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Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

Yang E, Qian W, Cao Z, Wang L, Bozeman EN, Ward C, Yang B, Selvaraj P, Lipowska M, Wang YA, Mao H, Yang L - Theranostics (2015)

Bottom Line: Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles.However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin.Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles.

View Article: PubMed Central - PubMed

Affiliation: 1. Departments of Surgery, Emory University School of Medicine, Atlanta, GA 30322;

ABSTRACT
Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

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Detection of anti-ScFvEGFR antibody in mouse serum samples using ELISA. A. The level of anti-ScFvEGFR antibody in the serially diluted serum samples of tumor bearing mice following two i.v. deliveries of 200 pmol of ScFvEGFR-IONPs or equivalent unconjugated ScFvEGFR (50 µg). The level of mouse IgG antibody was measured. B. ELISA of mouse serum samples obtained from negative control IONP or PEG-IONP injected tumor bearing mice. C. Detection of the production of ligand specific IgG or IgM antibodies. Three injections of ScFvEGFR-IONPs activated high levels of both IgG and IgM ligand specific antibodies. Mice injected with PEG modified ScFvEGFR-PEG-IONPs had significantly higher level of IgG ligand specific antibody, but not IgM antibody, than ScFvEGFR-IONP injected mice. n=3 mice for all bar figures.
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Figure 2: Detection of anti-ScFvEGFR antibody in mouse serum samples using ELISA. A. The level of anti-ScFvEGFR antibody in the serially diluted serum samples of tumor bearing mice following two i.v. deliveries of 200 pmol of ScFvEGFR-IONPs or equivalent unconjugated ScFvEGFR (50 µg). The level of mouse IgG antibody was measured. B. ELISA of mouse serum samples obtained from negative control IONP or PEG-IONP injected tumor bearing mice. C. Detection of the production of ligand specific IgG or IgM antibodies. Three injections of ScFvEGFR-IONPs activated high levels of both IgG and IgM ligand specific antibodies. Mice injected with PEG modified ScFvEGFR-PEG-IONPs had significantly higher level of IgG ligand specific antibody, but not IgM antibody, than ScFvEGFR-IONP injected mice. n=3 mice for all bar figures.

Mentions: To achieve a strong therapeutic effect, anticancer agents are often administrated multiple times to improve the delivery into heterogeneous tumors. We examined antibody responses against highly immunogenic human ScFvEGFR conjugated IONPs after repeated i.v. injections in mice bearing mammary tumors. A high level of anti-ScFvEGFR antibody was detected in the serially diluted serum samples of the mice that received two injections of 200 pmol of ScFvEGFR-IONPs using ELISA. Compared to the serum samples obtained from mice that received i.v. injections of the equal amount of free ScFvEGFR, the level of the antibody in the mice treated with nanoparticle-conjugated ScFvEGFR was three-fold higher (Figure 2A). Conjugation of ScFvEGFR to nanoparticles significantly increased the ligand specific antibody production (p<0.05, 1/200 and 1/2000 dilutions). Anti-ligand specific antibodies were not detected in control serum samples obtained from the mice injected with nanoparticles without targeting ligands (Figure 2B).


Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

Yang E, Qian W, Cao Z, Wang L, Bozeman EN, Ward C, Yang B, Selvaraj P, Lipowska M, Wang YA, Mao H, Yang L - Theranostics (2015)

Detection of anti-ScFvEGFR antibody in mouse serum samples using ELISA. A. The level of anti-ScFvEGFR antibody in the serially diluted serum samples of tumor bearing mice following two i.v. deliveries of 200 pmol of ScFvEGFR-IONPs or equivalent unconjugated ScFvEGFR (50 µg). The level of mouse IgG antibody was measured. B. ELISA of mouse serum samples obtained from negative control IONP or PEG-IONP injected tumor bearing mice. C. Detection of the production of ligand specific IgG or IgM antibodies. Three injections of ScFvEGFR-IONPs activated high levels of both IgG and IgM ligand specific antibodies. Mice injected with PEG modified ScFvEGFR-PEG-IONPs had significantly higher level of IgG ligand specific antibody, but not IgM antibody, than ScFvEGFR-IONP injected mice. n=3 mice for all bar figures.
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Related In: Results  -  Collection

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Figure 2: Detection of anti-ScFvEGFR antibody in mouse serum samples using ELISA. A. The level of anti-ScFvEGFR antibody in the serially diluted serum samples of tumor bearing mice following two i.v. deliveries of 200 pmol of ScFvEGFR-IONPs or equivalent unconjugated ScFvEGFR (50 µg). The level of mouse IgG antibody was measured. B. ELISA of mouse serum samples obtained from negative control IONP or PEG-IONP injected tumor bearing mice. C. Detection of the production of ligand specific IgG or IgM antibodies. Three injections of ScFvEGFR-IONPs activated high levels of both IgG and IgM ligand specific antibodies. Mice injected with PEG modified ScFvEGFR-PEG-IONPs had significantly higher level of IgG ligand specific antibody, but not IgM antibody, than ScFvEGFR-IONP injected mice. n=3 mice for all bar figures.
Mentions: To achieve a strong therapeutic effect, anticancer agents are often administrated multiple times to improve the delivery into heterogeneous tumors. We examined antibody responses against highly immunogenic human ScFvEGFR conjugated IONPs after repeated i.v. injections in mice bearing mammary tumors. A high level of anti-ScFvEGFR antibody was detected in the serially diluted serum samples of the mice that received two injections of 200 pmol of ScFvEGFR-IONPs using ELISA. Compared to the serum samples obtained from mice that received i.v. injections of the equal amount of free ScFvEGFR, the level of the antibody in the mice treated with nanoparticle-conjugated ScFvEGFR was three-fold higher (Figure 2A). Conjugation of ScFvEGFR to nanoparticles significantly increased the ligand specific antibody production (p<0.05, 1/200 and 1/2000 dilutions). Anti-ligand specific antibodies were not detected in control serum samples obtained from the mice injected with nanoparticles without targeting ligands (Figure 2B).

Bottom Line: Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles.However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin.Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles.

View Article: PubMed Central - PubMed

Affiliation: 1. Departments of Surgery, Emory University School of Medicine, Atlanta, GA 30322;

ABSTRACT
Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

Show MeSH
Related in: MedlinePlus