Primary Macrophage-Based Microrobots: An Effective Tumor Therapy In Vivo by Dual-Targeting Function and Near-Infrared-Triggered Drug Release

Abstract

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.

Magnetic bio-hybrid micro actuators

“…How can payloads be released at precise locations 52 ? How can microrobots be made such that they are biocompatible and do not elicit immune responses 53,54 ? How can microrobots be controlled to intelligently respond to a range of stimuli (i.e., actuate, percept, respond, and assess 55 ?…”

“…More recently, Nguyen et al constructed a multifunctional micromotor using macrophages isolated from mice. 53 These micromotors retain the chemotactic ability of the macrophage and contain responsive agents allowing steering through the use of magnetic fields and drug release in response to near infrared (NIR) laser irradiation (Fig. 2c).…”

“…2c). Work from Wu et al, 88 Guo et al, 65 Yasa et al, 54 and Nguyen et al 53 has shown that artificially implanted magnetic actuators can be used to transport, control, and influence eukaryotic cell behavior and immune response for biomedical applications. 69 On the other hand, Santomauro et al used microalgae incorporated with terbium as a bio-cyborg actuator.…”

“…Adapted with Permission. 53 Copyright 2020, ACS. the cell's dehydration and rehydration capabilities.…”

A Tumor Microenvironment-Triggered and Photothermal-Enhanced Nanocatalysis Multimodal Therapy Platform for Precise Cancer Therapy

“…As an emerging localized therapeutic modality, photothermal therapy (PTT), in particular near-infrared (NIR, 700–1100 nm in wavelength) laser-induced PTT, has received considerable attention due to its fewer adverse side effects, noninvasive nature, and spatiotemporally controllable irradiation in tumor tissues, in addition to the lower absorption and deeper penetration of NIR light in biological tissues. , PTT has been employed alone to treat cancer ,− or combined with other treatment modalities, such as chemotherapy, photodynamic therapy (PDT), , chemodynamic therapy (CDT), ,,,, sonodynamic therapy (SDT), , radiotherapy, and immunotherapy, to improve the therapeutic efficacy. However, in these PTT-combined regimens, in addition to the necessary photothermal (PT) conversion agents, other agents are often introduced.…”