Overcoming Multidrug Resistance in Drug Delivery Systems

Multidrug resistance (MDR) remains a major obstacle to effective pharmacotherapy in cancer, infectious diseases and central nervous system disorders. Resistance often arises through elevated activity of efflux transporters such as P-glycoprotein, alterations in drug-metabolising enzymes and changes in cellular uptake pathways. Modern drug delivery systems seek to circumvent these mechanisms by combining active inhibition of efflux pumps, bypassing barriers via nanocarrier design and co-delivery of synergistic agents. Strategies include the use of polymer- and lipid-based nanoparticles to encapsulate chemotherapeutics, stimuli-responsive materials that release payloads under specific conditions and formulation excipients with inherent transporter-modulating activity. By enhancing drug solubility, permeability and retention at target sites, these approaches aim to restore therapeutic efficacy while minimising systemic toxicity. Their global significance is underscored by advances in oral bioavailability of antibiotic and anticancer agents, improved penetration of the blood-brain barrier and the potential to overcome resistance in off-patent medicines, thereby reducing the costs of treatment and widening access to effective therapies.

Research from Nature Portfolio

Recent studies have investigated a quaternised high-molecular-weight chitosan derivative as an absorptive enhancer in intestinal epithelial models. This modified polymer transiently opened tight junctions, as evidenced by reversible reductions in transepithelial electrical resistance and disrupted localisation of junctional proteins. In parallel, the derivative bound to P-glycoprotein, inducing conformational changes that reduced efflux activity without altering expression levels. These combined effects led to significantly increased transport of model substrates across Caco-2 monolayers. The work demonstrates how chemical modification of biocompatible polymers can achieve dual modulation of paracellular permeability and efflux pump function, offering a promising route to enhance oral delivery of drugs subject to MDR mechanisms.

Overcoming Multidrug Resistance in Drug Delivery Systems publication trend

The graph below shows the total number of articles in overcoming multidrug resistance in drug delivery systems across all publications each year (not limited to Nature Index journals).

Technical terms

P-glycoprotein (P-gp): an ATP-dependent efflux transporter that extrudes a wide range of drugs from cells, contributing to multidrug resistance.

Efflux transporter: a membrane protein that actively exports substances from the intracellular to the extracellular space, reducing intracellular drug accumulation.

Nanocarrier: a nanoscale vehicle, such as a polymeric nanoparticle, liposome or micelle, designed to encapsulate and deliver therapeutic agents.

Liposome: a spherical vesicle composed of lipid bilayers used to encapsulate hydrophilic and hydrophobic drugs for controlled delivery.

Micelle: an aggregate of amphiphilic molecules that can solubilise hydrophobic drugs within its core for improved delivery.

Multidrug resistance (MDR): the capacity of cells or organisms to withstand treatment by multiple drugs, often due to overexpression of efflux transporters or metabolic enzymes.

References

1. Liposome-Micelle-Hybrid (LMH) Carriers for Controlled Co-Delivery of 5-FU and Paclitaxel as Chemotherapeutics. Pharmaceutics (2023).
2. Quaternization of high molecular weight chitosan for increasing intestinal drug absorption using Caco-2 cells as an in vitro intestinal model. Scientific Reports (2023).
3. Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability. Pharmaceutics (2021).
4. High Solubilization and Controlled Release of Paclitaxel Using Thermosponge Nanoparticles for Effective Cancer Therapy. Pharmaceutics (2021).