l -Type amino acid transporter 1 (lat1)-mediated targeted delivery of perforin inhibitors

Huttunen, Kristiina M.; Huttunen, Johanna; Aufderhaar, Imke; Gynther, Mikko; Denny, William A.; Spicer, Julie A.

doi:10.1016/j.ijpharm.2015.12.034

Cited by 35 publications

(79 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LAT1 was successfully targeted for the delivery of several prescription drugs to the brain, such as the antiparkinsonian drug l-dopa and the anticonvulsant drug gabapentin, through a prodrug approach 42 , and has been continuously studied for the delivery of various therapeutic molecules 11,33,49 . More recently, through substantial efforts, several key parameters for the selection of drug candidates and design of LAT1utilizing prodrugs with optimal pharmacokinetics and bioconversion efficiency have been determined [50][51][52][53][54][55][56] . This progress lays the foundation for the development of next generation LAT1-utilizing prodrugs and can be applied for synthesizing LAAM CQD-based prodrugs for management of diseases in the central nervous system as well as various cancers.…”

Section: Discussionmentioning

confidence: 99%

Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids

et al. 2020

Nat Biomed Eng

259

214

View full text Add to dashboard Cite

Strategies for selectively imaging and delivering drugs to tumours typically leverage differentially upregulated surface molecules on cancer cells. Here, we show that intravenously injected carbon quantum dots, functionalized with multiple paired α-carboxyl and amino groups that bind to the large neutral amino acid transporter 1 (which is expressed in most tumours), selectively accumulate in human tumour xenografts in mice and in an orthotopic mouse model of human glioma. The functionalized quantum dots, which structurally mimic large amino acids and can be loaded with aromatic drugs through π-π stacking interactions, enabled-in the absence of detectable toxicity-near-infrared fluorescence and photoacoustic imaging of the tumours and a reduction in tumour burden after the targeted delivery of chemotherapeutics to the tumours. The versatility of functionalization and high tumour selectivity of the quantum dots make them broadly suitable for tumour-specific imaging and drug delivery.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids

et al. 2020

Nat Biomed Eng

259

214

View full text Add to dashboard Cite

show abstract

“…Prodrug 2 has been shown to have higher OATPmediated uptake rate into MCF-7 cells in vitro, which may explain why probenecid alone was able to decrease the brain uptake of this prodrug. 16 The in vivo pharmacokinetic experiments revealed that neither of the parent drugs was able to reach the brain after i.p. bolus injection and that the systemic exposure was low as well.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Previously, it was shown that both prodrugs are able to utilize human LAT1 and organic transporting polypeptides (OATP) for cell permeation in vitro. 16 Therefore, the roles of Lat1 and murine organic anion transporting polypeptides (Oatp) in the blood−brain barrier permeation of the prodrugs were investigated by co-perfusing the prodrugs with a competing substrate of Lat1 (2 mM Ltryptophan), a nonspecific inhibitor of Oatps (500 μM probenecid) and with their combination. The function of Lat1-transporters at the mouse blood−brain barrier was confirmed with a known substrate for Lat1 ([ 14 C]-L-leucine).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…16 Sodiumindependent heterodimeric transmembrane protein LAT1 facilitates the cell entry of neutral and branched amino acids and also the disposition of several drugs in clinical use. 17 The LAT1 transporter is relatively highly and selectively expressed at the blood−brain barrier 18 but also in metabolically active cells, such as placental, tumor, brain, and activated immune cells.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

et al. 2016

Self Cite

View full text Add to dashboard Cite

We have recently reported that by converting a perforin inhibitor into an l-type amino acid transporter 1 (LAT1)-utilizing prodrug its cellular uptake can be greatly increased. The aim of the present study was to determine the in vivo and brain pharmacokinetics of two perforin inhibitors and their LAT1-utilizing prodrugs 1 and 2. In addition, the brain uptake mechanism and entry into primary mouse cortical neurons and astrocytes were evaluated. After 23 μmol/kg i.p. bolus injection, the prodrugs' unbound area under the concentration curve in brain was 0.3 nmol/g × min, whereas the parent drugs could not reach the brain. The unbound brain concentrations of the prodrugs after 100 μM in situ mouse brain perfusion were 521.4 ± 46.9 and 126.9 ± 19.9 pmol/g for prodrugs 1 and 2, respectively. The combination of competing transporter substrates for LAT1, l-tryptophan, and for organic anion transporting polypeptides, probenecid, decreased the brain concentrations to 352.4 ± 44.5 and 70.9 ± 7.0 pmol/g, respectively. In addition, in vitro uptake studies showed that at 100 μM prodrug 1 had 3.4-fold and 4.5-fold higher uptake rate into neurons and astrocytes, respectively, compared to its parent drug. Thus, the prodrugs enhance significantly the therapeutic potential of the parent drugs for the treatment of disorders of central nervous system in which neuroinflammation is involved.

show abstract

“…Along these lines, several different prodrugs based on drug-amino acid conjugates have been reported targeting such receptors allowing enhanced cell permeability profile. [25][26][27][28][29] Given the facts that:…”

Section: Introductionmentioning

confidence: 99%

Rational design and structure–activity relationship studies of quercetin–amino acid hybrids targeting the anti-apoptotic protein Bcl-xL

et al. 2017

View full text Add to dashboard Cite

Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein. IFD calculations determined their binding cavity while Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalised Born Surface Area (MM-GBSA) calculations provided an insight into the binding enthalpies of the analogues. The quercetin analogues were synthesized and their binding to Bcl-xL was verified with fluorescence spectroscopy. The binding affinity and the thermodynamic parameters between Bcl-xL and quercetin-glutamic acid were estimated through Isothermal Titration Calorimetry. 2D H-N HSQC NMR chemical shift perturbation mapping was used to chart the binding site of the quercetin analogues in the Bcl-xL that overlapped with the predicted poses generated by both IFD and MD calculations. Furthermore, evaluation of the four conjugates against the prostate DU-145 and PC-3 cancer cell lines, revealed quercetin-glutamic acid and quercetin-alanine as the most potent conjugates bearing the higher cytostatic activity. This pinpoints that the chemical space of natural products can be tailored to exploit new hits for difficult tractable targets such as protein-protein interactions.

show abstract

l -Type amino acid transporter 1 (lat1)-mediated targeted delivery of perforin inhibitors

Cited by 35 publications

References 43 publications

Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids

Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids

Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

Rational design and structure–activity relationship studies of quercetin–amino acid hybrids targeting the anti-apoptotic protein Bcl-xL

Contact Info

Product

Resources

About