Enhanced tissue distribution of ritonavir-loaded nanostructured lipid carriers-recommending its dose reduction
© 2023. Controlled Release Society..
Human immunodeficiency virus (HIV) mainly attacks lymphocytes of the human immune system. The untreated infection leads to acquired immune deficiency syndrome (AIDS). Ritonavir (RTV) belongs to protease inhibitors (PIs), the crucial contributors of the combination therapy used in the treatment of HIV that is called highly active antiretroviral therapy (HAART). Formulations targeting the lymphatic system (LS) play a key role in delivering and maintaining therapeutic drug concentrations in HIV reservoirs. In our previous study, we developed RTV-loaded nanostructured lipid carriers (NLCs), which contain the natural antioxidant alpha-tocopherol (AT). In the current study, the cytotoxicity of the formulation was studied in HepG2, MEK293, and H9C2 cell lines. The formulation efficacy to reach the LS was evaluated through a cycloheximide-injected chylomicron flow blockade model in Wistar rats. Biodistribution and toxicity studies were conducted in rodents to understand drug distribution patterns in various organs and to establish the safety profile of the optimized formulation (RTV-NLCs). From the MTT assay, it was found that the cell viability of the formulation is comparable with the pure drug (RTV-API). More than 2.5-folds difference in AUC was observed in animals treated with RTV-NLCs with and without cycloheximide injection. Biodistribution studies revealed higher drug exposure in the lymphoidal organs with the RTV-NLCs. No significant increase in serum biomarkers for hepatotoxicity was observed in rats dosed with the RTV-NLCs. The current study reveals the lymphatic uptake of the RTV-NLCs and their safety in rodents. As the tissue distribution of RTV-NLCs is high, hence re-adjusting the RTV-NLCs dose to get the response equivalent to RTV-API may be more beneficial with respect to its safety and efficacy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 2023 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
|---|---|
| Enthalten in: |
Drug delivery and translational research - 14(2023), 1 vom: 01. Jan., Seite 116-130 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Jitta, Srinivas Reddy [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
98600C0908 |
|---|
| Anmerkungen: |
Date Completed 25.12.2023 Date Revised 25.12.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s13346-023-01386-9 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359041248 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359041248 | ||
| 003 | DE-627 | ||
| 005 | 20231227140840.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s13346-023-01386-9 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1238.xml |
| 035 | |a (DE-627)NLM359041248 | ||
| 035 | |a (NLM)37402943 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Jitta, Srinivas Reddy |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Enhanced tissue distribution of ritonavir-loaded nanostructured lipid carriers-recommending its dose reduction |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.12.2023 | ||
| 500 | |a Date Revised 25.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. Controlled Release Society. | ||
| 520 | |a Human immunodeficiency virus (HIV) mainly attacks lymphocytes of the human immune system. The untreated infection leads to acquired immune deficiency syndrome (AIDS). Ritonavir (RTV) belongs to protease inhibitors (PIs), the crucial contributors of the combination therapy used in the treatment of HIV that is called highly active antiretroviral therapy (HAART). Formulations targeting the lymphatic system (LS) play a key role in delivering and maintaining therapeutic drug concentrations in HIV reservoirs. In our previous study, we developed RTV-loaded nanostructured lipid carriers (NLCs), which contain the natural antioxidant alpha-tocopherol (AT). In the current study, the cytotoxicity of the formulation was studied in HepG2, MEK293, and H9C2 cell lines. The formulation efficacy to reach the LS was evaluated through a cycloheximide-injected chylomicron flow blockade model in Wistar rats. Biodistribution and toxicity studies were conducted in rodents to understand drug distribution patterns in various organs and to establish the safety profile of the optimized formulation (RTV-NLCs). From the MTT assay, it was found that the cell viability of the formulation is comparable with the pure drug (RTV-API). More than 2.5-folds difference in AUC was observed in animals treated with RTV-NLCs with and without cycloheximide injection. Biodistribution studies revealed higher drug exposure in the lymphoidal organs with the RTV-NLCs. No significant increase in serum biomarkers for hepatotoxicity was observed in rats dosed with the RTV-NLCs. The current study reveals the lymphatic uptake of the RTV-NLCs and their safety in rodents. As the tissue distribution of RTV-NLCs is high, hence re-adjusting the RTV-NLCs dose to get the response equivalent to RTV-API may be more beneficial with respect to its safety and efficacy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a Hepatotoxicity | |
| 650 | 4 | |a Lymphatic targeting | |
| 650 | 4 | |a Nanostructured lipid carriers | |
| 650 | 4 | |a Ritonavir | |
| 650 | 4 | |a Tissue distribution | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
| 650 | 7 | |a Cycloheximide |2 NLM | |
| 650 | 7 | |a 98600C0908 |2 NLM | |
| 650 | 7 | |a Lipids |2 NLM | |
| 650 | 7 | |a Drug Carriers |2 NLM | |
| 700 | 1 | |a Salwa |e verfasserin |4 aut | |
| 700 | 1 | |a Bhaskaran, Navya Ajitkumar |e verfasserin |4 aut | |
| 700 | 1 | |a Marques, Shirleen Miriam |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Lalit |e verfasserin |4 aut | |
| 700 | 1 | |a Cheruku, Sri Pragnya |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Vanishree |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Pravesh |e verfasserin |4 aut | |
| 700 | 1 | |a Kulkarni, Onkar Prakash |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Drug delivery and translational research |d 2011 |g 14(2023), 1 vom: 01. Jan., Seite 116-130 |w (DE-627)NLM207177104 |x 2190-3948 |7 nnns |
| 773 | 1 | 8 | |g volume:14 |g year:2023 |g number:1 |g day:01 |g month:01 |g pages:116-130 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s13346-023-01386-9 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 14 |j 2023 |e 1 |b 01 |c 01 |h 116-130 | ||