Table 2:
Summary of multivalent nanoparticles (NPs) with phage-derived targeting peptides.
| Indication | Target | Targeting Peptide | Nanostructure and size | Result | Ref |
|---|---|---|---|---|---|
| Post-assembly peptide conjugation | |||||
| Femur fracture in murine model | Tartrate-resistant acid phosphatase6 | TPLSYLKGLV TVG | Micelle formation of PSMA-PS diblock copolymers by solvent exchange; carbodiimide peptide conjugation to form 50 nm micelles | Two-fold greater fracture accumulation relative to scrambled control in vivo. Fracture-specific drug delivery expedited healing and improved bone mechanical properties. | 62 |
| Liver-colonizing Colon 26 NL-17 cells in murine model | Human endothelial progenitor cells (hEPCs) | ASSHN | DPPC, CHOL, and DSPE-PEG2000-MAL liposomes modified with ASSHNC peptide to form 101 nm particles | Intratumoral distribution in vivo. Tumor-specific doxorubicin delivery reduced tumor volume more than untargeted control. | 63 |
| Neuroblastoma xenografts in nude mice | APA25 and APN30 | CPRECES and CNGRC | Dual conjugation of peptides to HSPC, CHOL, DSPE-PEG2000-NH2 liposomes via BS3 cross-linker to form 90–115 nm liposomes | Superior tumor uptake of dual-targeted liposomes in vivo. Tumor-specific doxorubicin delivery led to tumor vasculature-associated endothelial cell and pericyte death and significantly greater life spans of mice. | 64 |
| Lung cancer xenografts in nude mice | Tumors responding to VEGF inhibitor treatment | HVGGSSV65 | 100 nm liposomes composed of DSPC, CHOL, and MAL-PEG2000-DSPE modified with cysteine-functional peptide | Greater accumulation in irradiated tumors and time-dependent increase in doxorubicin delivery to tumors in vivo. Tumor-specific doxorubicin delivery induced apoptosis and delayed tumor growth. | 66 |
| Drug delivery through BBB | Brain | TGNYKALHP HNG | Cysteine-modified peptide conjugated to MAL-PEG-PLA micelles to form 110–120 nm particles | Uptake by brain-derived endothelial cells in vitro. High brain-to-liver and brain-to-spleen for TGN-NPs in vivo. Dye delivery to brain ~2- to 4-fold greater than controls. | 67 |
| Breast carcinoma xenografts in nude mice, glioma murine model | Glucose-regulated protein GRP78 | GIRLRG | Cysteine-modified peptide conjugated to allyl-functional poly(ester) NPs | Accumulation in irradiated tumors in vivo. Tumor-specific paclitaxel delivery resulted in 50% greater apoptosis and delayed tumor tripling time by 55 days. | 68 |
| Left carotid injury in rats | Human collagen IV | KLWVLPK | Cysteine-modified peptide conjugated to shell MAL-PEG-DSPE / core PLA-paclitaxel liposomes to form 60 nm particles. | Exhibited 10–12 day drug release and binding to injured aortas (percutaneous angioplasty) in vitro. Spatiotemporally control distribution to injured vessels in vivo. | 69 |
| Pre-assembly peptide conjugation | |||||
| Neuroblastoma, lung, ovarian, and prostate tumor xenografts in nude mice | APN30 | CGNGRGGVR SSSRTPSDKY C | Peptide conjugated to DSPE-PEG2000-MAL and combined with HSPC, CHOL, and DSPE-PEG2000 to form 90–115 nm liposomes | Dox-loaded NGR-liposomes exhibited high tumor uptake in vivo, tumor volumes were reduced, and mice achieved longer survival. | 70–72 |
| Glioblastoma xenograft in nude mice | VAV3 receptor73 | SSQPFWS | MAL-PEG-PLA modified with SSQPFWSC peptides to form 23 nm micelles | High cellular uptake efficiency and tumor spheroid penetration in vitro. Tumor vasculature accumulation in vivo. Tumor-specific paclitaxel delivery inhibited tumor growth more than untargeted control. | 74 |
| Carotid artery ligation atherosclerosis murine model | Filamin-A in atheroprone regions of disturbed blood flow | GSPREYTSY MPH | Peptide conjugated to DPHE and combined with DPPC to form 64 nm liposomes | Five-fold greater accumulation in disturbed flow regions in vivo. Artery-specific BH4 delivery decreased superoxide concentration and reduced plaque burden. | 75 |
| Liver-colonizing Colon 26 NL-17 cells and Meth A sarcoma in murine model | Angiogenic vessels in dorsal air sac murine model | APRPG | Stearoyl-peptide combined with DSPC and CHOL to form 100 nm Liposomes | Binding to human islet cell and glioblastoma tumors in vitro. Time-dependent tumor accumulation in vivo. Tumor vessel-specific doxorubicin slowed tumor growth and increased life span. | 76 |
| Carotid artery Ligation atherosclerosis murine model | Non-muscle myosin heavy chain IIA on endothelial cells in atheroprone vasculature | CLIRRTSIC | Peptide conjugated to NHS-PEG-MAL, then MAL reacted with disulfide-Crosslinked branched PEI. Complexed with siRNA to form 200 nm polyplexes | Binding to endothelial cells exposed to oscillatory shear stress in vitro. Selective binding to and gene knockdown in regions of disturbed flow in vivo. | 77 |
| RIP-Tag2 transgenic pancreatic cancer murine model | Pancreatic islet tumor78, Potentially Frizzled-5 Receptor | CKAAKN | Peptide conjugated to 6-(maleimidyl)-Hexanoic acid(trisnor-squalenylidene)-hydrazide. SQ-CKAAKN mixed with SQ-gemcitabine to form 130–170 nm NPs | Binding to secreted frizzled related protein-4 and low complement activation in vitro. Tumor-specific gemcitabine delivery reduced tumor burden by 30% and vessel area by 60% compared to untargeted. | 79 |
| Gene delivery to the brain | Brain67 | TGNYKALHP HNG | Peptide conjugated to MAL-PEG-pDMAEMA. Complexed with DNA to form 80 nm micelles | Uptake by brain capillary endothelial cells in vitro. Brain-specific DNA delivery qualitatively enhanced gene expression in the brain relative to untargeted. | 80 |
Table 2 Abbreviations: APA, Aminopeptidase A. APN, Aminopeptidase N. BBB, Blood-brain barrier. BH4, Tetrahydrobiopterin. BS3, bis(sulfosuccinimidyl)suberate. CD, Cluster of differentiation. CHOL, Cholesterol. DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane. DPHE, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-hexanoylamine. DPPC, Dipalmitoylphosphatidylcholine. DPPG, 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)]. DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine. DSPE, 1,2-distearoylphosphatidylethanolamine. ePC, L-α-phosphatidylcholine. HSPC, Hydrogenated soybean phosphatidylcholine. MAL, Maleimide. MCF, Michigan Cancer Foundation. NHS, N-hydroxysuccinimide. pDMAEMA, poly(2-(dimethylamino) ethyl methacrylate). PE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine. PEG, poly(ethylene glycol). PEI, poly(ethyleneimine). PLA, poly(lactic acid). PSMA, poly(styrene-alt-maleic anhydride). PS, poly(styrene). SPDP, N-succinimidyl 3-(2-pyridyldithio)proprionate. SQ, squalene. VEGF, endothelial growth factor.