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.