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Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations
PURPOSE: The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic-co-glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818879/ https://www.ncbi.nlm.nih.gov/pubmed/29497292 http://dx.doi.org/10.2147/IJN.S157391 |
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author | Kumar, Pranesh Singh, Ashok K Raj, Vinit Rai, Amit Keshari, Amit K Kumar, Dinesh Maity, Biswanath Prakash, Anand Maiti, Sabyasachi Saha, Sudipta |
author_facet | Kumar, Pranesh Singh, Ashok K Raj, Vinit Rai, Amit Keshari, Amit K Kumar, Dinesh Maity, Biswanath Prakash, Anand Maiti, Sabyasachi Saha, Sudipta |
author_sort | Kumar, Pranesh |
collection | PubMed |
description | PURPOSE: The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic-co-glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti-hepatocellular carcinoma (HCC) activity with parent B. METHODS: BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes. RESULTS: Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential −0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (≥80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t(1/2)), a higher maximum plasma concentration (C(max)) and took longer to reach the maximum plasma concentration (T(max)) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8. CONCLUSION: The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment. |
format | Online Article Text |
id | pubmed-5818879 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58188792018-03-01 Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations Kumar, Pranesh Singh, Ashok K Raj, Vinit Rai, Amit Keshari, Amit K Kumar, Dinesh Maity, Biswanath Prakash, Anand Maiti, Sabyasachi Saha, Sudipta Int J Nanomedicine Original Research PURPOSE: The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic-co-glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti-hepatocellular carcinoma (HCC) activity with parent B. METHODS: BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes. RESULTS: Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential −0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (≥80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t(1/2)), a higher maximum plasma concentration (C(max)) and took longer to reach the maximum plasma concentration (T(max)) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8. CONCLUSION: The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment. Dove Medical Press 2018-02-16 /pmc/articles/PMC5818879/ /pubmed/29497292 http://dx.doi.org/10.2147/IJN.S157391 Text en © 2018 Kumar et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Kumar, Pranesh Singh, Ashok K Raj, Vinit Rai, Amit Keshari, Amit K Kumar, Dinesh Maity, Biswanath Prakash, Anand Maiti, Sabyasachi Saha, Sudipta Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
title | Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
title_full | Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
title_fullStr | Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
title_full_unstemmed | Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
title_short | Poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
title_sort | poly(lactic-co-glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818879/ https://www.ncbi.nlm.nih.gov/pubmed/29497292 http://dx.doi.org/10.2147/IJN.S157391 |
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