Macrophage-Membrane-Coated Nanoparticles for Tumor-Targeted Chemotherapy

Abstract

Various delivery vectors have been integrated within biologically derived membrane systems to extend their residential time and reduce their reticuloendothelial system (RES) clearance during systemic circulation. However, rational design is still needed to further improve the in situ penetration efficiency of chemo-drug-loaded membrane delivery-system formulations and their release profiles at the tumor site. Here, a macrophage-membrane-coated nanoparticle is developed for tumor-targeted chemotherapy delivery with a controlled release profile in response to tumor microenvironment stimuli. Upon fulfilling its mission of tumor homing and RES evasion, the macrophage-membrane coating can be shed via morphological changes driven by extracellular microenvironment stimuli. The nanoparticles discharged from the outer membrane coating show penetration efficiency enhanced by their size advantage and surface modifications. After internalization by the tumor cells, the loaded drug is quickly released from the nanoparticles in response to the endosome pH. The designed macrophage-membrane-coated nanoparticle (cskc-PPiP/PTX@Ma) exhibits an enhanced therapeutic effect inherited from both membrane-derived tumor homing and step-by-step controlled drug release. Thus, the combination of a biomimetic cell membrane and a cascade-responsive polymeric nanoparticle embodies an effective drug delivery system tailored to the tumor microenvironment.

Keywords: biomimetic delivery system; breast-cancer targeting; cascade-responsiveness; macrophage-membrane coating; tumor microenvironment.

Figure 1.

A. Scheme of the preparation of membrane-coated nanoparticles. B. Microscope images (63× oil lens, crop) of cskc-PPiP/PTX@Ma (a) and PPC8/PTX@Ma (b) in buffers at pH 7.4 and pH 6.5.

Figure 2.

A. Illustration of membrane escape and drug-release mechanism. Cumulative drug-release profile of PPiP/PTX@Ma (B) and PPC8/PTX@Ma (C) at various pH values. DLS (D, E) and TEM (F,G) images of PPiP/PTX in buffer at pH 7.4 and pH 6.5. Changes in the zeta potential (H) and CMC value (I) of the polymers PPiP and PPC8 at various pH values.

Figure 3.

A. Penetration efficiency of PPC8@Ma and cskc-PPiP@Ma into tumor spheroids with 2 h incubation. Upper panels show results in in pH 7.4 medium and lower panels in pH 6.5, scale bar 100 μm, z-axis depth 20 μm. B. Tumor sections of mice 24 h after injection with cskc-PPiP, PPC8@Ma, PPiP@Ma and cskc-PPiP@Ma, scale bar 100 μm. DAPI (blue), CD34 (green) and Probe (red) stained the cell nuclei, blood vessels and formulation trace, respectively.

Figure 4.

Biodistribution and in vivo antitumor efficacy. A. IVIS images of mice injected with near-infrared probe-loaded cskc-PPiP and cskc-PPiP@Ma at designated time points. B. 3D reconstruction of fluorescence signal in cskc-PPiP@Ma treated mouse at 48 h. C. Heart (H), liver (Li), spleen (S), lung (Lu), kidney (K) and tumor (T) excised from the abovementioned mouse. D. Quantification of PTX concentration in organs and tumor tissue excised from mice treated with Taxol, cskc-PPiP/PTX, PPC8/PTX@Ma and cskc-PPiP/PTX@Ma (n=4). Body weight (E) and tumor volume (F) data were recorded during the 3-week treatment course. G. Tumor tissue apoptosis in mice treated with saline, Taxol, PPC8/PTX@Ma, PPiP/PTX@Ma, and cskc-PPiP/PTX@Ma. Green signals indicate apoptotic cells in tumor section. Scale bar, 100 μm.