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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

Optimization of DTX-LPH nanoparticles.Notes: Effect of (A) cationic lipid amount, (B) polyethylene glycol-b-polyaspartic acid concentration, and (C) drug concentration on formulation parameters: particle size, PDI, ZP. (D) Effect of drug concentration on drug entrapment efficiency and loading capacity. (E) Effect of exposed time on zeta potential at pH 5.5. Data are expressed as mean ± SD (n=3).Abbreviations: PDI, polydispersity index; SD, standard deviation; ZP, zeta potential.
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f1-ijn-10-5249: Optimization of DTX-LPH nanoparticles.Notes: Effect of (A) cationic lipid amount, (B) polyethylene glycol-b-polyaspartic acid concentration, and (C) drug concentration on formulation parameters: particle size, PDI, ZP. (D) Effect of drug concentration on drug entrapment efficiency and loading capacity. (E) Effect of exposed time on zeta potential at pH 5.5. Data are expressed as mean ± SD (n=3).Abbreviations: PDI, polydispersity index; SD, standard deviation; ZP, zeta potential.

Mentions: The DTX-LPH nanoparticles were prepared using the emulsification method and subsequently coated with polymer. Figure 1 shows the parameters for the various formulations. We coated the positively charged nanoparticles with PEG-b-PAsp in order to prolong plasma circulation and minimize carrier-mediated toxicity. The deposition of the polyelectrolyte layer on the LPH surface was confirmed by zeta potential experiments that showed charge reversal from highly positive (+41.4±1.3 mV) to negative (−22.6±0.3 mV) values when the polymer layer was added. The optimized DTX-LPH formulation consisted of Capryol 90 (300 mg), TPGS (100 mg), DDAB (5 mg), and DTX (30 mg). This formulation had a particle size of 199.2±15.9 nm with a narrow size distribution (PD =0.277±0.031). DTX-LPH showed high entrapment efficiency (91.4%) as well as LC (6.9%), indicating suitability for therapeutic applications. As shown in Figure 1, when added to acidic medium, the negative charge gradually became positive due to the protonation behavior of the aspartic acid residues of PEG-b-PAsp.


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)

Optimization of DTX-LPH nanoparticles.Notes: Effect of (A) cationic lipid amount, (B) polyethylene glycol-b-polyaspartic acid concentration, and (C) drug concentration on formulation parameters: particle size, PDI, ZP. (D) Effect of drug concentration on drug entrapment efficiency and loading capacity. (E) Effect of exposed time on zeta potential at pH 5.5. Data are expressed as mean ± SD (n=3).Abbreviations: PDI, polydispersity index; SD, standard deviation; ZP, zeta potential.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-10-5249: Optimization of DTX-LPH nanoparticles.Notes: Effect of (A) cationic lipid amount, (B) polyethylene glycol-b-polyaspartic acid concentration, and (C) drug concentration on formulation parameters: particle size, PDI, ZP. (D) Effect of drug concentration on drug entrapment efficiency and loading capacity. (E) Effect of exposed time on zeta potential at pH 5.5. Data are expressed as mean ± SD (n=3).Abbreviations: PDI, polydispersity index; SD, standard deviation; ZP, zeta potential.
Mentions: The DTX-LPH nanoparticles were prepared using the emulsification method and subsequently coated with polymer. Figure 1 shows the parameters for the various formulations. We coated the positively charged nanoparticles with PEG-b-PAsp in order to prolong plasma circulation and minimize carrier-mediated toxicity. The deposition of the polyelectrolyte layer on the LPH surface was confirmed by zeta potential experiments that showed charge reversal from highly positive (+41.4±1.3 mV) to negative (−22.6±0.3 mV) values when the polymer layer was added. The optimized DTX-LPH formulation consisted of Capryol 90 (300 mg), TPGS (100 mg), DDAB (5 mg), and DTX (30 mg). This formulation had a particle size of 199.2±15.9 nm with a narrow size distribution (PD =0.277±0.031). DTX-LPH showed high entrapment efficiency (91.4%) as well as LC (6.9%), indicating suitability for therapeutic applications. As shown in Figure 1, when added to acidic medium, the negative charge gradually became positive due to the protonation behavior of the aspartic acid residues of PEG-b-PAsp.

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