Drug Delivery Mechanisms in Solid Tumors

Solid tumours present a unique set of physical and biological barriers that impede the efficient delivery of anticancer agents. Leaky and heterogeneous vasculature gives rise to the enhanced permeability and retention effect, allowing nanoscale carriers to accumulate selectively in the tumour interstitium. However, elevated interstitial fluid pressure and dense extracellular matrix hinder convective transport and limit penetration depth. To overcome these challenges, a spectrum of strategies has been developed. Passive approaches exploit the tumour’s abnormal vasculature, while active targeting employs ligands or antibodies to bind cell-surface receptors. Multi-stage carriers undergo programmable transformations—such as size reduction or charge reversal—to navigate distinct compartments. Physical modalities including focused ultrasound or hyperthermia can transiently enhance vascular permeability and trigger on-demand drug release. Simultaneously, modulation of the tumour microenvironment through vascular normalisation or stromal reprogramming reduces pressure gradients and enhances perfusion. Computational models at molecular, cellular and tissue scales now guide the optimisation of carrier design, dosing schedules and combination regimens, with the aim of maximising intratumoural concentration, minimising off-target toxicity and achieving durable therapeutic responses.

Research from Nature Portfolio

Polymeric micelles have been engineered to deliver a fibroblast-reprogramming agent at markedly reduced doses, thereby alleviating stromal barrier functions and lowering tumour stiffness. Encapsulation of the small-molecule inhibitor yielded enhanced intratumoural accumulation and selective uptake by cancer-associated fibroblasts, resulting in tissue softening that was monitored non-invasively via shear wave elastography. When combined with nano-encapsulated chemotherapeutics and immune checkpoint blockade, this approach boosted T-cell infiltration, cured resistant tumours in preclinical models and established immunological memory. These findings illustrate how targeted remodelling of the microenvironment can potentiate both drug and immunotherapy delivery in solid malignancies.

Drug Delivery Mechanisms in Solid Tumors publication trend

The graph below shows the total number of articles in drug delivery mechanisms in solid tumors across all publications each year (not limited to Nature Index journals).

Technical terms

Enhanced Permeability and Retention (EPR) effect: phenomenon by which nanoparticles accumulate preferentially in tumour tissue due to abnormal vasculature and impaired lymphatic drainage.

Interstitial Fluid Pressure (IFP): hydrostatic pressure within the tumour interstitial space that opposes convective movement of fluids and therapeutic agents.

Micellar encapsulation: formation of amphiphilic assemblies that entrap hydrophobic drugs within their core, enabling controlled release profiles.

Nanocarrier: engineered nanoscale vehicle designed to transport and deliver drugs to specific cellular or tissue targets.

Stimuli-sensitive delivery: strategy in which carriers alter their properties or release their payload in response to external triggers such as ultrasound, temperature or pH.

References

1. Ultrasound‐mediated nano‐sized drug delivery systems for cancer treatment: Multi‐scale and multi‐physics computational modeling. Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology (2023).
2. Stimuli-sensitive nano-drug delivery with programmable size changes to enhance accumulation of therapeutic agents in tumors. Drug Delivery (2023).
3. Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models. Nature Communications (2022).
4. An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment. Cancers (2022).
5. Overview of Methods for Overcoming Hindrance to Drug Delivery to Tumors, with Special Attention to Tumor Interstitial Fluid. Frontiers in Oncology (2015).