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Selective Priming of Tumor Blood Vessels by Radiation Therapy Enhances Nanodrug Delivery
Sijumon Kunjachan1, Shady Kotb2,3, Robert Pola4
1Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States. sijumon@gmail.com.
Abstract:
Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.
Insights
This study introduces a novel method to enhance drug delivery in pancreatic cancer by using radiation-activated gold nanoparticles to disrupt tumor blood vessels. This approach significantly improves nanodrug penetration and delivery into solid tumors.
Area of Science:
- Oncology
- Nanomedicine
- Biomedical Engineering
Background:
- Solid tumors present significant pathophysiological barriers, limiting effective drug delivery.
- Poorly permeable tumor blood vessels in pancreatic adenocarcinoma restrict intratumoral drug permeation.
- Novel strategies are needed to overcome neoplastic barriers for improved cancer therapy.
Purpose of the Study:
- To investigate a novel strategy for enhancing drug delivery by selectively modulating the tumor vascular barrier.
- To assess the efficacy of radiation-activated gold nanoparticles in breaching tumor vascular barriers.
- To evaluate the impact of tumor vascular modulation on nanodrug delivery and tumor penetration.
Main Methods:
- Utilized a human pancreatic cancer model.
- Employed tumor endothelial-targeted gold nanoparticles activated by clinical radiation.
- Assessed changes in tumor vascular permeability using noninvasive MRI and fluorescence studies.
- Quantified changes in vascular parameters (Ktrans, Kep, Ve) to evaluate drug delivery.
Main Results:
- Radiation-activated gold nanoparticles induced physical vascular damage and altered tumor vascular permeability.
- Demonstrated a greater than two-fold increase in nanodrug delivery post-vascular modulation.
- Observed functional changes in tumor blood vessels correlating with augmented drug delivery.
Conclusions:
- The proposed dual-targeted therapy effectively breaches the tumor vascular barrier, improving nanodrug delivery in pancreatic cancer.
- This approach holds potential for treating other nonresectable, intransigent tumors resistant to standard therapies.
