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. 2018 Oct 10;18(10):6164-6174.
doi: 10.1021/acs.nanolett.8b01892. Epub 2018 Sep 17.

Leutusome: A Biomimetic Nanoplatform Integrating Plasma Membrane Components of Leukocytes and Tumor Cells for Remarkably Enhanced Solid Tumor Homing

Hongliang He  1   2 , Chunqing Guo  3   4   5 , Jing Wang  2 , William J Korzun  6 , Xiang-Yang Wang  3   4   5 , Shobha Ghosh  2 , Hu Yang  1   5   7
Affiliations

Leutusome: A Biomimetic Nanoplatform Integrating Plasma Membrane Components of Leukocytes and Tumor Cells for Remarkably Enhanced Solid Tumor Homing

Hongliang He et al. Nano Lett. .

Abstract

Cell membrane-camouflaged nanoparticles have appeared as a promising platform to develop active tumor targeting nanomedicines. To evade the immune surveillance, we designed a composite cell membrane-camouflaged biomimetic nanoplatform, namely, leutusome, which is made of liposomal nanoparticles incorporating plasma membrane components derived from both leukocytes (murine J774A.1 cells) and tumor cells (head and neck tumor cells HN12). Exogenous phospholipids were used as building blocks to fuse with two cell membranes to form liposomal nanoparticles. Liposomal nanoparticles made of exogenous phospholipids only or in combination with one type of cell membrane were fabricated and compared. The anticancer drug paclitaxel (PTX) was used to make drug-encapsulating liposomal nanoparticles. Leutusome resembling characteristic plasma membrane components of the two cell membranes were examined and confirmed in vitro. A xenograft mouse model of head and neck cancer was used to profile the blood clearance kinetics, biodistribution, and antitumor efficacy of the different liposomal nanoparticles. The results demonstrated that leutusome obtained prolonged blood circulation and was most efficient accumulating at the tumor site (79.1 ± 6.6% ID per gram of tumor). Similarly, leutusome composed of membrane fractions of B16 melanoma cells and leukocytes (J774A.1) showed prominent accumulation within the B16 tumor, suggesting the generalization of the approach. Furthermore, PTX-encapsulating leutusome was found to most potently inhibit tumor growth while not causing systemic adverse effects.

Keywords: Active targeting; cell membrane camouflage; leukocytes; nanoparticles; tumor cells; tumor microenvironment.

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Conflict of interest statement

The authors declare no competing interest.

Figures

Figure 1.
Figure 1.
Verification and characterizations of incorporating two cell membranes into leutusome. (A) Visualization of extracted dual dyes-labeled composite cells membrane before and after extrusion under confocal microscopy and TEM, respectively. DiO-labeled leukocyte membranes are shown as green fluorescence and DiD-labeled tumor cell membranes are shown as red fluorescence. Two types of cell membranes in microscale well fused together to form the nanoscale leutusome after extrusion. (B) Intracellular colocalization of composite nanoscale dual dyes-labeled cells membrane-derived vesicle in the source tumor cell HN12 after 6 h incubation. DAPI channel is for nuclei, DiO channel for leukocytes membrane and DiD channel for tumor cells.
Figure 2.
Figure 2.. Characterization of PTX-loaded liposomal nanoparticles.
(A) Membrane-specific and intracellular markers characterization by Western analysis for lysates from leukocytes and tumor cells (1), cell membranes extracted from those two cells (2), empty leutusome (3) and PTX-loaded leutusome (4). (B) TEM images. (C) PTX encapsulation efficiency as a function of drug-to-lipid mass ratio, (D) PTX loading content (mole %) of formulations prepared at various drug-to-lipid mass ratio. (E) Particle size change and (F) zeta potential change at 4 °C for 1 week-storage. (G) In vitro PTX release behavior from different PTX liposomes in PBS at 37 °C. NS, not significant; ** indicates p<0.01, and *** indicates p<0.001 (n=3).
Figure 3.
Figure 3.
Intracellular uptake of different cell membrane-camouflaged liposomal nanoparticles in the co-culture model established using J774A.1 leukocytes and YFP-expressing HN12 tumor cells. The cells were imaged after 6 h incubation and are shown in Figure 3A. The cells with both green signal and blue signal are YFP-expressing HN12, while the cells only with the blue signal are J774A.1. The red signal comes from the different DiI-labeled liposomal nanoparticles. Flow cytometric quantitative analysis results are shown in Figure 3B. ** indicates p<0.01.
Figure 4.
Figure 4.
In vitro cytotoxicity of (A) empty liposomal nanoparticles with and without different cell membrane camouflage, and different PTX-loaded liposomal nanoparticles (B) at various concentrations on HN12 cells after 24 h incubation. **indicates p<0.01 (n=6).
Figure 5.
Figure 5.
Leukocyte membrane helps reduce the uptake of nanoparticles by monocytes and neutrophils in the blood. * indicates p<0.05 and **indicates p<0.01 (n=4).
Figure 6.
Figure 6.
In vivo distribution and pharmacokinetics of liposomal nanoparticles (with and without cell membrane camouflage). (A) In vivo fluorescence imaging at different time points. (B) In vivo blood clearance of the liposomal nanoparticles as measured by the fluorescence intensity. (C) Ex vivo tissue distribution in the main organs at 48 h post-i.v. administration. (D) Quantitative analysis of fluorescence accumulation in the main organs. (E) Representative fluorescent images of the tumor sections. ** indicates p<0.01 and ***indicates p<0.001 (n=4).
Figure 7.
Figure 7.
Leutusome significantly suppressed tumor growth. (A) Relative tumor volume growth and (B) body weight changes were monitored over the treatments. Photographs of HN12 tumor-bearing mice (C), the excised tumors (D) and tumor tissue apoptosis (E) were recorded after the various treatments. NS, not significant; ** indicates p<0.01, and *** indicates p<0.001 (n=6).
Scheme 1.
Scheme 1.
Schematic presentation of composite leukocyte and tumor cell membrane-camouflaged liposome (leutusome) as a carrier for paclitaxel (LTM-PTXL) and potential application in cancer treatment and diagnosis. Both leukocyte and tumor cell membranes are extracted and applied to hydrate the thin film containing payloads (paclitaxel or fluorescent dyes) to obtain the resulting leutusome via sonication and extrusion. The resulting LTM-PTXL would integrate each original cell’s biofunctions (leukocyte’s avoidance of the uptake by the MPS, long residency in blood and recruitment to the tumor microenvironment, and tumor cell’s homotypic tumor targeting) into one entity, thus prolonging the blood circulation, increasing the tumor accumulation and improving antitumor efficacy.
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