Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia
Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted consi...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Salaheldin, Taher A. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022transfer abstract |
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| Übergeordnetes Werk: |
Enthalten in: Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu - Shen, Zhen ELSEVIER, 2022, New York, NY |
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| Übergeordnetes Werk: |
volume:40 ; year:2022 ; pages:0 |
| Links: |
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| DOI / URN: |
10.1016/j.nano.2021.102480 |
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| 245 | 1 | 0 | |a Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia |
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| 520 | |a Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. | ||
| 520 | |a Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. | ||
| 700 | 1 | |a Godugu, Kavitha |4 oth | |
| 700 | 1 | |a Bharali, Dhruba J. |4 oth | |
| 700 | 1 | |a Fujioka, Kazutoshi |4 oth | |
| 700 | 1 | |a Elshourbagy, Nabil |4 oth | |
| 700 | 1 | |a Mousa, Shaker A. |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier |a Shen, Zhen ELSEVIER |t Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu |d 2022 |g New York, NY |w (DE-627)ELV008639612 |
| 773 | 1 | 8 | |g volume:40 |g year:2022 |g pages:0 |
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10.1016/j.nano.2021.102480 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001690.pica (DE-627)ELV056950195 (ELSEVIER)S1549-9634(21)00123-4 DE-627 ger DE-627 rakwb eng 333.7 570 690 VZ BIODIV DE-30 fid 48.00 bkl Salaheldin, Taher A. verfasserin aut Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Godugu, Kavitha oth Bharali, Dhruba J. oth Fujioka, Kazutoshi oth Elshourbagy, Nabil oth Mousa, Shaker A. oth Enthalten in Elsevier Shen, Zhen ELSEVIER Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu 2022 New York, NY (DE-627)ELV008639612 volume:40 year:2022 pages:0 https://doi.org/10.1016/j.nano.2021.102480 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA SSG-OPC-FOR 48.00 Land- und Forstwirtschaft: Allgemeines VZ AR 40 2022 0 |
| spelling |
10.1016/j.nano.2021.102480 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001690.pica (DE-627)ELV056950195 (ELSEVIER)S1549-9634(21)00123-4 DE-627 ger DE-627 rakwb eng 333.7 570 690 VZ BIODIV DE-30 fid 48.00 bkl Salaheldin, Taher A. verfasserin aut Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Godugu, Kavitha oth Bharali, Dhruba J. oth Fujioka, Kazutoshi oth Elshourbagy, Nabil oth Mousa, Shaker A. oth Enthalten in Elsevier Shen, Zhen ELSEVIER Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu 2022 New York, NY (DE-627)ELV008639612 volume:40 year:2022 pages:0 https://doi.org/10.1016/j.nano.2021.102480 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA SSG-OPC-FOR 48.00 Land- und Forstwirtschaft: Allgemeines VZ AR 40 2022 0 |
| allfields_unstemmed |
10.1016/j.nano.2021.102480 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001690.pica (DE-627)ELV056950195 (ELSEVIER)S1549-9634(21)00123-4 DE-627 ger DE-627 rakwb eng 333.7 570 690 VZ BIODIV DE-30 fid 48.00 bkl Salaheldin, Taher A. verfasserin aut Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Godugu, Kavitha oth Bharali, Dhruba J. oth Fujioka, Kazutoshi oth Elshourbagy, Nabil oth Mousa, Shaker A. oth Enthalten in Elsevier Shen, Zhen ELSEVIER Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu 2022 New York, NY (DE-627)ELV008639612 volume:40 year:2022 pages:0 https://doi.org/10.1016/j.nano.2021.102480 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA SSG-OPC-FOR 48.00 Land- und Forstwirtschaft: Allgemeines VZ AR 40 2022 0 |
| allfieldsGer |
10.1016/j.nano.2021.102480 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001690.pica (DE-627)ELV056950195 (ELSEVIER)S1549-9634(21)00123-4 DE-627 ger DE-627 rakwb eng 333.7 570 690 VZ BIODIV DE-30 fid 48.00 bkl Salaheldin, Taher A. verfasserin aut Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Godugu, Kavitha oth Bharali, Dhruba J. oth Fujioka, Kazutoshi oth Elshourbagy, Nabil oth Mousa, Shaker A. oth Enthalten in Elsevier Shen, Zhen ELSEVIER Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu 2022 New York, NY (DE-627)ELV008639612 volume:40 year:2022 pages:0 https://doi.org/10.1016/j.nano.2021.102480 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA SSG-OPC-FOR 48.00 Land- und Forstwirtschaft: Allgemeines VZ AR 40 2022 0 |
| allfieldsSound |
10.1016/j.nano.2021.102480 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001690.pica (DE-627)ELV056950195 (ELSEVIER)S1549-9634(21)00123-4 DE-627 ger DE-627 rakwb eng 333.7 570 690 VZ BIODIV DE-30 fid 48.00 bkl Salaheldin, Taher A. verfasserin aut Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia 2022transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. 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Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. |
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Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. |
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Proprotein convertase subtilisin/kexin type 9 is a protease enzyme secreted by liver that downregulates hepatic low-density lipoprotein receptor (LDLR) by binding and chaperoning LDLR to lysosomes for degradation, causing hypercholesteremia. The development of anti-PCSK9 therapeutics attracted considerable attention for the management of cardiovascular disease risk. However, only subcutaneous injectable PCSK9 monoclonal antibodies have been FDA approved. Oral administration of small-molecule PCSK9 inhibitors has the potential to become a practical therapeutic option if achievable. In the present work, we used nanotechnological approaches to develop the first small oral molecule nano-hepatic targeted anti-PCSK9. Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist. |
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Using high-throughput optimization and a series of evaluations, a stable water-dispersible 150-200 nm nano-encapsulated drug (named P-4) conjugated with hepatic targeting moiety was synthesized and characterized (named P-21). Pharmacodynamic (PD), pharmacokinetic (PK) and bioavailability studies were conducted using a high fat diet nutritionally induced hypercholesterolemia mouse model to evaluate the efficacy of P-21 as an anti-PCSK9 LDL-cholesterol lowering hepatic targeted nanodrug. The PD results demonstrate that P-21 in a dose-dependent manner is highly effective in lowering LDL-C by 50-90%. PK results show the maximum plasma concentration (Cmax ) of P-4 was observed after 30 min of administration with 31% oral bioavailability and had a sustained longer half-life up to 24 h. In vivo safety studies in rats showed no apparent adverse effects, normal chemical biomarkers and normal histopathological findings in all P-21 treated groups at different escalating doses. Compared to the FDA-approved monoclonal antibodies, P-21 offers a more efficient, and practical treatment protocol for targeting uncontrolled hypercholesterolemia in reducing the risk of cardiovascular diseases. The present study introduced a nano-targeted drug delivery approaches for PCSK9/LDLR antagonist.</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Godugu, Kavitha</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bharali, Dhruba J.</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fujioka, Kazutoshi</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Elshourbagy, Nabil</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Mousa, Shaker A.</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Elsevier</subfield><subfield code="a">Shen, Zhen ELSEVIER</subfield><subfield code="t">Similar assembly mechanisms but distinct co-occurrence patterns of free-living vs. particle-attached bacterial communities across different habitats and seasons in shallow, eutrophic Lake Taihu</subfield><subfield code="d">2022</subfield><subfield code="g">New York, NY</subfield><subfield code="w">(DE-627)ELV008639612</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:40</subfield><subfield code="g">year:2022</subfield><subfield code="g">pages:0</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.nano.2021.102480</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OPC-FOR</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">48.00</subfield><subfield code="j">Land- und Forstwirtschaft: Allgemeines</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">40</subfield><subfield code="j">2022</subfield><subfield code="h">0</subfield></datafield></record></collection>
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