Targeting Ligands Deliver Model Drug Cargo into the Central Nervous System along Autonomic Neurons

Sellers, Drew L.; Tan, James-Kevin Y; Pineda, Julio Marco B.; Peeler, David J.; Porubsky, Veronica L.; Olden, Brynn R; Salipante, Stephen J.; Pun, Suzie H.

doi:10.1021/acsnano.9b01515

Cited by 22 publications

(19 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our laboratory has previously used this technique for peptide cyclization with a decafluorobiphenyl (DFBP) linker ( Fig. 1 B ) and demonstrated increased serum stability and affinity of DFBP-cyclized peptides compared with counterparts with disulfide, amide, or triazole cyclization ( 54 , 55 ). We therefore synthesized six unique A20FMDV2 peptide sequences with cysteine substitutions primarily at N- and C-terminal amino-acid positions for cyclization by DFBP to stabilize and close the hairpin peptide structure ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Peptides were incubated and extracted from serum as previously described ( 54 , 55 ) but with some adjustments to limit serum protein carryover during extractions. Briefly, peptide stocks were diluted to 10 mg/ml in H 2 O and subsequently diluted 1:10 (v/v) in normal mouse serum for incubation at 37 °C in an incubator.…”

Section: Methodsmentioning

confidence: 99%

“…Resulting mass spectrums at the different time points were aligned and plotted in FlexAnalysis software (Bruker). Predicted sequences of degradation products based on product molecular weight were determined using a custom Java program called stability.jar ( https://github.com/juliomarcopineda/peptide-serum-stability/releases ) ( 55 ).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting

Cardle

Jensen

Pun

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The integrin αvβ6 is an antigen expressed at low levels in healthy tissue but upregulated during tumorigenesis, which makes it a promising target for cancer imaging and therapy. A20FMDV2 is a 20-mer peptide derived from the foot-andmouth disease virus that exhibits nanomolar and selective affinity for αvβ6 versus other integrins. Despite this selectivity, A20FMDV2 has had limited success in imaging and treating αvβ6 + tumors in vivo because of its poor serum stability. Here, we explore the cyclization and modification of the A20FMDV2 peptide to improve its serum stability without sacrificing its affinity and specificity for αvβ6. Using cysteine amino acid substitutions and cyclization by perfluoroarylation with decafluorobiphenyl, we synthesized six cyclized A20FMDV2 variants and discovered that two retained binding to αvβ6 with modestly improved serum stability. Further D-amino acid substitutions and C-terminal sequence optimization outside the cyclized region greatly prolonged peptide serum stability without reducing binding affinity. While the cyclized A20FMDV2 variants exhibited increased nonspecific integrin binding compared with the original peptide, additional modifications with the non-natural amino acids citrulline, hydroxyproline, and D-alanine were found to restore binding specificity, with some modifications leading to greater αvβ6 integrin selectivity than the original A20FMDV2 peptide. The peptide modifications detailed herein greatly improve the potential of utilizing A20FMDV2 to target αvβ6 in vivo, expanding opportunities for cancer targeting and therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting

Cardle

Jensen

Pun

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…TAxI peptides as drug delivery motors carry protein drugs aimed at axons [17]. First, we synthesized TAxI (SACQSQSQMRCGGG) peptides.…”

Section: Preparation Of Taxi-exosmentioning

confidence: 99%

“…The SACQSQSQMRCGGG peptide (targeted axonal import, TAxI) is a novel targeting ligand with high a nity for axons, which delivers functional proteins to spinal cord motor neurons after peripheral administration [17]. Accordingly, we developed CNS-targeting TAxI-exos by modifying UMSC-exos with the TAxI peptides for MS therapy.…”

mentioning

confidence: 99%

Chimeric CNS-Targeting-Peptide Engineered Exosomes for Experimental Allergic Encephalomyelitis Therapy

Wang¹,

Ye²,

Lan³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), leads to demyelination, neuronal injury, and loss of white matter, yet still can't be cured. Exosomes are double-layered membrane vesicles of 30–200 nm in size, which can easily penetrate the blood–brain barrier (BBB). Exosomes derived from umbilical cord mesenchymal stem cells exosomes (UMSC-exos) has been shown to treat experimental autoimmune encephalomyelitis (EAE) through the action of anti-inflammatory and immunomodulatory, but its clinical translation has been hampered by their inefficacious accumulation in CNS. Therefore, we developed a TAxI-peptide-chimeric UMSC-exos termed TAxI-exos for CNS-specific accumulation and curative effect in EAE.Methods: We used an EAE model in vivo, and actived T cells and BV-2 cells models in vitro. After two immunizations to establish the EAE model, UMSC-exos, TAxI-exos or DiR labeled exosomes were administered to EAE mice EAE mice for one dose (150μg) before the peak at day 15. On day 30, the mice were sacrificed to collect spinal cords, spleens, and blood for analysis of demyelination, inflammation, microglia, the proportions of T-cell subsets, and the expression of inflammatory cytokines. In vitro, for immune mechanism analyses, PBMCs and splenocytes isolated from healthy C57BL/6 mice, were activated and incubated with 0.15mg/mL UMSC-exos or TAxI-exos. Activated BV-2 cells were used to explore the targeting-ability and polarization-regulating ability of UMSC-exos and TAxI-exos.Results: As expected, TAxI-exos had significant curative effects in EAE mice compared with UMSC-exos via an enhanced targeting-ability. The treatment alleviated inflammation, facilitated microglial cell polarization from M1 to M2, reduced the proportions of T-cell subsets, increased the expression levels of IL-4, IL-10, TGF-β, and IDO-1, and decreased the levels of IL-2, IL-6, IL-17A, IFN-γ, and TNF-α. Conclusions: TAxI-exos have a great CNS-targeting ability and suppress pathological processes in EAE mice, which have a great potential therapeutic utility for MS and other CNS diseases.

show abstract

Co‐Delivery of Paclitaxel and shMCL‐1 by Folic Acid‐Modified Nonviral Vector to Overcome Cancer Chemotherapy Resistance

Nie

Wang

et al. 2021

Small Methods

View full text Add to dashboard Cite

Acquired chemoresistance presents a major clinical impediment, which is an urgent problem to be solved. Interestingly, myeloma cell leukemia‐1 (MCL‐1) and folate receptor expression levels are higher in chemotherapy‐resistant patients than in pretreatment patients. In this study, a multifunctional folic acid (FA)‐targeting core–shell structure is presented for simultaneous delivery of shMCL‐1 and paclitaxel (PTX). The transfection efficiency of shMCL‐1 with the FA‐targeting delivery system is higher than with a nontargeting delivery system in Skov3 and A2780T cells. The FA‐targeting system significantly inhibits cell growth, blocks cell cycles, and promotes apoptosis of cancer cells in vitro. The mechanisms involved in inhibiting growth are related to Bcl‐2/Bax and cdc2/Cyclin B1 pathways. An analysis of RNA sequencing suggests that shMCL‐1 reverses chemoresistance through regulating genes such as regulator of chromosome condensation 2 (RCC2). The synergetic effect of shMCL‐1 and PTX effectively inhibits tumor growth in both PTX‐resistant and normal cancer models by inducing tumor apoptosis, inhibiting proliferation, and limiting tumor angiogenesis. The study results indicate that a FA‐targeting delivery system combining shMCL‐1 with PTX can simultaneously target tumor sites and restore the sensitivity of chemotherapy‐resistant cancer to PTX. These findings have important implications for patients with normal or PTX‐resistant cancer.

show abstract

Targeting Ligands Deliver Model Drug Cargo into the Central Nervous System along Autonomic Neurons

Cited by 22 publications

References 71 publications

Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting

Optimized serum stability and specificity of an αvβ6 integrin-binding peptide for tumor targeting

Chimeric CNS-Targeting-Peptide Engineered Exosomes for Experimental Allergic Encephalomyelitis Therapy

Co‐Delivery of Paclitaxel and shMCL‐1 by Folic Acid‐Modified Nonviral Vector to Overcome Cancer Chemotherapy Resistance

Contact Info

Product

Resources

About