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Immunoliposome co-delivery of bufalin and anti-CD40 antibody adjuvant induces synergetic therapeutic efficacy against melanoma.

Li Y, Yuan J, Yang Q, Cao W, Zhou X, Xie Y, Tu H, Zhang Y, Wang S - Int J Nanomedicine (2014)

Bottom Line: The purpose of this study was to design and evaluate immunoliposome co-delivery of bufalin and anti-CD40 to induce synergetic therapeutic efficacy while eliminating systemic side effects.Meanwhile, anti-CD40-BFL elicited unapparent body-weight changes and a significant reduction in serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, interferon-γ, and hepatic enzyme alanine transaminase, suggesting minimized systemic side effects.Taken together, the results demonstrated a highly promising strategy for liposomal vehicle transport of anti-CD40 plus bufalin that can be used to enhance antitumor effects via synergetic systemic immunity while blocking systemic toxicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Natural Medicine and Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, People's Republic of China.

ABSTRACT
Liposomes constitute one of the most popular nanocarriers for improving the delivery and efficacy of agents in cancer patients. The purpose of this study was to design and evaluate immunoliposome co-delivery of bufalin and anti-CD40 to induce synergetic therapeutic efficacy while eliminating systemic side effects. Bufalin liposomes (BFL) conjugated with anti-CD40 antibody (anti-CD40-BFL) showed enhanced cytotoxicity compared with bufalin alone. In a mouse B16 melanoma model, intravenous injection of anti-CD40-BFL achieved smaller tumor volume than did treatment with BFL (average: 117 mm(3) versus 270 mm(3), respectively); the enhanced therapeutic efficacy through a caspase-dependent pathway induced apoptosis, which was confirmed using terminal deoxynucleotidyl transferase-mediated dUTP-Fluorescein nick end labeling and Western blot assay. Meanwhile, anti-CD40-BFL elicited unapparent body-weight changes and a significant reduction in serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, interferon-γ, and hepatic enzyme alanine transaminase, suggesting minimized systemic side effects. This may be attributed to the mechanism by which liposomes are retained within the tumor site for an extended period of time, which is supported by the following biodistribution and flow cytometric analyses. Taken together, the results demonstrated a highly promising strategy for liposomal vehicle transport of anti-CD40 plus bufalin that can be used to enhance antitumor effects via synergetic systemic immunity while blocking systemic toxicity.

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Serum circulating inflammatory marker levels.Notes: Serum circulating levels 24 hours after the first dose of saline, free anti-CD40, bufalin, BFL, or anti-CD40-BFL. (A) Hepatic enzyme ALT. Inflammatory cytokines (B) TNF-α, (C) IL-6, (D) IL-1β, and (E) IFN-γ. P-values determined by unpaired Student’s t-test: **P<0.01.Abbreviations: ALT, alanine transaminase; BFL, bufalin liposomes; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.
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f6-ijn-9-5683: Serum circulating inflammatory marker levels.Notes: Serum circulating levels 24 hours after the first dose of saline, free anti-CD40, bufalin, BFL, or anti-CD40-BFL. (A) Hepatic enzyme ALT. Inflammatory cytokines (B) TNF-α, (C) IL-6, (D) IL-1β, and (E) IFN-γ. P-values determined by unpaired Student’s t-test: **P<0.01.Abbreviations: ALT, alanine transaminase; BFL, bufalin liposomes; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

Mentions: Serum cytokine levels administered 24 hours posttreatment were measured to evaluate systemic toxicity (Figure 6). Anti-CD40-BFL treatment resulted in significantly lower serum levels of TNF-α, IL-1β, IL-6, and IFN-γ compared with soluble anti-CD40 mAbs, indicating that the anchoring of anti-CD40 to the liposome could reduce systemic toxicity. The serum levels of TNF-α were 1.56±0.73 ng/L, 40.14±1.91 ng/L, 13.72±2.27 ng/L, 10.14±5.18 ng/L, and 24.3±0.76 ng/L for the physiological saline, anti-CD40 solution, bufalin solution, BFL, and anti-CD40-BFL groups, respectively. Similar trends were observed with IL-1β (2.54±1.07 ng/L, 40.14±1.91 ng/L, 13.89±2.21 ng/L, 16.28±2.76 ng/L, and 14.15±2.53 ng/L, respectively), IL-6 (1.99±0.96 ng/L, 28.07±2.19 ng/L, 6.86±2.64 ng/L, 7.37±1.48 ng/L, and 11.98±2.34 ng/L, respectively) and IFN-γ (13.81±4.92 ng/L, 776.90±37.82 ng/L, 487.23±98.62 ng/L, 332.86±75.95 ng/L, and 534.83±55.14 ng/L, respectively). The serum levels of ALT enzyme (0.709±0.065 ng mL, 5.872±0.146 ng/mL, 1.613±0.267 ng/mL, 1.808±0.445 ng mL, and 2.492±0.453 ng/mL, respectively) suggested that the liposome has low toxicity in the liver and that there were no significant safety issues.


Immunoliposome co-delivery of bufalin and anti-CD40 antibody adjuvant induces synergetic therapeutic efficacy against melanoma.

Li Y, Yuan J, Yang Q, Cao W, Zhou X, Xie Y, Tu H, Zhang Y, Wang S - Int J Nanomedicine (2014)

Serum circulating inflammatory marker levels.Notes: Serum circulating levels 24 hours after the first dose of saline, free anti-CD40, bufalin, BFL, or anti-CD40-BFL. (A) Hepatic enzyme ALT. Inflammatory cytokines (B) TNF-α, (C) IL-6, (D) IL-1β, and (E) IFN-γ. P-values determined by unpaired Student’s t-test: **P<0.01.Abbreviations: ALT, alanine transaminase; BFL, bufalin liposomes; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260685&req=5

f6-ijn-9-5683: Serum circulating inflammatory marker levels.Notes: Serum circulating levels 24 hours after the first dose of saline, free anti-CD40, bufalin, BFL, or anti-CD40-BFL. (A) Hepatic enzyme ALT. Inflammatory cytokines (B) TNF-α, (C) IL-6, (D) IL-1β, and (E) IFN-γ. P-values determined by unpaired Student’s t-test: **P<0.01.Abbreviations: ALT, alanine transaminase; BFL, bufalin liposomes; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.
Mentions: Serum cytokine levels administered 24 hours posttreatment were measured to evaluate systemic toxicity (Figure 6). Anti-CD40-BFL treatment resulted in significantly lower serum levels of TNF-α, IL-1β, IL-6, and IFN-γ compared with soluble anti-CD40 mAbs, indicating that the anchoring of anti-CD40 to the liposome could reduce systemic toxicity. The serum levels of TNF-α were 1.56±0.73 ng/L, 40.14±1.91 ng/L, 13.72±2.27 ng/L, 10.14±5.18 ng/L, and 24.3±0.76 ng/L for the physiological saline, anti-CD40 solution, bufalin solution, BFL, and anti-CD40-BFL groups, respectively. Similar trends were observed with IL-1β (2.54±1.07 ng/L, 40.14±1.91 ng/L, 13.89±2.21 ng/L, 16.28±2.76 ng/L, and 14.15±2.53 ng/L, respectively), IL-6 (1.99±0.96 ng/L, 28.07±2.19 ng/L, 6.86±2.64 ng/L, 7.37±1.48 ng/L, and 11.98±2.34 ng/L, respectively) and IFN-γ (13.81±4.92 ng/L, 776.90±37.82 ng/L, 487.23±98.62 ng/L, 332.86±75.95 ng/L, and 534.83±55.14 ng/L, respectively). The serum levels of ALT enzyme (0.709±0.065 ng mL, 5.872±0.146 ng/mL, 1.613±0.267 ng/mL, 1.808±0.445 ng mL, and 2.492±0.453 ng/mL, respectively) suggested that the liposome has low toxicity in the liver and that there were no significant safety issues.

Bottom Line: The purpose of this study was to design and evaluate immunoliposome co-delivery of bufalin and anti-CD40 to induce synergetic therapeutic efficacy while eliminating systemic side effects.Meanwhile, anti-CD40-BFL elicited unapparent body-weight changes and a significant reduction in serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, interferon-γ, and hepatic enzyme alanine transaminase, suggesting minimized systemic side effects.Taken together, the results demonstrated a highly promising strategy for liposomal vehicle transport of anti-CD40 plus bufalin that can be used to enhance antitumor effects via synergetic systemic immunity while blocking systemic toxicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Natural Medicine and Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, People's Republic of China.

ABSTRACT
Liposomes constitute one of the most popular nanocarriers for improving the delivery and efficacy of agents in cancer patients. The purpose of this study was to design and evaluate immunoliposome co-delivery of bufalin and anti-CD40 to induce synergetic therapeutic efficacy while eliminating systemic side effects. Bufalin liposomes (BFL) conjugated with anti-CD40 antibody (anti-CD40-BFL) showed enhanced cytotoxicity compared with bufalin alone. In a mouse B16 melanoma model, intravenous injection of anti-CD40-BFL achieved smaller tumor volume than did treatment with BFL (average: 117 mm(3) versus 270 mm(3), respectively); the enhanced therapeutic efficacy through a caspase-dependent pathway induced apoptosis, which was confirmed using terminal deoxynucleotidyl transferase-mediated dUTP-Fluorescein nick end labeling and Western blot assay. Meanwhile, anti-CD40-BFL elicited unapparent body-weight changes and a significant reduction in serum levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, interferon-γ, and hepatic enzyme alanine transaminase, suggesting minimized systemic side effects. This may be attributed to the mechanism by which liposomes are retained within the tumor site for an extended period of time, which is supported by the following biodistribution and flow cytometric analyses. Taken together, the results demonstrated a highly promising strategy for liposomal vehicle transport of anti-CD40 plus bufalin that can be used to enhance antitumor effects via synergetic systemic immunity while blocking systemic toxicity.

Show MeSH
Related in: MedlinePlus