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Shuttle Peptides for Cancer Therapeutics

Shuttle peptides are peptides or peptide conjugates designed to allow the transport or delivery of therapeutic payloads, such as drugs, oligonucleotides, or proteins, through cell or tissue barriers, for example, the blood-brain barrier, to their targets in cells, for instance, to targets in the nervous system.

The delivery of drugs into the brain is a significant challenge. The blood-brain barrier (BBB) prevents most drugs from reaching targets in the brain. Molecular transport vehicles or shuttles based on peptides offer new avenues of crossing the BBB. Well-designed shuttle peptides are of lower cost, have reduced immunogenicity, and are biological and chemical very versatile. Improved drugs for the central nervous system (CNS) can potentially enhance the well-being of many people suffering from neurological diseases such as brain cancer.


The BBB is a complex of tight junctions of the brain’s capillary endothelial cells. Several transport systems are part of this cell complex. For energy, the BBB supplies creatine to the brain, transported by the creatine transporter localized at the brain capillary endothelial cells.

Brain capillary endothelial cells express serotonin and norepinephrine transporters, organic anion transporter 3 (OAT3), and the amino acid transporter ASCT2.

Oller-Salvia et al., in 2016, reported a list of shuttle peptides that cross the BBB (Table 1). 

Table 1: Features of some BBB shuttle peptides

Peptide

Typical sequence

Proposed transporter

Origin

Main cargoes

BBB passage evidence

Angiopep-2

TFFYGGSRGK RNNFKTEEY-OH

LRP1

Neurotropic endog. Protein

Small drugs, proteins, nanopart., and DNA/RNA

BBBCM

Capillary depletion

Fluorescence microscopy

TEM

Effect on glioma, epilepsy and Parkinson's mouse models

ApoB

(3371–3409)

SSVIDALQYK LEGTTRLTRK-
RGLKLATALS LSNKFVEGS

LRP2LDLR

Neurotropic endog. Protein

Proteins

Capillary depletion
Effect on MPS mouse model

ApoE (159–167)2

(LRKLRKRLL)2

LRP1LRP2LDLR

Neurotropic endog. protein

Proteins and nanopart.

BBBCM
Capillary depletion

Fluorescence microscopy
Effect on the MLD mouse model

Peptide-22

Ac-C(&)MPRLRGC(&)-NH2

LDLR

Phage display (receptor)

Nanopart.

BBBCM
Live fluorescence microscopy

THR

THRPPMWSPVWP-NH2

TfR1

Phage display (cells)

RNA and nanopart.

BBBCM
TEM

THR retro-enantio

pwvpswmpprht-NH2

TfR1

Phage display-derived

Small drugs and nanopart.

BBBCM
Live fluorescence microscopy

CRT

C(&)RTIGPSVC(&)

TfR1

Phage display (mice)

Virus

Capillary depletion

Leptin30

YQQILTSMPS RNVIQISND-
LENLRDLLHV L

Leptin receptors

Neurotropic endog. protein

DNA

Capillary depletion

RVG29

YTIWMPENPR PGTPCDIFT-
NSRGKRASNG-OH

nAchR

Neurotropic exog. protein

Nanopart. and RNA/DNA

Capillary depletion

BBBCM

Effect in viral encephalitis and mouse models of Parkinson's disease

DCDX

GreirtGraerwsekf-OH

nAchR

Neurotoxin-derived

Nanopart.

BBBCM

Effect on glioblastoma

Apamin

C(&1)NC(&2)KAPETALC(&1)-
AR-RC(&2)QQH-NH2

KCa channel?

Neurotoxin

Proteins and nanopart.

BBBCM

MiniAp-4

[Dap](&)KAPETALD(&)

KCa channel?

Neurotoxin-derived

Small drugs, proteins and nanopart.

Human BBBCM

Fluorescence microscopy

GSH

γ-l-glutamyl-CG-OH

GSH transporter

Endog. peptide

Nanopart.

Intracerebral microdialysis

Effect on glioma and MS mouse models

G23

HLNILSTLWKYRC

GM1

Phage display (receptor)

Nanopart.

BBBCM
Fluorescence microscopy

g7

GFtGFLS(O-β-Glc)-NH2

Unknown receptor

Endog. peptide-derived

Nanopart.

Fluorescence microscopy

TEM

TGN

TGNYKALHPHNG

Unknown receptor

Phage display (in vivo)

Nanopart.

Fluorescence microscopy

Effect on glioma and AD mouse models

TAT (47–57)

YGRKKRRQRRR-NH2

AMT

Exog. protein

Proteins and nanopart.

BBBCM

Capillary depletion

Fluorescence microscopy
TEM

SynB1

RGGRLSYSRR RFSTSTGR

AMT

Toxin

Small drugs

Brain perfusion

Capillary depletion

Diketopiperazines

&(N-MePhe)–(N-MePhe) Diketo-piperazines

Passive diffusion

Design (+serendipity)

Small drugs

PAMPA

BBBCM

PhPro

(Phenylproline)4-NH2

Passive diffusion

Design

Small drug

PAMPA

 

“BBB passage evidence” includes the main strategies used to assess the presence of the compound targeted by the BBB-shuttle in the brain parenchyma or the effects derived from it. These approaches do not provide information about brain selectivity and do not prove that the whole cargo-shuttle construct crosses the BBB.

Abbreviations: Endog.: endogenous; Exog.: exogenous; nanopart.: nanoparticles; BBBCM: a cell-based BBB model; MPS: mucopolysaccharidosis; MLD: metachromatic leukodystrophy; AD: Alzheimer's disease. Nomenclature for cyclic peptides (&) is adapted to the 3-letter amino acid code from the one described by Spengler et al. [Dap] stands for diaminopropionic acid. Only selected references relevant to the study of these peptides as BBB-shuttle. (Source: Oller-Salvia et al. 2016)

 

Reference

Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17867-72. [PMC]

Ohtsuki S. New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system. Biol Pharm Bull. 2004 Oct;27(10):1489-96. [
pdf]

Oller-Salvia, Benjamí and Sánchez-Navarro, Macarena and Giralt, Ernest and Teixidó, Meritxell. Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery, Chem. Soc. Rev., 2016, 45, 17, 4690-4707. The Royal Society of Chemistry. [
RSC]

J. Spengler, J. C. Jiménez, K. Burger, E. Giralt and F. Albericio; Abbreviated nomenclature for cyclic and branched homo- and hetero-detic peptides. J. Pept. Res., 2005, 65 , 550-555. [PubMed]


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