self-assembled
nanocarrier is a recent trend in its potential design. There are interesting examples in the
literature concerning this mechanism of drug delivery.
6,21
Verma and coworkers
22
(2015) reported urea and triazole as core in the planning of self-assembling peptide
dendrimers. The branches are composed of glutamic and aspartic acids. The branches
coupling through N-terminals by a carbonyl group provides the urea core formation,
which has benefits, such as strong intrinsic self-assembly and anionic binding
properties. In this context, urea function is an interesting entity, which may be
employed as core for the development of self-assembling dendrimers.
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4
Transdermal delivery has also attracted interest in the academic community and
there are some peptide nanocarriers designed for this application. Conjugation with
iontophoresis was described by Mutaliki and colleagues
23
(2013) (Figure 1), who
synthesized peptide dendrimers, constituted of arginine and histidine, as terminal groups
and composed of 4, 6 and 8 molecules of each amino acids. Their stability was tested in
receptor solution on epidermis, dermis and skin, and showed that there was not
noticeable degradation, with 98.9% stability in all these tests after 6 h at room
temperature. In passive diffusion, dendrimers with higher molecular weight did not
permeate across the skin. On the other hand, dendrimers with lower molecular weight
permeated across the skin, with good stability profile. Iontophoresis increased
significantly the permeation of all compounds, meaning that permeation is dependent on
molecular weight rather than on the positive charges of the amino acids.
Figure 1 – Nanocarrier designed for transdermal delivery.
The capacity of peptide dendrimers to cell-internalize has been a challenge to the
delivery of some drugs, mainly in oncology. With the purpose of finding chemical
architectures of peptide dendrimers, Yan and coworkers
24
(2015)
conjugated Cell-
Penetrating Linear Peptides, CPPs, with PAMAM dendrimer. The conjugates were
labeled with a fluorescent dye, boron-dipyrromethene, BODIPY (BP), and linked to
Tat-peptide (GRKKRRQRRRPQ), which is derived from the transactivator of human
immunodeficiency transcription (BPT). The internalization showed to be dependent on
the amount of Tat-peptide conjugated with PAMAM. Submitted to cytotoxicity tests,
PAMAM conjugate was less toxic than free dendrimer. This effect could be related to
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Citations
More filters
Journal ArticleDOI
TL;DR: The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.
Abstract: Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and β-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials.

224 citations

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TL;DR: In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented.
Abstract: Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named ‘starburst polymers’. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.

160 citations

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TL;DR: This review focused in providing examples of dendrimers used in nanomedicine, with a total of six derivatives in clinical trials and seven products available in the market.

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Abstract: Bacterial infections caused by 'superbugs' are increasing globally, and conventional antibiotics are becoming less effective against these bacteria, such that we risk entering a post-antibiotic era. In recent years, antimicrobial peptides (AMPs) have gained significant attention for their clinical potential as a new class of antibiotics to combat antimicrobial resistance. In this review, we discuss several facets of AMPs including their diversity, physicochemical properties, mechanisms of action, and effects of environmental factors on these features. This review outlines various chemical synthetic strategies that have been applied to develop novel AMPs, including chemical modifications of existing peptides, semi-synthesis, and computer-aided design. We will also highlight novel AMP structures, including hybrids, antimicrobial dendrimers and polypeptides, peptidomimetics, and AMP-drug conjugates and consider recent developments in their chemical synthesis.

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Abstract: Dendrimers have attracted immense interest in science and technology due to their unique chemical structure that offers a myriad of opportunities for researchers. Dendritic design allows us to pres...

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Frequently Asked Questions (2)
Q1. What are the contributions in this paper?

Immune compounds and vaccines were shortly presented herein, as well as uses of other peptide dendrimers briefly discussed in this review, which encompasses around 10 years of work. 

Exploring the activity per se of these compounds is another interesting possibility of findings, especially, antinfectious agents. In all those areas the versatility of the peptide dendrimers, especially considering the possibility of using pH-sensitive linkage, self-assembly forming micelles, and the conjugation with different molecular architectures, is a quality that has to be better scrutinized toward innovation.