Augmented Anticancer Efficacy of Doxorubicin-Loaded Polymeric Nanoparticles after Oral Administration in a Breast Cancer Induced Animal Model (original) (raw)
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Journal of Chromatography B, 2012
The long-term clinical use of doxorubicin (Dox), one of the most important anticancer agent in use, is limited by dose-related acute cardiotoxicity, myelo-suppression and multidrug resistance developed by cancer cells. To improve the antitumor efficacy and reduce the toxicity of Dox, many drug delivery systems have been developed, including poly(alkylcyanoacrylate) (PACA) nanoparticles. A new formulation of PACA nanoparticles with potential stealth properties were prepared by redox radical emulsion polymerization and associated to Dox in our laboratory. To comparatively investigate the pharmacokinetics and the biodistribution of different formulations of Dox associated PACA nanoparticles, a simple and rapid high performance liquid chromatographic method (HPLC) was developed for the quantification of Dox in plasma and tissues of rats treated with Dox loaded PACA nanoparticle (Dox-PACA). Dox was eluted at 4.4 min and it was well separated from its main metabolites doxorubicinol (Doxl) and doxorubicinon (Doxon) and idarubicin (Ida) used as internal standard (IS). Extraction of Dox from biological media was achieved by liquid-liquid extraction. The recovery of total Dox (i.e. free Dox and Dox associated with nanoparticles) from plasma and tissues (liver, spleen and heart) spiked with Dox-PACA were 71 and 78% for 0.05 and 1 g/mL in rat plasma, respectively, and 73% and 80% for 0.5 and 10 g/g in tissues, respectively. The method is linear from 0.05 to 1.5 g/mL of Dox in plasma. The limit of detection of the method is 0.5 ng of Dox per injection (50 L). The between-day and within-day precisions of the method were 97.1-102.9% and 97.3-101.7% for concentrations ranging from 0.05 to 1 g/mL, respectively. Preliminary data suggested that this method can be applied to determine the pharmacokinetic and biodistribution of Dox associated with PACA nanoparticles after intravenous administration to rats.
A Novel Strategy for the Delivery of Doxorubicin to Reduce Cardiotoxicity
Pharmacy & Pharmacology International Journal, 2016
Doxorubicin (DOX) is an effective anticancer drug but its effectiveness is limited due to their toxicities after long term use required in cancer chemotherapy which leads to damage of the cardiac muscles and may be irreversible in nature. The approach based on novel drug delivery system gives the new hopes and ray of light to overcome the problems associated with the Dox as well as other anticancer drugs. In present research paper the DOX bearing nano-aggregates (DN) and folic acid conjugated DOX bearing nano-aggregates (FDN) were prepared to increase the therapeutics index of drug by enhancing the drug concentration at target site and avoiding their effect or by passing the healthy organ and cells. In present study PLGA-PEG block polymeric system was synthesized by ring opening polymerization techniques using NHS and then conjugated with DOX. The synthesis of F-PEG-PLGA-DOX was confirmed by 1H-nuclear magnetic resonance (NMR). Prepared nano-aggregates of DOX were studied for particle size, entrapment efficiency, in-vitro and in-vivo studies. The size of DN was found to be 135±0.6 nm whereas slightly increased size i.e. 141±0.8 nm was found in case of FDN. The %entrapment efficiency was found to be 79.3±0.5% and 71.7±0.5% of DN and FDN respectively. The in-vitro drug release studies show initially fast release of drug for 10 h. The in-vivo biodistribution studies showed the lesser uptake of DOX in heart in case of nano-aggregates formulation (DN and FDN) as compare to plain DOX after i.v. administration. This may be due to less concentration of free drug available for the absorption by the organ, which indirectly indicated that the drug may be available for targeting to the cancer cells via receptor mediated endocytosis due to the presence of folic acid with the nano-aggregates.
2004
The aim of the study is to determine and compare the pharmacokinetics and tissue distribution of Doxorubicin (Dox) delivered as solution or through nanoparticles after intravenous (i.v.) and intraperitoneal (i.p.) injection. Doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles were synthesized by dispersion polymerization (DP) and emulsion polymerization (EP) techniques. The drug loaded DP and EP nanoparticles were administered by i.v. or i.p. routes and the respective pharmacokinetics and tissue distribution were determined. Both types of nanoparticles significantly enhanced the elimination half-life (T 1/2 ), mean residence time (MRT) AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox in blood after i.v. injection. Dox delivered through DP nanoparticles rapidly disappeared from blood and distributed to the organs of reticuloendothelial system (RES). But, the clearance of Dox delivered through EP nanoparticles from blood was slower than this of the DP nanoparticles and Dox solution. After i.p. injection, the Dox loaded into DP nanoparticles quickly appeared in blood and undergone rapid distribution to the organs of RES, while the Dox loaded into EP nanoparticles absorbed slowly into blood and remained in the circulation for longer time. The absorption into blood of Dox delivered through DP and EP nanoparticles after i.p. injection was relatively rapid and higher than Dox solution. The T 1/2 , MRT, AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox in blood were significantly higher and the clearance (Cl) was lower than for the Dox solution after i.p. injection. The tissue concentrations of Dox delivered through nanoparticles after i.p. injection were significantly lower than after i.v. injection. The bioavailability (F) of Dox was greatly enhanced by DP (∼1.9 fold) and EP nanoparticles (∼2.12 fold) compared to Dox solution after i.p. injection. EP nanoparticles significantly enhanced the bioavailability, MRT, T 1/2 , AUC 0-8 , AUC 0-∞ and AUMC 0-8 of Dox than DP nanoparticles. This signifies the advantage of EP nanoparticles in increasing the elimination half-life of Dox both after i.v. and i.p. injection and enhanced bioavailability after i.p. injection, which is expected to improve the therapeutic efficacy of Dox and reduce the Dox-associated systemic toxicity. Importantly, both DP and EP nanoparticles greatly reduced the distribution of Dox to heart both after i.v. and i.p. injection, suggesting their potential in reducing Dox-associated cardiotoxicity.
Background and Aims: Doxorubicin is a potent anticancer drug and a major limiting factor that hinders therapeutic use as its high levels of systemic circulation often associated with various off-target effects, particularly cardiotoxicity. The present study focuses on evaluation of the efficacy of doxorubicin when it is loaded into the protein nanoparticles and delivered intravenously in rats bearing Hepatocellular carcinoma (HCC). The proteins selected as carrier were Apotransferrin and Lactoferrin, since the receptors for these two proteins are known to be over expressed on cancer cells due to their iron transport capacity.
Journal of Nanoparticle Research, 2013
We investigated the bioavailability, efficacy, and toxicity of doxorubicin-loaded solid lipid nanoparticles (DOX-SLNs) prepared by a simple modified double-emulsification method. A 3-factor, 3-level Box-Behnken statistical design was adopted in the optimization of DOX-SLN formulation considering dependent factors particle size and entrapment efficiency. Optimized SLN formulation composed of lipid (2 %) consisting of soya lecithin and Precirol ATO 5 (1:3) with Pluronic F68 (0.3 %) resulted in 217.36 ± 3.31 nm particle size and 59.45 ± 1.75 % entrapment efficiency. DOX-SLN exhibited significant enhancement (p \ 0.05) in bioavailability as compared with free DOX in Sprague-Dawley (SD) rats. DOX-SLN exhibited higher peak plasma concentration (6.761 ± 0.08 vs. 2.412 ± 0.04 lg/ml), increased AUC (61.368 ± 3.54 vs. 5.812 ± 0.49 lg/ml h), decreased clearance (36 ± 0.01 vs. 619 ± 0.005 mL/h kg), and volume of distribution (733 ± 0.092 vs. 2,064 ± 0.061 mL/kg) when compared to free DOX. The collective results of cardiac and kidney enzyme assay, antioxidant enzyme levels, hematological parameters, effect on body weight and tumor volume, tumor necrosis factor-a level, histopathological examination, and survival analysis confirmed the improved efficacy and safety profile of DOX-SLN in 7,12-dimethyl benzanthracene-induced breast cancer in SD rats. Keywords Doxorubicin Á Solid lipid nanoparticles Á Box-Behnken design Á Pharmacokinetics Á Efficacy Á Toxicity Á Health and safety effects Electronic supplementary material The online version of this article (
Pharmaceutics, 2021
In this report, we investigated whether the use of chitosan-carrying-glutathione nanoparticles (CH-GSH NPs) can modify proliferation and apoptosis, and reduce cell damage induced by doxorubicin on breast cancer cells. Doxorubicin is a widely used antineoplasic agent for the treatment of various types of cancer. However, it is also a highly toxic drug because it induces oxidative stress. Thus, the use of antioxidant molecules has been considered to reduce the toxicity of doxorubicin. CH-GSH NPs were characterized in size, zeta potential, concentration, and shape. When breast cancer cells were treated with CH-GSH nanoparticles, they were localized in the cellular cytoplasm. Combined doxorubicin exposure with nanoparticles increased intracellular GSH levels. At the same time, decreasing levels of reactive oxygen species and malondialdehyde were observed and modified antioxidant enzyme activity. Levels of the Ki67 protein were evaluated as a marker of cell proliferation and the activity...
Nitric oxide-releasing nanoparticles improve doxorubicin anticancer activity
International Journal of Nanomedicine, 2018
Anticancer drug delivery systems are often limited by hurdles, such as off-target distribution, slow cellular internalization, limited lysosomal escape, and drug resistance. To overcome these limitations, we have developed a stable nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle (SMA-Dox) carrier. Materials and methods: Effects of SMA-tDodSNO and/or in combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial membrane potential, lysosomal membrane permeability, tumor tissue, and tumor growth were studied using in vitro and in vivo model of triple-negative breast cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination with SMA-tDodSNO were measured in cells and tumor tissues. Results: Combination of SMA-tDodSNO and Dox synergistically decreased cell viability and induced apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 µM) significantly enhanced the cellular uptake of SMA-Dox and increased Dox concentration in the cells resulting in a twofold increase (P,0.001). Lysosomal membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 40 µM SMA-tDodSNO (P,0.05 vs control) and when combined with SMA-Dox, this effect was significantly potentiated (P,0.001 vs SMA-Dox). Subcutaneous administration of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the control group. SMA-tDodSNO in combination with SMA-Dox resulted in a statistically significant 4.7-fold reduction in the tumor volume (P,0.001 vs control), without causing significant toxicity as monitored through body weight loss. Conclusion: Taken together, these results suggest that SMA-tDodSNO can be used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a model of TNBC.
Preparation, Characterization and In-vitro Cytotoxic Study of Doxorubicin PLGA Nanoparticles
UK Journal of Pharmaceutical Biosciences, 2013
In the current study we had developed and characterized Poly (lactic-co-glycolide) acid nanoparticles for anticancer drug Doxorubicin and further studied in-vitro cytotoxic effect of free and encapsulated nanoparticle drug delivery system. PLGA-drug nanoparticles were prepared by oil-water emulsion solvent evaporation method. The morphology of drug loaded nanoparticles was analyzed using a scanning electron microscope. The drug loaded nanoparticles were evaluated for cell cytotoxicity by sulforhodamine B assay. Images of formulation indicate the surface morphology of formulation. The in vitro cytotoxicity results showed Doxorubicin NPs to be active against A431 and NCI-H322 cell line compared to Doxorubicin free drug. The IC50 values were found to be 1.73 µM with A431 cell line whereas 1.64 µM for NCI-H322 cell line. This indicates that Doxorubicin NPs have more pronounced activity towards A431cell line.
Research Square (Research Square), 2021
Extensive studies have been conducted on natural materials due to their unique and biodegradable properties for oral drug delivery. In the current research, we fabricated sodium caseinate nanomicelles (NaCNs) using casein as a natural polymer to develop a controlled-release oral drug delivery system. NaCNs was explored to improve the therapeutic potential of Doxorubicin (DOX) with reduced toxicity in healthy organs. The synthesized and thoroughly characterized DOX-loaded NaCNs were subjected to in vivo anti-tumour evaluation and bio-distribution analysis in a 4T1-induced breast cancer model. Our ndings indicated an almost eight-fold reduction in tumour size in the group orally treated with DOX-NaCNs when compared to free DOX. It is plausible that the enhanced anti-tumour effects of oral DOX-NaCNs is related to the controlled release of DOX from the delivery system as well as the longer circulatory time of the drug in the blood, as con rmed by the bio-distribution study, when compared with free DOX and the intravenous formulation of DOX-NaCNs. Additionally, the tumour drug accumulation for the orally administered DOX-NaCNs was 1.27-and 6.8-fold higher than that of the intravenously administered DOX-NaCNs and free DOX, respectively and overall, was 8.34-times higher than the orally administered free DOX. In comparison, the orally administered DOX-NaCNs showed signi cant reduction in tumour size (5.66 ± 4.36mm 3) after the two doses as compared to intravenously administered DOX-NaCNs (10.29 ± 4.86 mm 3) on day 17 of the experimental period. Moreover, NaCNs were well tolerated in the mice at a single dose of 2,000 mg/kg in an acute oral toxicity study. Moreover, no signi cant change in the body weight was observed after treatment with the single dose of NaCNs when compared to the control group. Thus, NaCNs emerge as a safe and non-toxic delivery system with excellent biodistribution pro le and high anti-tumour effects that present as a potential option for oral chemotherapy.
2018
Solid lipid nanoparticles carrying lipophilic derivatives of doxorubicin: preparation, characterization, and in vitro cytotoxicity studies / Peira, Elena; Chirio, Daniela; Battaglia, Luigi; Barge, Alessandro; Chegaev, Konstantin; Gigliotti, Casimiro Luca; Ferrara, Benedetta; Dianzani, Chiara; Gallarate, Marina. In: JOURNAL OF MICROENCAPSULATION. ISSN 0265-2048. 33:4(2016), pp. 381-390. Original Citation: Solid lipid nanoparticles carrying lipophilic derivatives of doxorubicin: preparation, characterization, and in vitro cytotoxicity studies