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Updated: May 29, 2026
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Tumor vasculature is a key determinant for the efficiency of nanoparticle-mediated siRNA delivery
1siRNA Therapeutics, Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.
Abstract:
Delivering small interfering RNA (siRNA) to tumors using clinically viable formulations remains the primary technical hurdle that prevents the development of siRNA therapy for cancer treatment. Over the past several years, significant effort has been devoted to explore novel delivery strategies, whereas relatively little attention has been paid to understand the impact of physiological constrains such as tumor vasculature on the efficiency of siRNA delivery. Using the previously described positive-readout tumor models where successful siRNA delivery leads to an upregulation of β-galactosidase within tumor sections, we analyzed the spatial distribution of localized target knockdown within tumor sections relative to tumor hypoxia and found that stable nucleic acid lipid particle (SNALP), a lipid nanoparticle-based delivery system, predominantly delivers siRNA to areas adjacent to functional tumor blood vessels. Increasing tumor vascularity by ectopic expression of VEGF resulted in more efficient siRNA delivery to tumors using SNALP. SNALP-mediated delivery of a siRNA-targeting Ran GTPase led to target knockdown and significant antitumor efficacy in the highly vascularized HepG2-derived liver tumors, but not in the poorly vascularized HCT-116-derived liver tumors. These results highlight the significant impact of tumor vasculature on siRNA delivery and call for a more focused effort on addressing tumor penetration after extravasation, an area of only limited attention currently.
Insights
Stable nucleic acid lipid particles (SNALP) effectively deliver small interfering RNA (siRNA) to tumors near blood vessels. Tumor vascularity significantly impacts siRNA delivery efficiency and therapeutic outcomes in cancer treatment.
Area of Science:
- Biomedical research
- Cancer therapy
- RNA interference
Background:
- Effective delivery of small interfering RNA (siRNA) to tumors is crucial for cancer treatment.
- Tumor vasculature significantly impacts the efficiency of siRNA delivery, yet this factor is often overlooked.
- Stable nucleic acid lipid particle (SNALP) is a promising delivery system for siRNA therapeutics.
Purpose of the Study:
- To investigate the impact of tumor vasculature on siRNA delivery efficiency using SNALP.
- To analyze the spatial distribution of siRNA delivery relative to tumor hypoxia and vascularity.
- To evaluate the therapeutic efficacy of SNALP-mediated siRNA delivery in tumors with varying vascularity.
Main Methods:
- Utilized positive-readout tumor models to assess siRNA delivery and target knockdown.
- Analyzed spatial distribution of siRNA delivery in relation to tumor hypoxia and vascularity.
- Modulated tumor vascularity by ectopic expression of VEGF and evaluated SNALP delivery efficiency.
- Assessed SNALP-mediated siRNA delivery targeting Ran GTPase in HepG2 and HCT-116 liver tumor models.
Main Results:
- SNALP predominantly delivers siRNA to tumor areas adjacent to functional blood vessels.
- Increased tumor vascularity, achieved through VEGF expression, enhanced SNALP-mediated siRNA delivery.
- Significant target knockdown and antitumor efficacy were observed in highly vascularized HepG2 tumors.
- Limited siRNA delivery and efficacy were noted in poorly vascularized HCT-116 tumors.
Conclusions:
- Tumor vasculature is a critical determinant of SNALP-mediated siRNA delivery efficiency.
- Strategies to improve siRNA penetration into tumors after extravasation are needed for effective cancer therapy.
- Optimizing delivery systems considering tumor physiological constraints is essential for advancing siRNA-based cancer treatments.
