Using macrophage recruitment in tumors, we develop active, transportable, cancer theragnostic macrophage-based microrobots as vector to deliver therapeutic agents to tumor regions. The macrophage-based microrobots contain docetaxel (DTX)-loaded poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs) for chemotherapy and Fe3O4 magnetic NPs (MNPs) for active targeting using an electromagnetic actuation (EMA) system. And, the macrophage-based microrobots are synthesized through the phagocytosis of the drug NPs and MNPs in the macrophages. The anticancer effects of the microrobots on tumor cell lines (CT-26 and 4T1) are evaluated in vitro by cytotoxic assay. In addition, the active tumor targeting by the EMA system and macrophage recruitment, and the chemotherapeutic effect of the microrobots are evaluated using three-dimensional (3D) tumor spheroids. The microrobots exhibited clear cytotoxicity toward tumor cells, with a low survivability rate (<50%). The 3D tumor spheroid assay showed that the microrobots demonstrated hybrid actuation through active tumor targeting by the EMA system and infiltration into the tumor spheroid by macrophage recruitment, resulting in tumor cell death caused by the delivered antitumor drug. Thus, the active, transportable, macrophage-based theragnostic microrobots can be considered to be biocompatible vectors for cancer therapy.
Macrophages
(MΦs) have the capability to sense chemotactic
cues and to home tumors, therefore presenting a great approach to
engineer these cells to deliver therapeutic agents to treat diseases.
However, current cell-based drug delivery systems usually use commercial
cell lines that may elicit an immune response when injected into a
host animal. Furthermore, premature off-target drug release also remains
an enormous challenge. Here, we isolated and differentiated MΦs
from the spleens of BALB/c mice and developed dual-targeting MΦ-based
microrobots, regulated by chemotaxis and an external magnetic field,
and had a precise spatiotemporal controlled drug release at the tumor
sites in response to the NIR laser irradiation. These microrobots
were prepared by coloading citric acid (CA)-coated superparamagnetic
nanoparticles (MNPs) and doxorubicin (DOX)-containing thermosensitive
nanoliposomes (TSLPs) into the MΦs. CA-MNPs promoted a magnetic
targeting function to the microrobots and also permitted photothermal
heating in response to the NIR irradiation, triggering drug release
from TSLPs. In vitro experiments showed that the
microrobots effectively infiltrated tumors in 3D breast cancer tumor
spheroids, particularly in the presence of the magnetic field, and
effectively induced tumor cell death, further enhanced by the NIR
laser irradiation. In vivo experiments confirmed
that the application of the magnetic field and NIR laser could markedly
inhibit the growth of tumors with a subtherapeutic dose of DOX and
a single injection of the microrobots. In summary, the study proposes
a strategy for the effective anticancer treatment using the developed
microrobots.
Although
great efforts have been undertaken to develop a nanoparticle-based
drug delivery system (DDS) for the treatment of solid tumors, the
therapeutic outcomes are still limited. Immune cells, which possess
an intrinsic ability to phagocytose nanoparticles and are recruited
by tumors, can be exploited to deliver nanotherapeutics deep inside
the tumors. Photothermal therapy using near-infrared light is a promising
noninvasive approach for solid tumor ablation, especially when combined
with chemotherapy. In this study, we design and evaluate a macrophage-based,
multiple nanotherapeutics DDS, involving the phagocytosis by macrophages
of both small-sized gold nanorods and anticancer drug-containing nanoliposomes.
The aim is to treat solid tumors, utilizing the tumor-infiltrating
properties of macrophages with synergistic photothermal–chemotherapy.
Using a 3D cancer spheroid as an in vitro solid tumor model,
we show that tumor penetration and coverage of the nanoparticles are
both markedly enhanced when the macrophages are used. In addition,
in vivo experiments involving both local and systemic administrations
in breast tumor-bearing mice demonstrate that the proposed DDS can
effectively target and kill the tumors, especially when the synergistic
therapy is used. Consequently, this immune cell-based theranostic
strategy may represent a potentially important advancement in the
treatment of solid tumors.
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