Details

Autor(en) / Beteiligte

• Choi, Jeong Uk
• Maharjan, Ruby
• Pangeni, Rudra
• Jha, Saurav Kumar
• Lee, Na Kyeong
• Kweon, Seho
• Lee, Ha Kyeong
• Chang, Kwan-Young
• Choi, Young Kweon
• Park, Jin Woo
• Byun, Youngro

Titel

Modulating tumor immunity by metronomic dosing of oxaliplatin incorporated in multiple oral nanoemulsion

Ist Teil von

• Journal of controlled release, 2020-06, Vol.322, p.13-30

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2020

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• In this study, a system for oral delivery of oxaliplatin (OXA) was prepared for metronomic chemotherapy to enhance antitumor efficacy and modulate tumor immunity. OXA was complexed with Nα-deoxycholyl-l-lysyl-methylester (DCK) (OXA/DCK) and formulated as a nanoemulsion (OXA/DCK-NE). OXA/DCK-NE showed 3.35-fold increased permeability across a Caco-2 cell monolayer, resulting in 1.73-fold higher oral bioavailability than free OXA. In addition, treatment of the B16F10.OVA cell line with OXA/DCK-NE resulted in successful upregulation of immunogenic cell death (ICD) markers both in vitro and in vivo. In a B16F10.OVA tumor-bearing mouse model, treatment with OXA/DCK-NE substantially impeded tumor growth by 63.9 ± 13.3% compared to the control group, which was also greater than the intravenous (IV) OXA group. Moreover, treatment with a combination of oral OXA/DCK-NE and anti-programmed cell death protein-1 (αPD-1) antibody resulted in 78.3 ± 9.67% greater inhibition compared to controls. More important, OXA/DCK-NE alone had immunomodulatory effects, such as enhancement of tumor antigen uptake, activation of dendritic cells in tumor-draining lymph nodes, and augmentation of both the population and function of immune effector cells in tumor tissue as well as in the spleen; no such effects were seen in the OXA IV group. These observations provide a rationale for combining oral metronomic OXA with immunotherapy to elicit synergistic antitumor effects. [Display omitted] •OXA/DCK-NE was permeated through intestine via bile acid transport-mediated uptake.•The oral bioavailability of OXA/DCK-NE was greater than that of free oxaliplatin.•Oral metronomic OXA/DCK-NE treatment effectively modulated tumor immunity.•OXA/DCK-NE induced immunogenic cell death and enhanced immune cell numbers.•OXA/DCK-NE and αPD-1 exhibited synergistic antitumor effects.