Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability

Laksitorini, Marlyn Dian; Kiptoo, Paul; On, Ngoc; Thliveris, James A.; Miller, Donald W.; Siahaan, Teruna J.

doi:10.1002/jps.24309

Cited by 42 publications

(70 citation statements)

References 42 publications

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“…22 Similarly, HAV4 peptide enhanced the in vivo brain delivery of Gd-DTPA better than HAV6 in Balb/c mice as detected by MRI. 26 …”

Section: Discussionmentioning

confidence: 99%

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Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

Alaofi

Kiptoo

et al. 2016

Journal of Pharmaceutical Sciences

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The aim of this study is to evaluate the effect of peptide cyclization on the BBB modulatory activity and plasma stability of HAV peptides, which are derived from the EC1 domain of human E-cadherin. The activities to modulate the intercellular junctions by linear HAV4 (Ac-SHAVAS-NH2), cyclic cHAVc1 (Cyclo(1,8)Ac-CSHAVASC-NH2), and cyclic cHAVc3 (Cyclo(1,6)Ac-CSHAVC-NH2) were compared in in vitro and in vivo BBB models. Linear HAV4 and cyclic cHAVc1 have the same junction modulatory activities as assessed by in vitro MDCK monolayer model and in-situ rat brain perfusion model. In contrast, cyclic cHAVc3 was more effective than linear HAV4 in modulating MDCK cell monolayers and in improving in vivo brain delivery of Gd-DTPA upon i.v. administration in Balb/c mice. Cyclic cHAVc3 (t1/2 = 12.95 h) has better plasma stability compared to linear HAV4 (t1/2 = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2–4 h) compared to HAV4 (<1 h). Both HAV4 and cHAVc3 peptides also enhanced the in vivo brain delivery of IRdye800cw-PEG (25 kDa) as detected by near IR imaging. The result showed that cyclic cHAVc3 peptide had better activity and plasma stability than linear HAV4 peptide.

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“…22 Similarly, HAV4 peptide enhanced the in vivo brain delivery of Gd-DTPA better than HAV6 in Balb/c mice as detected by MRI. 26 …”

Section: Discussionmentioning

confidence: 99%

“…22,23 Recently, both HAV6 (Table 1) and ADTC5 peptides have been shown to enhance the brain delivery of both small and large molecules into the brain of rats and mice. 24-26 …”

Section: Introductionmentioning

confidence: 99%

Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

Alaofi

Kiptoo

et al. 2016

Journal of Pharmaceutical Sciences

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“…Mgf was analysed in both the A and B compartments to calculate the value of Papp (Figure 11). The TEER values were continuously recorded while performing experiment, showing miniscule reduction (i.e., <10%) in TEER value on the treated cells wrt the control cells which indicated that there was slight opening of the tight junctions of Caco-2 cells, signifying paracellular transport (Sha et al, 2005;Chen et al, 2015;Laksitorini et al, 2015).…”

Section: Bidirectional Permeability Assaymentioning

confidence: 99%

Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation

Khurana

Bansal

Beg

et al. 2017

International Journal of Pharmaceutics

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Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgfphospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with various molar ratios of Mgf and Phospholipon 90 G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line indicated insignificant cytotoxicity, and P-gp efflux, bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signified boosted biopharmaceutical potential of the optimized PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf.

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“…Dengan demikian, kehadiran BBB menjadi tantangan tersendiri dalam proses penghantaran obat menuju sel target. Salah satu cara untuk meningkatkan sistem penghantaran obat adalah dengan meningkatkan porositas tight junction dengan menghambat interaksi kadherin-kadherin pada adherens junction [6].…”

Section: Pendahuluanunclassified

Molecular Docking of Interaction between E-Cadherin Protein and Conformational Structure of Cyclic Peptide ADTC3 (Ac-CADTPC-NH2) Simulated on 20 ns

et al. 2017

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A r t i c l e I n f o A b s t r a c t Keywords:ADTC3, E-cadherin domain EC1, Gromacs, dockingThe treatment of diseases that attack the brain is very difficult, because the delivery of drug molecules to the brain is often hindered by the molecules of blood-brain barrier (BBB). Thus, it was developed the new method using synthetic peptide which derived from the amino acids sequence of cadherin and ADTC3 predicted able to modulate the intercellular junction peptide. The intermolecular interaction between ADTC3 and Ecadherin is hypothesized as the driving force of modulation. In this research have been calculated the interaction energy between ADTC3 and E-cadherin. The method used in this research is molecular dynamics (MD) and molecular docking. The results show that cyclic peptide ADTC3 (Ac-CADTPC-NH2) simulated for 20 ns (20,000 ps) has considerable interaction with EC1 domain of E-cadherin which have the binding energies -31.55 kJ.mol -1 and inhibition constant Ki 2.96 μM at the 4487 conformation. This highly interaction energy was predicted as the driving force in modulating intercellular junctions. The binding site of E-cadherin reside on amino acid residues Asp1, Trp2, Val3, Ile4, Lys25, Met92 in the adhesion arm-acceptor pocket region. A b s t r a kKata kunci: ADTC3, E-cadherin domain EC1, Gromacs, docking Pengobatan penyakit yang menyerang otak sangat sulit dilakukan karena penghantaran molekul obat menuju otak terhalang oleh molekul-molekul blood-brain barrier (BBB). Untuk mengatasinya telah dikembangkan metode baru dengan memodulasi junction antar sel menggunakan peptida. Salah satu peptida yang diperkirakan mampu memodulasi adalah ADTC3, yang diturunkan dari susunan asam amino kadherin. Modulasi terjadi diduga karena interaksi antara ADTC3 dengan E-kadherin. Pada penelitian ini telah dihitung energi interaksi antara ADTC3 dengan E-kadherin. Metode yang digunakan adalah dinamika molekul (DM) dan molecular docking. Hasil penelitian menunjukkan bahwa peptida siklik ADTC3 (Ac-CADTPC-NH2) hasil simulasi 20 ns (20.000 ns) berinteraksi kuat dengan domain EC1 E-kadherin dengan energy binding sebesar -31,55 kJ.mol -1 dan tetapan inhibisi Ki sebesar 2,96 µM pada konformasi ke-4487. Interaksi yang kuat ini diperkirakan sebagai daya penggerak memodulasi junction antar sel. Interaksi antara ADTC3 dengan E-kadherin terjadi pada situs residu Ekadherin Asp1, Trp2, Val3, Ile4, Lys25, Met92 yang berada pada daerah adhesion armacceptor pocket.

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Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability

Cited by 42 publications

References 42 publications

Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation

Molecular Docking of Interaction between E-Cadherin Protein and Conformational Structure of Cyclic Peptide ADTC3 (Ac-CADTPC-NH2) Simulated on 20 ns

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