Engineering in Medicine To Address the Challenge of Cancer Drug Resistance: From Micro- and Nanotechnologies to Computational and Mathematical Modeling

Abstract

Drug resistance has profoundly limited the success of cancer treatment, driving relapse, metastasis, and mortality. Nearly all anticancer drugs and even novel immunotherapies, which recalibrate the immune system for tumor recognition and destruction, have succumbed to resistance development. Engineers have emerged across mechanical, physical, chemical, mathematical, and biological disciplines to address the challenge of drug resistance using a combination of interdisciplinary tools and skill sets. This review explores the developing, complex, and under-recognized role of engineering in medicine to address the multitude of challenges in cancer drug resistance. Looking through the "lens" of intrinsic, extrinsic, and drug-induced resistance (also referred to as "tolerance"), we will discuss three specific areas where active innovation is driving novel treatment paradigms: (1) nanotechnology, which has revolutionized drug delivery in desmoplastic tissues, harnessing physiochemical characteristics to destroy tumors through photothermal therapy and rationally designed nanostructures to circumvent cancer immunotherapy failures, (2) bioengineered tumor models, which have benefitted from microfluidics and mechanical engineering, creating a paradigm shift in physiologically relevant environments to predict clinical refractoriness and enabling platforms for screening drug combinations to thwart resistance at the individual patient level, and (3) computational and mathematical modeling, which blends in silico simulations with molecular and evolutionary principles to map mutational patterns and model interactions between cells that promote resistance. On the basis that engineering in medicine has resulted in discoveries in resistance biology and successfully translated to clinical strategies that improve outcomes, we suggest the proliferation of multidisciplinary science that embraces engineering.

Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer

“…Exocytosis of nanomedicines and endosomal recycling escape is a challenge-solution that is often considered during engineering of nanoparticle-based drugs [ 4 ]. This biological requires that nanoparticles retain properties to allow endosomal escape and release of therapeutic payloads within cells [ 8 ].…”

“…A variety of materials and technologies have been deployed to achieve this goal, which includes the use of lipids, polymers, inorganic carriers, hydrogels, and even plasmonic strategies that exploit thermal dynamics [ 3 ]. However, drug resistances have been shown to affect both the therapies themselves and the bioengineering strategies that are used to improve treatment response [ 4 ]. Therefore, rational development of engineered nanotherapeutics that harnesses discoveries in cancer biology and drug resistance may overcome many of these challenges.…”

“…For example, decorating nanoparticles with aptamers, antibodies, proteins, and small peptides, such as arginylglycylaspartic acid (RGD), have shown improvement in reaching tumor cells and avoiding some of the toxicity associated with the cytotoxic payloads [ 3 ]. However, resistance mechanisms such as endosomal recycling and molecular biological signals that rely on cell survival pathways can limit the efficacy of these approaches [ 4 ]. For example, we recently made the discovery that dense lipid rafts are induced and accumulate on the surface of taxane-experienced cancer cells, which have phenotypically switched to a drug tolerant state [ 6 ].…”

Photoacoustics for listening to metal nanoparticle super-aggregates

“…The diameter D of the sphere has been extrapolated by the dimensionless parameter x = n m D/λ obtained from equation (3).…”

Structural Study of the Hydration of Lipid Membranes Upon Interaction With Mesoporous Supports Prepared by Standard Methods and/or X‐Ray Irradiation

“…The ability to manipulate small amounts of fluids, in particular in the field of medicine and biology, where some samples are available in small quantities and/or very expensive, has boosted the development of both microfluidics and, more recently, nanofluidics (Xu, 2018;Scheler et al, 2019;Craig et al, 2020). A further improvement of micro/nanofluidic systems for handling and detecting (bio)samples would consist in the insertion of materials presenting desired functionalities in chosen areas of the devices.…”