Study of a Multidrug Delivery Microrobot for the Synergistic Therapy of Cancer


Student thesis: Doctoral Thesis

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Award date22 Sept 2023


Multiple-drug combination therapy provides an effective strategy for malignant tumor treatment. A major problem associated with the administration of drug combinations is the inability to control drug ratios in vivo due to the diverse pharmacokinetic properties of each drug. Therefore, co-delivery of drugs to cancer cells at a predefined synergistic ratio is vital for combination cancer therapy. In this study, we propose that the loading of different drugs on different regions of a single magnetic microrobot can enhance the synergistic effect of cancer treatment by combining magnetic targeting transportation.

Firstly, we designed a three-dimensional-printed multidrug delivery microrobot with an ellipsoidal structure, which was inspired by the fish structure with three hydrogel components: skeleton, head, and body. The skeleton was made by poly(ethylene glycol) diacrylate (PEGDA) embedded with iron oxide (Fe3O4) nanoparticles, and it can respond to magnetic fields for microrobot actuation and drug-targeted delivery. The head and body were made of biodegradable gelatin methacryloyl (GelMA) and served as drug storage units. Compared with traditional microrobots made of a single material, the use of two different hydrogels on the same microrobot provided the microrobot with sufficient mechanical strength and satisfied the biodegradation and drug-carrying requirements for cancer treatment.

Secondly, the locomotion behaviour and drug release of multidrug delivery microrobots were analysed. The results verified that the microrobot can be transported precisely to the desired position in a microchannel under a gradient electromagnetic field. We further actuated the multiple microrobots in cell culture environment. They can be simultaneously transported in a biological environment to achieve targeted drug delivery. The release results of Dil encapsulated by GelMA microrobots demonstrated the sustained release of Dil and verified that delivery using GelMA not only allowed drugs to exert their functional effects but also avoided the accumulation of large drug doses around the desired site. In addition, the degradation results of GelMA microrobots indicated that enzymatic degradation of GelMA can further accelerate the release of encapsulated drugs.

Thirdly, a case study of the cancer therapy effects of multidrug delivery microrobots carrying acetylsalicylic acid (ASA) and doxorubicin (DOX) was conducted, and the synergistic anticancer effect was verified in vitro and in vivo. The in vitro results showed that compared with single-drug delivery GelMA@ASA and GelMA@DOX microrobots, the multidrug delivery microrobots have better anticancer effects by accelerating HeLa cell apoptosis and inhibiting HeLa cell metastasis. And the synergistic therapeutic effect of ASA and DOX carried by multidrug delivery microrobots is even better than the treatment effect using a random mixture of GelMA@ASA and GelMA@DOX microrobots. In vivo studies further demonstrated that the multidrug delivery microrobots improved the efficiency of tumor inhibition and induced response to anti-angiogenesis.

In summary, multidrug delivery microrobots carrying ASA and DOX exhibited excellent anticancer effects. These microrobots reveal for the first time the concept of separate loading of multiple drugs to different parts of the same microrobot for synergistic cancer therapy. This method provides a way for developing effective combination therapies for cancer.