Atorvastatin-Loaded Peptide Amphiphiles Against Corneal Neovascularization

Sánchez-López, Elena; Gómara, Maria José; Haro, Isabel

doi:10.2217/nnm-2023-0133

Cited by 4 publications

(3 citation statements)

References 48 publications

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“…However, Tat technology did not translate into a clinical application due to the ubiquitous transduction of multiple tissue types, including neuronal tissue with crossing of the blood–brain barrier. These hurdles were initially ameliorated by topical use of Tat conjugated to a therapeutic [ 25 , 26 , 27 ], or in a compartment-restricted manner such as intra-articular [ 28 , 29 , 30 ] or intra-ocular administration [ 31 , 32 , 33 ]. Another use of non-specific CPP was the use of activatable peptides given a certain tissue milieu in oncological applications [ 34 , 35 , 36 , 37 , 38 ] or enzyme-activatable cell penetrating peptides [ 39 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Toxicity Studies of Cardiac-Targeting Peptide Reveal a Robust Safety Profile

Sahagun,

Lopuszynski,

Feldman

et al. 2024

Pharmaceutics

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Targeted delivery of therapeutics specifically to cardiomyocytes would open up new frontiers for common conditions like heart failure. Our prior work using a phage display methodology identified a 12-amino-acid-long peptide that selectively targets cardiomyocytes after an intravenous injection in as little as 5 min and was hence termed a cardiac-targeting peptide (CTP: APHLSSQYSRT). CTP has been used to deliver imaging agents, small drug molecules, photosensitizing nanoparticles, exosomes, and even miRNA to cardiomyocytes. As a natural extension to the development of CTP as a clinically viable cardiac vector, we now present toxicity studies performed with the peptide. In vitro viability studies were performed in a human left ventricular myocyte cell line with 10 µM of Cyanine-5.5-labeled CTP (CTP-Cy5.5). In vitro ion channel profiles were completed for CTP followed by extensive studies in stably transfected cell lines for several GPCR-coupled receptors. Positive data for GPCR-coupled receptors were interrogated further with RT-qPCRs performed on mouse heart tissue. In vivo studies consisted of pre- and post-blood pressure monitoring acutely after a single CTP (10 mg/Kg) injection. Further in vivo toxicity studies consisted of injecting CTP (150 µg/Kg) in 60, 6-week-old, wild-type CD1, male/female mice (1:1), with cohorts of mice euthanized on days 0, 1, 2, 7, and 14 with inhalational CO2, followed by blood collection via cardiac puncture, complete blood count analysis, metabolic profiling, and finally, liver, renal, and thyroid studies. Lastly, mouse cardiac MRI was performed immediately before and after CTP (150 µg/Kg) injection to assess changes in cardiac size or function. Human left ventricular cardiomyocytes showed no decrease in viability after a 30 min incubation with CTP-Cy5.5. No significant activation or inhibition of any of seventy-eight protein channels was observed other than OPRM1 and COX2 at the highest tested concentration, neither of which were expressed in mouse heart tissue as assessed using RT-qPCR. CTP (10 mg/Kg) injections led to no change in blood pressure. Blood counts and chemistries showed no evidence of significant hematological, hepatic, or renal toxicities. Lastly, there was no difference in cardiac function, size, or mass acutely in response to CTP injections. Our studies with CTP showed no activation or inhibition of GPCR-associated receptors in vitro. We found no signals indicative of toxicity in vivo. Most importantly, cardiac functions remained unchanged acutely in response to CTP uptake. Further studies using good laboratory practices are needed with prolonged, chronic administration of CTP conjugated to a specific cargo of choice before human studies can be contemplated.

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Section: Discussionmentioning

confidence: 99%

Toxicity Studies of Cardiac-Targeting Peptide Reveal a Robust Safety Profile

Sahagun,

Lopuszynski,

Feldman

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…However, Tat technology did not translate into a clinical application due to the ubiquitous transduction of multiple tissue types, including neuronal tissue with crossing of the blood-brain barrier. These hurdles were initially ameliorated by topical use of Tat conjugated to a therapeutic [19][20][21], or in a compartment-restricted manner such as intra-articular [22], or intra-ocular administration [23][24][25]. Another use of non-specific CPP was use of activatable peptides given a certain tissue milieu in oncological applications [26].…”

Section: Discussionmentioning

confidence: 99%

Toxicity Studies of Cardiac Targeting Peptide Reveal a Robust Safety Profile

Sahagun,

Lopuszynski,

Feldman

et al. 2023

Preprint

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Despite great strides in diagnosis and treatment, cardiac diseases remain the number one cause of mortality in the developed world, with rates catching up at an alarming rate in the developing world. Targeted delivery of therapeutics, specifically to cardiomyocytes, would open up new frontiers. Our prior work using a combinatorial in vitro and in vivo phage display methodology identified a 12-amino acid long peptide that targets cardiomyocytes selectively after an intravenous injection in as little as 5 mins, and hence was termed cardiac targeting peptide (CTP: APHLSSQYSRT). CTP has been used to deliver imaging agents, small drug molecules, photosensitizing nanoparticles, exosomes, and even miRNA to cardiomyocytes. As a natural extension for development of CTP as a clinically viable cardiac vector, we now present toxicity studies performed on the peptide. In vitro viability studies were performed in a human left ventricular myocyte cell line with 10µM of Cyanine-5.5 labeled CTP (CTP-Cy5.5). In vitro ion channel profiles were completed for CTP followed by more extensive studies performed by Eurofins in stably transfected cell lines for an extensive list of GPCR-coupled receptors. Positive data for GPCR-coupled receptors was interrogated further with RT-qPCRs performed on mouse heart tissue. In vivo studies consisted of pre- and post-blood pressure monitoring acutely after a single CTP (10 mg/Kg) injection. Further in vivo toxicity studies consisted of injecting 60, 6-week-old, wild-type CD1, male/female mice (1:1) injected with CTP (150 µg/Kg) intravenously. Mice were weighed immediately before injections and daily thereafter. Cohorts of mice were euthanized on day 0, 1, 2, 7 and 14 with inhalational CO2, followed by opening of the chest cavity, collection of blood via cardiac puncture, complete blood count analysis, metabolic profiling, and finally, liver, renal and thyroid studies. Lastly, mouse cardiac MRI was performed immediately before and after injections of CTP (150 µg/Kg) to assess changes in cardiac size or function. Human left ventricular cardiomyocytes showed no decrease in viability after a 30 min incubation with CTP-Cy5.5. In the Eurofins Cardiac Profiler Qube, no significant activation or inhibition of any of seventy-eight protein channels was observed other than OPRM1 and COX2 at the highest tested concentration, neither of which were expressed in mouse heart tissue as assessed by RT-qPCR. There was no change in blood pressures before and after injections with CTP at 10 mg/Kg. Blood counts and chemistries showed no evidence of significant hematological, hepatic or renal toxicities. Lastly, there was no significant difference in cardiac function, size or mass before and after CTP injections. Our studies with CTP showed no activation or inhibition of GPCR-associated receptors in vitro. We found no signals indicative of toxicity in vivo. Most importantly, cardiac functions remained unchanged acutely in response to CTP uptake. Further studies, in good laboratory practices fashion, are needed with more prolonged, chronic administration of CTP conjugated to a specific cargo of choice before human studies can be contemplated.

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“…Additionally, aganirsen is an antisense oligonucleotide and, unlike other agents, has FDA orphan drug designation to prevent corneal graft rejection; current phase III study results have suggested a significant inhibition of keratitis-induced corneal NV [65]. Targeted immunotherapy is a rapidly developing field with additional targets and delivery methods being considered, including nanoplatforms, atorvastatin-loaded peptide amphiphiles, and fenofibrate targeting the PPARα signaling pathway [66 ▪ ,67,68 ▪ ].…”

Section: Medical Therapiesmentioning

confidence: 99%

Current trends in the management of corneal neovascularization

Rangu,

Dang,

Riaz

2024

Current Opinion in Ophthalmology

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Purpose of review The aim of this study was to highlight recent developments in the medical and surgical management of corneal neovascularization (NV). Recent findings Improved understanding and diagnostic criteria among clinicians have led to advancements in the characterization of corneal NV and objective assessment of treatment response through ancillary imaging devices. Developments in corneal NV treatments, such as antivascular endothelial growth factor, fine needle diathermy, and photodynamic therapy, have improved treatment success rates and visual outcomes. More recent surgical treatment advancements include corneal cross-linking, endothelial keratoplasty, and mitomycin intravascular chemoembolization. Finally, a greater appreciation of the molecular pathogenesis and angiogenic factors involved in corneal NV has identified numerous potential targeted therapies in the future. Summary The management of corneal NV has evolved to include several standalone and combination medical and surgical options. Additionally, improvements in quantifying corneal NV and understanding its molecular basis have contributed to new management strategies with improved outcomes.

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Atorvastatin-Loaded Peptide Amphiphiles Against Corneal Neovascularization

Cited by 4 publications

References 48 publications

Toxicity Studies of Cardiac-Targeting Peptide Reveal a Robust Safety Profile

Toxicity Studies of Cardiac-Targeting Peptide Reveal a Robust Safety Profile

Toxicity Studies of Cardiac Targeting Peptide Reveal a Robust Safety Profile

Current trends in the management of corneal neovascularization

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