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Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells.

Tran TH, Ramasamy T, Choi JY, Nguyen HT, Pham TT, Jeong JH, Ku SK, Choi HG, Yong CS, Kim JO - Int J Nanomedicine (2015)

Bottom Line: The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX.The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice.The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Yeungnam University, Dae-Dong, South Korea.

ABSTRACT
The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH) nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX) was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp) using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH) nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.

No MeSH data available.


Related in: MedlinePlus

In vivo antitumor activity in SCC-7 bearing nude mice treated with free DTX (○) or DTX-LPH nanoparticles (■).Notes: (A) Tumor growth curves showing changes in tumor volume *P<0.05, **P<0.01. The downward arrow represents administration time points. (B) Alteration in body weight of SCC-7 bearing nude mice. (C) Representative histopathological images of tumor mass were examined by hematoxylin and eosin staining. (D) Immunohistochemical images of representative tumor tissues stained with Caspase-3 and PARP antibody. Scale bars = 120 μm.Abbreviations: DTX, docetaxel; DTX-LPH, docetaxel-loaded lipid polymer hybrid; H&E, hematoxylin and eosin; PARP, poly ADP ribose polymerase.
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f8-ijn-10-5249: In vivo antitumor activity in SCC-7 bearing nude mice treated with free DTX (○) or DTX-LPH nanoparticles (■).Notes: (A) Tumor growth curves showing changes in tumor volume *P<0.05, **P<0.01. The downward arrow represents administration time points. (B) Alteration in body weight of SCC-7 bearing nude mice. (C) Representative histopathological images of tumor mass were examined by hematoxylin and eosin staining. (D) Immunohistochemical images of representative tumor tissues stained with Caspase-3 and PARP antibody. Scale bars = 120 μm.Abbreviations: DTX, docetaxel; DTX-LPH, docetaxel-loaded lipid polymer hybrid; H&E, hematoxylin and eosin; PARP, poly ADP ribose polymerase.

Mentions: The in vivo antitumor efficacy of DTX-LPH was examined in SCC-7 tumor cell-bearing xenograft mice (Figure 8A). As shown, free DTX had limited influence on tumor growth, while DTX-LPH most effectively reduced tumor volume. This enhanced antitumor effect of DTX-LPH was attributed to multiple factors including sustained drug release and prolonged circulation in the bloodstream, which resulted in higher accumulation of drug in the tumor via enhanced permeability and retention effect. Importantly, the P-gp inhibitory property of TPGS might enhance the absorption of drugs by effectively reducing P-gp-mediated drug removal. The toxicity of the formulations was assessed by measuring the change in the body weight (Figure 8B). DTX-LPH did not reduce the body weight of experimental mice, whereas mice treated with free DTX underwent a weight loss of ~20% indicating a severe drug-induced toxicity. This observation indicated that the drug-related toxicity could be overcome when the drugs were encapsulated into LPH nanoparticles.19


Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells.

Tran TH, Ramasamy T, Choi JY, Nguyen HT, Pham TT, Jeong JH, Ku SK, Choi HG, Yong CS, Kim JO - Int J Nanomedicine (2015)

In vivo antitumor activity in SCC-7 bearing nude mice treated with free DTX (○) or DTX-LPH nanoparticles (■).Notes: (A) Tumor growth curves showing changes in tumor volume *P<0.05, **P<0.01. The downward arrow represents administration time points. (B) Alteration in body weight of SCC-7 bearing nude mice. (C) Representative histopathological images of tumor mass were examined by hematoxylin and eosin staining. (D) Immunohistochemical images of representative tumor tissues stained with Caspase-3 and PARP antibody. Scale bars = 120 μm.Abbreviations: DTX, docetaxel; DTX-LPH, docetaxel-loaded lipid polymer hybrid; H&E, hematoxylin and eosin; PARP, poly ADP ribose polymerase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4552257&req=5

f8-ijn-10-5249: In vivo antitumor activity in SCC-7 bearing nude mice treated with free DTX (○) or DTX-LPH nanoparticles (■).Notes: (A) Tumor growth curves showing changes in tumor volume *P<0.05, **P<0.01. The downward arrow represents administration time points. (B) Alteration in body weight of SCC-7 bearing nude mice. (C) Representative histopathological images of tumor mass were examined by hematoxylin and eosin staining. (D) Immunohistochemical images of representative tumor tissues stained with Caspase-3 and PARP antibody. Scale bars = 120 μm.Abbreviations: DTX, docetaxel; DTX-LPH, docetaxel-loaded lipid polymer hybrid; H&E, hematoxylin and eosin; PARP, poly ADP ribose polymerase.
Mentions: The in vivo antitumor efficacy of DTX-LPH was examined in SCC-7 tumor cell-bearing xenograft mice (Figure 8A). As shown, free DTX had limited influence on tumor growth, while DTX-LPH most effectively reduced tumor volume. This enhanced antitumor effect of DTX-LPH was attributed to multiple factors including sustained drug release and prolonged circulation in the bloodstream, which resulted in higher accumulation of drug in the tumor via enhanced permeability and retention effect. Importantly, the P-gp inhibitory property of TPGS might enhance the absorption of drugs by effectively reducing P-gp-mediated drug removal. The toxicity of the formulations was assessed by measuring the change in the body weight (Figure 8B). DTX-LPH did not reduce the body weight of experimental mice, whereas mice treated with free DTX underwent a weight loss of ~20% indicating a severe drug-induced toxicity. This observation indicated that the drug-related toxicity could be overcome when the drugs were encapsulated into LPH nanoparticles.19

Bottom Line: The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX.The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice.The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Yeungnam University, Dae-Dong, South Korea.

ABSTRACT
The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH) nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX) was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp) using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH) nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.

No MeSH data available.


Related in: MedlinePlus