Technology Reviews

Peptide- and Aptamer-Functionalized Nanovectors for Targeted Delivery of Therapeutics

[+] Author and Article Information
Todd O. Pangburn, Matthew A. Petersen, Brett Waybrant, Maroof M. Adil

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455

Efrosini Kokkoli1

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455kokkoli@cems.umn.edu


Corresponding author.

J Biomech Eng 131(7), 074005 (Jul 31, 2009) (20 pages) doi:10.1115/1.3160763 History: Received August 21, 2008; Revised January 08, 2009; Published July 31, 2009

Targeted delivery of therapeutics is an area of vigorous research, and peptide- and aptamer-functionalized nanovectors are a promising class of targeted delivery vehicles. Both peptide- and aptamer-targeting ligands can be readily designed to bind a target selectively with high affinity, and more importantly are molecules accessible by chemical synthesis and relatively compact compared with antibodies and full proteins. The multitude of peptide ligands that have been used for targeted delivery are covered in this review, with discussion of binding selectivity and targeting performance for these peptide sequences where possible. Aptamers are RNA or DNA strands evolutionarily engineered to specifically bind a chosen target. Although use of aptamers in targeted delivery is a relatively new avenue of research, the current state of the field is covered and promises of future advances in this area are highlighted. Liposomes, the classic drug delivery vector, and polymeric nanovectors functionalized with peptide or aptamer binding ligands will be discussed in this review, with the exclusion of other drug delivery vehicles. Targeted delivery of therapeutics, from DNA to classic small molecule drugs to protein therapeutics, by these targeted nanovectors is reviewed with coverage of both in vitro and in vivo deliveries. This is an exciting and dynamic area of research and this review seeks to discuss its broad scope.

Copyright © 2009 by American Society of Mechanical Engineers
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Figure 1

Pictorial representation of the morphologies of liposomes and the polymeric nanovectors discussed in this review (not drawn to scale). As a cartoon, the orientation of the polymers, lipids, and targeting ligands is not truly representative of the orientation in the actual nanovectors.

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Figure 2

The EPR effect illustrated. (a) Illustration of how the leaky vasculature in the region of tumors (ii) as compared with that in healthy tissue (i) allows for the enhanced permeability of molecules and nanoparticles into a tumor. (b) Illustration of how there is enhanced retention and accumulation over time of high Mw molecules and nanosized particles in tumors due to the tumors slowed lymphatic clearance. Reprinted from Ref. 18, with permission from Elsevier.

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Figure 3

Confocal images that show internalization of targeted stealth liposomes to CT26 colon carcinoma cells. The cell membrane is shown in red, the nucleus in blue, and the drug delivery systems in green. Different formulations with low densities of PEG2000 (2–3%) were incubated with CT26 at 37°C for 24 h. The scale bar is 50 μm for all images (63).

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Figure 4

Light microscopy of frozen tissue sections from Lewis lung carcinoma tumors in mice demonstrates transfection with TAT-liposome-DNA complexes in vivo. Section from a nontreated tumor ((a) and (b)), from a tumor injected with liposome-DNA complexes without TAT ((c) and (d)), and from a tumor injected with TAT-liposome-DNA complexes ((e) and (f)). Bright field light microscopy after hematoxylin/eosin staining ((a), (c), and (e)), and epiflourescence microscopy of green fluorescent protein present as a result of transfection ((b), (d), and (f)). Reprinted with permission from Ref. 86. Copyright 2003 National Academy of Sciences, USA.

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Figure 5

At physiological pH of 7.4 the PEG-polysulfonamide block copolymers electrostatically associate with the TAT peptides on the surface of the nanoparticle essentially fully masking the particle with PEG (a). However, in acidic environments, such as around a tumor, the sulfonamide chain protinates and dissociates from the TAT peptides, so that drug internalization occurs selectively at the tumor site (b). Reprinted from Ref. 187, with permission from Elsevier.

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Figure 6

In vivo images of mice with xenografts of human ovarian carcinoma. Mice were injected with PEG ((a), (b), (e), and (f)) and PEG–LHRH ((c), (d), (g), and (h)) polymers both labeled with near-infrared fluorophore cyanine dye (Cy5.5). Tumors were excised 72 h postinjection and imaged. After 1 h a uniform distribution is observed, but at 72 h there is a clear accumulation at the tumor site of the PEG with the targeting peptide, LHRH. Reprinted with permission from Ref. 204. Copyright 2007 American Chemical Society.

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Figure 7

Schematic showing the functionalization of fluorescein-labeled (FTSC-labeled) SCK nanoparticles with the PTD of HIV-TAT, via solid phase synthesis. Micelles are formed from poly(ε-caprolactone)-block-poly(acrylic acid) (PCL-b-PAA) block copolymer and then converted to SCK nanoparticles by cross-linking the PAA corona layer. Reprinted with permission from Ref. 196. Copyright 2001 American Chemical Society.

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Figure 8

In vivo gene transfer efficiency of mono and dual peptide-functionalized PEI/DNA complexes. HeLa (human cervical cancer) or PC-3 (human prostate cancer) model cells were subcutaneously injected in mice and allowed to grow to 250 mm3 in size. HeLa cells express both FGFR and integrins (targeted by YC25 and CP9 peptides, respectively), while CP9 cells only express integrins. A strong synergistic targeting effect is observed. Reprinted with permission from Ref. 230. Copyright 2007 Brill.

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Figure 9

Biodistribution of aptamer-targeted nanoparticles in mice 24 h after injection of nanoparticles (NPs) with varying levels of targeting aptamer (Apt) or with a mutant control aptamer (MutApt), expressed as percentage of injected dose per gram (IDPG). Reprinted with permission from Ref. 193. Copyright 2008 National Academy of Sciences, USA.



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