Article Figures & Data
Figures
- Fig. 1.
FAP-α responsive nanocarriers based on a cleavable amphiphilic peptide. (A) The structure of peptide cleavable amphiphilic peptide (CAP), which contains a TGPA sequence that can be cleaved by FAP-α. (B) Proposed mechanism of peptide self-assembly, drug-induced reassembly, and peptide and drug coassembly in the hydrophobic drug and amphiphilic peptide mixed solution. The components form the stable nanoparticles. The morphology of peptide assembly during Dox loading was observed by transmission electron microscopy. The assemblies transformed from mace-like (I) to spherical (II) with prolonged ultrasonication. (C) Drug-release profiles of CAP-Dox and uncleavable amphiphilic peptide (UAP)-Dox) in the presence or absence of FAP-α. (D) Penetration of Dox into prostate tumor (PC-3 and CAF coimplanted) tissues after intravenous injection of different Dox formulations. Frozen tumor sections were stained with DAPI (blue) to label nuclei and CD31 (green) antibody to label tumor vasculature. Red: Dox. (E) Growth curves of PC-3 and CAF coimplanted prostate tumors in mice treated with different Dox formulations (used with permission from Angew Chem Int Ed, John Wiley & Sons; Ji et al., 2016b.). **P < 0.01 vs. Control, Dox, and UAP-Dox groups.
- Fig. 2.
A β-cyclodextrin (β-CD) modified MMP-2–responsive liposome loaded with the antifibrotic and anti-inflammatory agent pirfenidone (PFD) and the chemotherapeutic drug gemcitabine (GEM). (A) Illustration of the nanomedicine LRC-GEM-PFD (liposome with RGD and β-cyclodextrin containing GEM and PFD). (B) Immunohistochemical staining of collagen I and tumor growth factor-β (TGF) in pancreatic tumor tissue slices after LRC, PFD, and LRC-PFD treatment. (C) Penetration of rhodamine into pancreatic tumor (Panc-1 and PSCs coimplanted) tissues after intravenous injection of different PFD formulations. Red: rhodamine. (D) Tumor growth curves of PSCs/Panc-1 pancreatic tumors in mice treated with different GEM formulations (Used with permission from ACS Appl Mater Interfaces, American Chemical Society; Ji et al., 2016a.). *P < 0.05, **P < 0.01 vs. Control.
- Fig. 3.
A smart therapeutic peptide for inhibiting angiogenesis and tumor growth. (A) Schematic structure of the DEAP-C16Y peptide. (B) Proposed antitumor mechanism of DEAP-C16Y nanostructures. (C) Migration of human umbilical vein endothelial cell (HUVECs) treated by peptides in a transwell migration assay; cells were chemoattracted by 5% fetal bovine serum/RPMI-1640 medium. The number of migrated cells in each group was quantified. Tubule formation was assessed in HUVECs treated by C16Y or DEAP-C16Y. The total network length in each treatment group was quantified. *P < 0.05, **P < 0.01 compared with the PBS group. (D) Growth curves and metastatic foci number of 4T1 tumors. Mice bearing 4T1 tumors were treated with DEAP-HSAF: a fragment of human serum albumin, DELRDEGKASSAKQ. nanostructures (negative control) or with C16Y or DEAP-C16Y nanostructures for indicated periods. Tumor volume was calculated every other day. Lung sections from 4T1-bearing mice were stained with H&E or proliferating cell nuclear antigens. The number of metastatic foci was quantified. *P < 0.05, **P < 0.01 compared with DEAP-HSAF group. (E) Antitumor efficacy of DEAP-C16Y-Dox nanostructures. Mice bearing 4T1 tumors were treated with the indicated formulations every third day. Tumor volume was calculated every other day. The number of metastatic foci per lung was quantified (Used with permission from Mol Cancer Ther, American Association for Cancer Research; Ding et al., 2015). *P < 0.05, **P < 0.01 compared with DEAP-HSAF group.
- Fig. 4.
Modularized construction of nanoformulations. (A) Amphipathic peptide consisting of a hydrophilic head and hydrophobic tail, based on various modules that self assembles into nanostructures such as micelles, vesicles, and fibers in response to intermolecular forces. (B) Preformed nanostructures can be modified with functional modules for enhanced therapeutic efficacy.
Tables
Targeting Position Names Sequence Receptors References Tumor vasculature RGD RGD Integrin αVβ3 αVβ5 Pasqualini et al., 1997 NGD NGD Aminopeptidase N Arap et al., 1998 IF7 IFLLWQR Annexin 1 Hatakeyama et al., 2011 F3 KDEPQRRSARLSAKPAPPKPEPKPKKAPAKK Nucleolin Porkka et al., 2002 CTL1 CGLIIQKNEC Clotted plasma protein Pilch et al., 2006 CTL2 CNAGESSKNC Clotted plasma protein Pilch et al., 2006 CREAK CREAK Clotted plasma protein Simberg et al., 2007 TAM Lyp-1 CGNKRTRGC P32/gC1q Uchida et al., 2011 M2pep YEQDPWGVKWWY Unclear Cieslewicz et al., 2013 MSC WAT CSWKYWFGEC Unclear Daquinag et al., 2011 ECM a CRRHWGFEFC MMP-2/9 Koivunen et al., 1999 a CTTHWGFTLC MMP-2/9 Koivunen et al., 1999 MSC, mesenchymal stromal cell.
↵a No specific names.
Stimuli Peptide Sequence Therapeutic Strategy Result References Enzymes GPLG↓IAGQ (MMP-2) Linked protective PEG to CPP-modified liposome via MMP-2-responsive sequence Enhanced target ability and internalization of nanocarriers in cancer cells Zhu et al., 2012 PVG↓LIG (MMP-2/9) Gao et al., 2013 GP↓AX (FAP-α) Ji et al., 2016b Acidosis ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGTG Combined pH LIP with a microRNA miR-155 via disulfide bond Delivery of miR-155 specifically to tumor site and efficient uptake by tumor cells Andreev et al., 2007 H7 Conjugated cell-penetrating peptide (R2)2 and H7 modify to polymeric micelle Activation of cell-penetrating peptide by response of H7 to the acidic tumor microenvironment Zhao et al., 2016 E4K4 Mask to a cell-penetrating peptide via linking by an enzyme-responsive cleavable sequence Cell-penetrating peptide exposed via E4K4 charge transforming and linker cleaving Huang et al., 2013a Hyperthermia VSSLESKVSSLESKVSKLESKKSKLESKVSKLESKVSSLESK Leucine zipper peptide-lipid hybrid nanovesicles loaded with Dox inside Superior serum stability at physiologic temperature and increased drug accumulation in tumor Al-Ahmady et al., 2012 (VPGVG)40(VPGXG)60 Temperature triggered activation of the cell penetrating ability of ELP-penta-arginine copolymer Thermal triggered copolymer assembly increased the local density of arginine and the cell penetrating activity at higher temperature Macewan and Chilkoti, 2012 X=A:G; 1:1 ELPs, Elastin-like polypeptides; X: any amino acid;↓: cleavable site.
Categories Names Sequences Origin References CenR motif iRGD CRGDKGPD ECM proteins Sugahara et al., 2010 Cationic Nonaarginine R9 Synthetic Walrant et al., 2011 TAT YGRKKRRQRRR Human immunodeficiency virus (HIV) type 1 Takeshima et al., 2003 Hydrophobic K-FGF AAVALLPAVLLALLAP K-FGF Dokka et al., 1997 FGF-12 PIEVCMYREP FGF-12 Nakayama et al., 2011 Amphipathic Antp RQIKIWFQNRRMKWKK Third helix of the antennapedia homeodomain Derossi et al., 1994 pVEC LLIILRRRIRKQAHAHSK Murine vascular endothelial-cadherin protein Elmquist et al., 2006 Penetratin RQIKIWFQNRRMKWKK Antennapedia homoeodomain in Drosophila Amand et al., 2008 TP10 AGYLLGKINLKALAALAKKIL Synthetic peptide Islam et al., 2014 M918 MVTVLFRRLRIRRACGPPRVRV Tumor suppressor protein p14RF El-Andaloussi et al., 2007 VP22 NAKTRRHERRRKLAIER Herpesvirus structural protein Elliott and O'Hare, 1997 SAP VRLPPPVRLPPPVRLPPP Synthetic Fernández-Carneado et al., 2004 MPG GALFLGFLGAAGSTMGAWSQPKKKRKV Combination of hydrophobic domain from HIV GP41 and NLS of SV40 large T antigen Morris et al., 2008 Pep-1 KETWWETWWTEWSQPKKKRKV Combination of reverse transcriptase of HIV-1 and NLS of SV40 large T antigen Morris et al., 2008 S413-PV ALWKTLLKKVLKAPKKKRKV Combination of DernaSeptin S4 peptide with NLS of SV40 large T antigen Hariton-Gazal et al., 2002 NLS, nuclear localization signa; SV40, simian virus 40; TP-10, transportan 10.
Names Sequences Origin Receptors Mechanism References T4 NLLMAAS Phage-displayed peptide library Tie 2 Blocking the interaction between Ang1 and Tie2 Tournaire et al., 2004 C16Y DFKLFAVYIKYR Scrambled laminin-1 C16 sequence Integrin αVβ3 and αVβ1 Antagonistically binding to integrin, blocking laminin-1 induced angiogenesis Ponce et al., 2003 6a-p KSVRGKGKGQKRKRKKSRYK Exon 6a-encoded domain of VEGF HSPG Inhibiting the binding of VEGF and HSPG, blocking the angiogenesis pathway Lee et al., 2010 Glypican-3 peptide FVGEFFTDV Glypican-3 CTL Loading to tumor cells and enhancing the recognition of tumor cells by CTL Nobuoka et al., 2013 DPPA-1 NYSKPTDRQYHF Phage-displayed peptide library PD-1 Binding to immune checkpoint protein PD-1 and inhibiting the interaction between PD-1 and PD-L1 Chang et al., 2015 KLA KLAKLAKKLAKLAK Natural antibacterial peptide Mitochondria membrane Disrupting mitochondrial membrane and induce apoptosis (can be used in regulating stromal cell number in future) An et al., 2010 HSPG, heparin sulfate proteoglycan.
Targets Therapeutic agents Targeting ligands Cell lines Results References Integrins RGD modified and Dox-loaded selenium nanoparticles RGD HUVECs and MCF-7 breast cancer cells Selectively binding to tumor vessel and achieving antiangiogenesis. Fu et al., 2016 c(RGDfk) mediated nanoparticle encapsulatedVEGFR2-siRNA C(RGDfk) HUVECs and A549 lung cancer cells Inducing effective gene silence in vitro and inhibiting tumor growth in vivo Liu et al., 2014 Neuropilin-1 Peptide modified liposome loaded with Dox ATWLPPR peptide B16-F1 murine melanoma cells Increased tumor targeting and suppressed tumor growth Herringson and Altin, 2011 gC1qR LyP-1 conjugated to PEGylated liposomes loaded with or Dox Lyp-1 SPC-A1 lung adenocarcinoma cells Enhanced inhibition effect on tumor cells in vitro and lymphatic metastatic tumors in vivo Yan et al., 2012 M2-like TAM Nanoformulations composed of (RNAi)-peptide biohybrid M2pep Mouse BALB/c macrophage J774.2 cells Immunomodulating TAMs in tumor microenvironment and efficaciously eradicating tumor cells Conde et al., 2015 HUVEC, human umbilical vein endothelial cell.
In this issue
Peptide Nanoformulations against the Tumor Microenvironment
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- Article
- Abstract
- Introduction
- Functional Peptides
- Tumor Microenvironment Targeting and Responsive Peptide-Based Nanoformulations
- Ligand Peptides Mediate Nanoformulations to Target Tumor Microenvironment
- Enhanced Tumor Penetration via Tumor Microenvironment Responsive Peptides
- Peptide Self-Assembled Nanoformulations Targeting CAFs to Break Stromal Barriers
- Therapeutic Peptide Self-Assembled Nanoformulations Targeting Tumor Vasculatures
- Conclusions
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters