Engineering microrobots for targeted cancer therapies from a medical perspective

Abstract

Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.

Fig. 1. Different approaches towards targeting of cancer over normal cells.

a Biological targeting: example of targeted killing of cancer cells through synthetic lethality by exploiting genetic differences in the BRCA genes between normal and cancer cells using conventional small-molecule drugs (PARP inhibitors). b Physical targeting: engineering drug-delivery systems that can reach and deliver cargo to cancer over normal cells, based on passive/targeted diffusion of nanoparticles that can vary in their make-up (organic and inorganic materials), and display a wide range of physical properties (top). Drug loading, targeting and shielding of nanoparticles can be achieved in distinct ways, as illustrated for nanoliposomes as a key example (bottom). Analogous options exist for other nanoparticle types but require different engineering methods depending on the underlying material, e.g., to allow for surface functionalisation with targeting ligands. PEG polyethylene glycol. *Strictly speaking nanoparticles are defined by the International Union of Pure and Applied Chemistry (IUPAC) as particles of any shape ranging in dimension from 1 to 100 nm, but structures up to several 100 nm in size are commonly included.

Fig. 2. Characteristics of solid tumours and their drug accessibility.

a Drugs applied by various routes face a variety of long-range targeting challenges such as clearance by the mononuclear phagocyte system (MPS), and organs such as the kidney, liver, lung and spleen, as well as endothelial barriers applicable to tumours developing for instance in the brain or testis. b Solid tumours develop a higher-order architecture leading to different characteristics in their core versus their exterior, aspects important for considering/exploiting when developing therapeutic strategies efficient for shorter-term physical tumour targeting towards the hypoxic core. Poor vascularisation inside the core region of the tumour (left) is at the core of the enhanced permeability and retention (EPR) effect (right).

Fig. 3. Mechanisms of actuation for microrobots.

Key examples for a biological migration modes, b physical propulsion and c chemical actuation.

Fig. 4. Microrobot approaches for overcoming long-range tumour-targeting challenges.

a Magnetic field (left) and light (right) steering approaches applicable for in vivo applications. b Exploiting physiological travel routes: Left: sperm microrobots in female reproductive tract; tissues relevant for a variety of cancers are highlighted. Right: RBCs and leucocytes travel through vessels that connect and supply tumour tissues. c Resisting and exploiting harsh physiological environments: chemically actuated microrobots have a neutralising effect on the acidic environment inside the stomach lumen. Aq aqueous, g gaseous, RBCs red blood cells.

Fig. 5. Microrobot approaches for overcoming short-range tumour-targeting challenges.

a Intrinsic tumouritaxis exhibited by some bacteria, such as Clostridia, and higher eukaryotic immune cells. b FDA-approved pipeline for engineering CAR-T cells as a personalised cancer medicine (left). CAR-T cells target cancer cells by recognising tumour antigens on their surface that induce downstream TCR signalling, including cytotoxic perforin and granzyme reactions. c Targeting tumours via specific surface markers on the cells themselves, or on the vessels that supply the tumour. Using chemical/physical engineering methods, targeting moieties can be coupled directly to the microrobot surfaces or as part of non-motile nanoparticles, as illustrated for nanoliposomes as a key example. Analogous approaches can be applied to other nanoparticles (see also Fig. 1B). Particularly for the nanoparticle-coupling approach, care needs to be taken to limit microrobot size to regimes appropriate for the intended application (see main text for details). For most cellular strategies, the underlying cells can be genetically engineered to express targeting moieties on their surface. CAR chimeric antigen receptor, TCR T-cell receptor.

Fig. 6. Drug-loading and release mechanisms for the three classes of microrobots: cellular, synthetic and hybrid types.

a Surface loading of drugs applicable to all three microrobot classes. b Drug internalisation via integration of drug-loaded porous materials such as hydrogels into the manufacturing process of mostly synthetic microrobots (top), cellular uptake of external drugs by passive (e.g., diffusion, osmosis) or active (e.g., endocytosis) means (bottom left) as well as drug loading of cellular or cell-based hybrid microrobots through cellular expression/production of therapeutic endogenous compounds such as granzymes/perforin by T cells or genetically engineered drugs such as prodrug enzymes (bottom right). Red arrow indicates overlapping methods for the indicated processes. c Release of surface-loaded and/or internalised microrobot drugs can be mediated by chemical, biochemical, enzymatic and/or physical means. d Attractive biological drug-release methods include somatic cell fusion of sperm/spermbots. NIR near infra-red light.

Fig. 7. Key synthetic and hybrid microrobot examples for in vivo applications towards cancer treatment.

a Synthetic chemical microrobots tested in the gastrointestinal system in living mice. Reproduced with permission from ref. © AAAS. b Hybrid microrobots based on magnetotactic bacteria targeting hypoxic tumour cores. Reproduced with permission from ref. © Springer. c Spirulina-based magnetic hybrid microrobots explored in vivo. MBs magnetic beads, NIR near infra-red light, IR infra-red light. Reproduced with permission from ref. © AAAS.

Fig. 8. Cross-disciplinary approaches required to maximise translatability and patient uptake of microrobotic drugs in the future.

Interactions between basic scientists such as biological, chemical and physical engineers, as well as input from clinicians, patients and the public are critical for further developing microrobots as therapeutic and diagnostic anticancer tools.