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Modulation of Nanostructure-Based Lipopolysaccharide Active Immunotherapy in Cancer: Size and Composition Determine Short- and Long-Term Tolerability
journal contribution
posted on 2019-10-01, 13:34 authored by Maryam
A. Shetab Boushehri, Tawfek Yazeji, Valentin Stein, Alf LamprechtDespite holding promise for cancer
immunotherapy, the strong pro-inflammatory
properties of lipopolysaccharide (LPS) also account for severe localized
and systemic side effects, restricting its administrable dosage and
the possibility of chronic dosing. Herein, we exploited the surface-active
properties of LPS molecules to develop pathogen-mimicking LPS-decorated
nanostructures with different compositions (lipid nanoemulsion vs
polymeric nanospheres) and sizes (volumetric mean diameters of 100
nm vs 700 nm). The formulations were tested in cell culture for their
immunostimulatory properties and in vivo against
a murine subcutaneous colorectal cancer model. While all nanostructures
resulted in similar levels of apoptotic cell death in tumor cells
cultured with splenocytes, both the size and the composition of the
nanostructures were found to govern the short- and long-term tolerability
of LPS-based immunotherapy in vivo. The toxicity-related
end point of the animal trials was decided upon in the case of a body
condition score (BCS) of 1 and poor hair coat, or more than 15% loss
of the original body weight, while in the absence of long-term intolerability,
the experiments were terminated in the case of full remission or once
the tumor surpassed a volume of 1000 mm3. Size was an important
determinant of short-term tolerability, with larger particles being
associated with higher incidence and extent of localized necrosis
(3–6% necrotic surface area). Nanostructure composition, on
the other hand, predominantly governed the long-term systemic tolerability.
Within this context, the higher affinity of LPS molecules to the triglyceride
core of the nanoemulsion compared to the polymeric matrix significantly
improved the tolerability of the former over time. In fact, the mean
survival estimate of the animals treated with small LPS nanoemulsion
(LPS-NE (small)) was at least 42 days longer than that of the LPS
and the LPS-decorated polymeric nanoparticle (LPS-NP) groups. Unlike
other treatment groups, the experiments on 80% of the animals in LPS-NE
(small) were terminated due to complete remission or tumor volume
>1000 mm3. While a better understanding of these findings
requires a larger scale, mechanistic-oriented trial on larger animal
models, they indicate the role of nanostructures as beyond the carriers
of the incorporated immunotherapeutic cargos. This highlights the
importance of a wise selection of nanoparticle composition and a purposeful
tuning of their physicochemical properties to enhance the safety profile
and improve the eventual immunotherapeutic outcome.
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murine subcutaneous colorectal cancer modeltolerabilitynanoparticleremissionbody condition scoreexperimentLPS-NEBCSLPS-NPtumorimmunotherapeuticimmunotherapy1000 mm 3apoptotic cell deathlipid nanoemulsion vsvolumetoxicity-related end pointvivo100 nm vs 700 nmLPS moleculespathogen-mimicking LPS-decorated nanostructures
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