Table 1.

Summary of physical strategies for EPR-adaptive delivery

Technique	Physiological Effect	Strengths	Weaknesses
Radiation	Decreased intratumoral and interstitial fluid pressure, reduced perfusion, alteration of ECM and vessel growth	Established therapeutic benefit, fits clinical workflow, high penetration depth, utilizes existing clinical resources	Radiation dose and fractionation schedule must be optimized for different tumor types to prevent delivery impairment, damage to surrounding tissue
Ultrasound	Transient disruption of endothelium increases vascular permeability	High penetration depth, non-invasive, localized, minimal damage to surrounding tissue, amenable to repeated treatments, can use existing clinically-approved microbubbles	Some strategies require image guidance, some techniques are not compatible with current clinical ultrasound systems
Hyperthermia	Vasodilation, increased vessel permeability	Versatile modes of delivery, potentially non-invasive, localized, exploitable side-effect of other external stimuli	Delivery resistance after repeat sessions, size limitations on eligible sensitizing agents
Photodynamic Therapy	Damage to vessels causes transient vascular leakiness	Co-registration of photosensitizer and applied light gives high specificity to area of illumination, potentially non-invasive	Low penetration depth of light necessitates superficial targets or invasive light delivery probes, delay required for photosensitizer build-up before light administration extends clinical burden