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Small molecule PZL318: forming fluorescent nanoparticles capable of tracing their interactions with cancer cells and activated platelets, slowing tumor growth and inhibiting thrombosis.

Li S, Wang Y, Wang F, Wang Y, Zhang X, Zhao M, Feng Q, Wu J, Zhao S, Wu W, Peng S - Int J Nanomedicine (2015)

Bottom Line: In vivo, 10 nmol/kg of PZL318 slowed the tumor growth of S180 mice and alleviated the thrombosis of ferric chloride-treated ICR mice, while 100 μmol/kg of PZL318 did not injure healthy mice and they exhibited no liver toxicity.By using mesoscale simulation, a nanoparticle of 3.01 nm in diameter was predicted containing 13 trimers.Scavenging free radicals, downregulating sP-selectin expression and intercalating toward DNA were correlated with the antitumor mechanism of PZL318.

View Article: PubMed Central - PubMed

Affiliation: Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing Laboratory of Biomedical Materials, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, College of Pharmaceutical Sciences of Capital Medical University, Beijing, People's Republic of China.

ABSTRACT
Low selectivity of chemotherapy correlates with poor outcomes of cancer patients. To improve this issue, a novel agent, N-(1-[3-methoxycarbonyl-4-hydroxyphenyl]-β-carboline-3-carbonyl)-Trp-Lys-OBzl (PZL318), was reported here. The transmission electron microscopy, scanning electron microscopy, and atomic force microscopy images demonstrated that PZL318 can form nanoparticles. Fluorescent and confocal images visualized that PZL318 formed fluorescent nanoparticles capable of targeting cancer cells and tracing their interactions with cancer cells. In vitro, 40 μM of PZL318 inhibited the proliferation of tumorigenic cells, but not nontumorigenic cells. In vivo, 10 nmol/kg of PZL318 slowed the tumor growth of S180 mice and alleviated the thrombosis of ferric chloride-treated ICR mice, while 100 μmol/kg of PZL318 did not injure healthy mice and they exhibited no liver toxicity. By analyzing Fourier transform-mass spectrometry and rotating-frame Overhauser spectroscopy (ROESY) two-dimensional nuclear magnetic resonance spectra, the chemical mechanism of PZL318-forming trimers and nanoparticles was explored. By using mesoscale simulation, a nanoparticle of 3.01 nm in diameter was predicted containing 13 trimers. Scavenging free radicals, downregulating sP-selectin expression and intercalating toward DNA were correlated with the antitumor mechanism of PZL318.

No MeSH data available.


Related in: MedlinePlus

The in vitro intercalation of PZL318 towards CT DNA.Notes: (A) Hypochromic effect and bathochromic shift occurred in the UV spectra of PZL318 plus CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, and 30.0 μM). (B) Course of fluorescence quenching of PZL318. In PBS (pH 7.4) the titration of 20 μL of CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, 30.0 μM, and 36.0 μM) concentrations dependently resulted in the typical course of fluorescence quenching of PZL318. (C) Effect of PZL318 on the CD spectra of CT DNA. A consistent variation of the intensity of both positive and negative bands in the CD spectra of CT DNA resulted from the intercalation of PZL318 toward CT DNA. (D) Effect of PZL318 at various concentrations on the relative viscosity of CT DNA (5.0×10−4 M; 28°C).Abbreviations: CT DNA, calf thymus DNA; UV, ultraviolet; PBS, phosphate buffered saline; CD, circular dichroic.
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f3-ijn-10-5273: The in vitro intercalation of PZL318 towards CT DNA.Notes: (A) Hypochromic effect and bathochromic shift occurred in the UV spectra of PZL318 plus CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, and 30.0 μM). (B) Course of fluorescence quenching of PZL318. In PBS (pH 7.4) the titration of 20 μL of CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, 30.0 μM, and 36.0 μM) concentrations dependently resulted in the typical course of fluorescence quenching of PZL318. (C) Effect of PZL318 on the CD spectra of CT DNA. A consistent variation of the intensity of both positive and negative bands in the CD spectra of CT DNA resulted from the intercalation of PZL318 toward CT DNA. (D) Effect of PZL318 at various concentrations on the relative viscosity of CT DNA (5.0×10−4 M; 28°C).Abbreviations: CT DNA, calf thymus DNA; UV, ultraviolet; PBS, phosphate buffered saline; CD, circular dichroic.

Mentions: The intercalation of PZL318 toward DNA could be mirrored with the relative viscosity of DNA; the relative viscosity assay was performed, and the data are shown in Figure 3D (recorded on a Ubbelohde viscometer, immersed in a thermostated water bath maintained at 28°C). In the assay, to the solution of CT DNA in PBS (13 mL, 5.0×10−4 M), the solution of PZL318 in PBS (130 μL; final concentration: 5.0 μM; 10.0 μM; 20.0 μM; 40.0 μM; and 60.0 μM) was added to keep the ratio of (PZL318):(CT DNA) in the range of 0–0.36 to form the samples, and the flow time of the samples was measured after a thermal equilibrium time of 5 minutes. The flow time of each sample was calculated. The relative viscosities of CT DNA in the presence and absence of PZL318 were calculated from the equation,η=(t−t0)/t0,(1)where in t0 and t were the observed flow time in the absence and presence of PZL318, respectively. Data are presented as (η/η0)1/3 versus the binding ratio, wherein η is the viscosity of CT DNA in the presence of PZL318 and η0 is the viscosity of CT DNA alone.


Small molecule PZL318: forming fluorescent nanoparticles capable of tracing their interactions with cancer cells and activated platelets, slowing tumor growth and inhibiting thrombosis.

Li S, Wang Y, Wang F, Wang Y, Zhang X, Zhao M, Feng Q, Wu J, Zhao S, Wu W, Peng S - Int J Nanomedicine (2015)

The in vitro intercalation of PZL318 towards CT DNA.Notes: (A) Hypochromic effect and bathochromic shift occurred in the UV spectra of PZL318 plus CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, and 30.0 μM). (B) Course of fluorescence quenching of PZL318. In PBS (pH 7.4) the titration of 20 μL of CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, 30.0 μM, and 36.0 μM) concentrations dependently resulted in the typical course of fluorescence quenching of PZL318. (C) Effect of PZL318 on the CD spectra of CT DNA. A consistent variation of the intensity of both positive and negative bands in the CD spectra of CT DNA resulted from the intercalation of PZL318 toward CT DNA. (D) Effect of PZL318 at various concentrations on the relative viscosity of CT DNA (5.0×10−4 M; 28°C).Abbreviations: CT DNA, calf thymus DNA; UV, ultraviolet; PBS, phosphate buffered saline; CD, circular dichroic.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4554418&req=5

f3-ijn-10-5273: The in vitro intercalation of PZL318 towards CT DNA.Notes: (A) Hypochromic effect and bathochromic shift occurred in the UV spectra of PZL318 plus CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, and 30.0 μM). (B) Course of fluorescence quenching of PZL318. In PBS (pH 7.4) the titration of 20 μL of CT DNA (0 μM, 6.0 μM, 12.0 μM, 18.0 μM, 24.0 μM, 30.0 μM, and 36.0 μM) concentrations dependently resulted in the typical course of fluorescence quenching of PZL318. (C) Effect of PZL318 on the CD spectra of CT DNA. A consistent variation of the intensity of both positive and negative bands in the CD spectra of CT DNA resulted from the intercalation of PZL318 toward CT DNA. (D) Effect of PZL318 at various concentrations on the relative viscosity of CT DNA (5.0×10−4 M; 28°C).Abbreviations: CT DNA, calf thymus DNA; UV, ultraviolet; PBS, phosphate buffered saline; CD, circular dichroic.
Mentions: The intercalation of PZL318 toward DNA could be mirrored with the relative viscosity of DNA; the relative viscosity assay was performed, and the data are shown in Figure 3D (recorded on a Ubbelohde viscometer, immersed in a thermostated water bath maintained at 28°C). In the assay, to the solution of CT DNA in PBS (13 mL, 5.0×10−4 M), the solution of PZL318 in PBS (130 μL; final concentration: 5.0 μM; 10.0 μM; 20.0 μM; 40.0 μM; and 60.0 μM) was added to keep the ratio of (PZL318):(CT DNA) in the range of 0–0.36 to form the samples, and the flow time of the samples was measured after a thermal equilibrium time of 5 minutes. The flow time of each sample was calculated. The relative viscosities of CT DNA in the presence and absence of PZL318 were calculated from the equation,η=(t−t0)/t0,(1)where in t0 and t were the observed flow time in the absence and presence of PZL318, respectively. Data are presented as (η/η0)1/3 versus the binding ratio, wherein η is the viscosity of CT DNA in the presence of PZL318 and η0 is the viscosity of CT DNA alone.

Bottom Line: In vivo, 10 nmol/kg of PZL318 slowed the tumor growth of S180 mice and alleviated the thrombosis of ferric chloride-treated ICR mice, while 100 μmol/kg of PZL318 did not injure healthy mice and they exhibited no liver toxicity.By using mesoscale simulation, a nanoparticle of 3.01 nm in diameter was predicted containing 13 trimers.Scavenging free radicals, downregulating sP-selectin expression and intercalating toward DNA were correlated with the antitumor mechanism of PZL318.

View Article: PubMed Central - PubMed

Affiliation: Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing Laboratory of Biomedical Materials, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, College of Pharmaceutical Sciences of Capital Medical University, Beijing, People's Republic of China.

ABSTRACT
Low selectivity of chemotherapy correlates with poor outcomes of cancer patients. To improve this issue, a novel agent, N-(1-[3-methoxycarbonyl-4-hydroxyphenyl]-β-carboline-3-carbonyl)-Trp-Lys-OBzl (PZL318), was reported here. The transmission electron microscopy, scanning electron microscopy, and atomic force microscopy images demonstrated that PZL318 can form nanoparticles. Fluorescent and confocal images visualized that PZL318 formed fluorescent nanoparticles capable of targeting cancer cells and tracing their interactions with cancer cells. In vitro, 40 μM of PZL318 inhibited the proliferation of tumorigenic cells, but not nontumorigenic cells. In vivo, 10 nmol/kg of PZL318 slowed the tumor growth of S180 mice and alleviated the thrombosis of ferric chloride-treated ICR mice, while 100 μmol/kg of PZL318 did not injure healthy mice and they exhibited no liver toxicity. By analyzing Fourier transform-mass spectrometry and rotating-frame Overhauser spectroscopy (ROESY) two-dimensional nuclear magnetic resonance spectra, the chemical mechanism of PZL318-forming trimers and nanoparticles was explored. By using mesoscale simulation, a nanoparticle of 3.01 nm in diameter was predicted containing 13 trimers. Scavenging free radicals, downregulating sP-selectin expression and intercalating toward DNA were correlated with the antitumor mechanism of PZL318.

No MeSH data available.


Related in: MedlinePlus