Stimuli-sensitive nano-drug delivery with programmable size changes to enhance accumulation of therapeutic agents in tumors

Abstract

Nano-based drug delivery systems hold significant promise for cancer therapies. Presently, the poor accumulation of drug-carrying nanoparticles in tumors has limited their success. In this study, based on a combination of the paradigms of intravascular and extravascular drug release, an efficient nanosized drug delivery system with programmable size changes is introduced. Drug-loaded smaller nanoparticles (secondary nanoparticles), which are loaded inside larger nanoparticles (primary nanoparticles), are released within the microvascular network due to temperature field resulting from focused ultrasound. This leads to the scale of the drug delivery system decreasing by 7.5 to 150 times. Subsequently, smaller nanoparticles enter the tissue at high transvascular rates and achieve higher accumulation, leading to higher penetration depths. In response to the acidic pH of tumor microenvironment (according to the distribution of oxygen), they begin to release the drug doxorubicin at very slow rates (i.e., sustained release). To predict the performance and distribution of therapeutic agents, a semi-realistic microvascular network is first generated based on a sprouting angiogenesis model and the transport of therapeutic agents is then investigated based on a developed multi-compartment model. The results show that reducing the size of the primary and secondary nanoparticles can lead to higher cell death rate. In addition, tumor growth can be inhibited for a longer time by enhancing the bioavailability of the drug in the extracellular space. The proposed drug delivery system can be very promising in clinical applications. Furthermore, the proposed mathematical model is applicable to broader applications to predict the performance of drug delivery systems.

Keywords:

• Drug delivery
• cancer nanomedicine
• tumor penetration
• hyperthermia
• multi-stage delivery system
• focused ultrasound
• temperature-sensitive nanoparticles
• pH-responsive nanoparticles

Acknowledgments

M. Soltani and Farshad Moradi Kashkooli would like to acknowledge the Iran Science Elites Federation for their support.

Author contributions

M.S (Mohammad Souri): Conceptualization, Investigation, Methodology, Formal analysis, Visualization, Validation, Writing-original draft; M.K.S: Methodology, Formal analysis, Visualization, Validation; M.C: Investigation, Resources, Writing—review & editing; F.M.K. Investigation, Methodology, Supervision, Writing—review & editing; A.F: Investigation, Resources; M.R.M: Supervision, Project administration; A.R: Writing—review & editing, Funding acquisition; V.M.S: Methodology, Writing—review & editing; M.S (M. Soltani): Supervision, Project administration, Writing_review & Editing.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval statement

NA

Data availability statement

The data supporting this work are accessible upon reasonable request from the corresponding author.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.