Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates

Abstract

Peptides are attracting increasing attention as therapeutic agents, as the technologies for peptide development and manufacture continue to mature. Concurrently, with booming research in nanotechnology for biomedical applications, peptides have been studied as an important class of components in nanomedicine, and they have been used either alone or in combination with nanomaterials of every reported composition. Peptides possess many advantages, such as smallness, ease of synthesis and modification, and good biocompatibility. Their functions in cancer nanomedicine, discussed in this review, include serving as drug carriers, as targeting ligands, and as protease-responsive substrates for drug delivery.

Figure 1

Schematic representation of amphiphilic peptides. Top: the amphiphilic character results from the sequential assembly of hydrophobic and hydrophilic domains. Bottom: the amphiphilic character appears after folding into a helical conformation. Reprinted with permission from ref [83]. Copyright 2005 Springer.

Figure 2

Non-covalent complexation between CPPs and cargo. Electrostatic and hydrophobic forces facilitate the complexation between CPPs and cargos, such as (from left to right) nucleic acids, proteins and antibodies. Reprinted with permission from ref [79]. Copyright 2009 Elsevier.

Figure 3

Specific accumulation of lymphatic homing peptide LyP-1 in tumors. 16–20 h after mice bearing MDA-MB-435 xenograft tumors were injected i.v. with (A) fluorescein-conjugated LyP-1 or (B) a fluorescein-conjugated control peptide (ARALPSQRSR). (C) LyP-1 produced intense fluorescence in the tumor, whereas no fluorescence was detectable in other organs. (D) No fluorescence was observed in the control peptide-injected tumor. Adapted from ref with permission. Reprinted with permission from ref [42]. Copyright 2004 National Academy of Sciences.

Figure 4

Brain-specific gene silencing after i.v. injection of siRNA/RVG-9R complex. (a) After injection of GFP siRNA/peptide complex, brain, spleen and liver cells were analyzed for GFP expression. Histograms (top) and cumulative data (bottom) are shown. Dotted lines in the upper panel, cells from wild-typemice; grey fill, mock; black lines and columns, RV-MAT-9R; red lines and columns, RVG-9R. (b) After injection of SOD1 siRNA/peptide complexes, brain, spleen and livers were examined for SOD1 mRNA (top) and SOD1 protein (bottom) levels. Black columns, RV-MAT-9R (C); red columns, RVG-9R (T). The numbers below the western blot represent the ratios of band intensities of SOD-1 normalized to those of β-actin. (c) Small RNAs isolated from different organs of SOD1 siRNA/RVG-9R injected mice were probed with siRNA sense strand oligonucleotide. Antisense strand oligonucleotide was used as a positive control (first and last lanes). (d) Mice were injected intravenously with SOD siRNA/RVG-9R, and the duration of gene silencing was determined by quantification of SOD1 mRNA levels (top) and SOD1 protein enzyme activity (bottom) on the indicated days after siRNA administration. Reprinted with permission from ref [47]. Copyright 2007 Nature Publishing Group.

Figure 5

(A) The lipid-peptide N-Ac-AA-DOPE can be converted into DOPE by elastase. (B) The liposome is stable with negatively charged surface. Removal of N-Ac-AA by elastase results in charge reversal, thus enhancing its ability to fuse with the plasma membrane for drug delivery. Reprinted with permission from ref [162]. Copyright 2009 American Chemical Society.

Figure 6

Logical nanoparticle sensors. Self-Assembly is gated to occur in the presence of both MMP-2 and MMP-7 (Logical AND) (Left) or in the presence of either or both proteases (Logical OR) (Right) by attachment of protease-removable PEG polymers. Reprinted with permission from ref [54]. Copyright 2007 American Chemical Society.

Figure 7

Proposed mechanism of protease-sensitive liposome. Upon dilution into physiological osmolarity, the protease-triggerable, caged liposomes do not release their contents. When treated with protease uPA, the polymer is degraded, allowing the liposome to swell osmotically and release its contents, or possibly to fuse (in vivo) with nearby planar membranes. Reprinted with permission from ref [59]. Copyright 2011 American Chemical Society.