Related Experiment Video
Updated: Jul 14, 2025
Author Spotlight: Validating Cancer Therapy Responses with Desmoplastic Spheroid Models
Published on: September 27, 2024
Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic
Jinxu Cao1,2, Jing Wu1, Peng Yang1
1Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
Abstract:
In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.
Insights
This study developed a nanoparticle delivering all-trans retinoic acid (ATRA) to pancreatic tumors. The nanoparticle enhances drug delivery by reducing tumor stroma, significantly suppressing pancreatic cancer growth and metastasis.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Pancreatic cancer features dense desmoplastic stroma limiting drug penetration.
- Activated pancreatic stellate cells (PSCs) drive this pro-tumorigenic stroma.
- All-trans retinoic acid (ATRA) can revert PSCs to quiescence but faces delivery challenges.
Purpose of the Study:
- To develop a nanoparticle system for enhanced ATRA delivery to pancreatic tumors.
- To overcome limitations in ATRA's efficacy due to poor tumor penetration and PSC targeting.
- To improve the tumor microenvironment for better chemotherapy delivery and efficacy.
Main Methods:
- Constructed RFC-modified gelatin/oleic acid nanoparticles loaded with ATRA (RNP@ATRA).
- Utilized enzyme-triggered release (APN, MMP-2) for nanoparticle accumulation and ATRA release within the tumor.
- Evaluated nanoparticle accumulation, PSC reversion, stroma reduction, and anti-tumor efficacy in vivo.
Main Results:
- RNP@ATRA demonstrated significantly higher intratumoral accumulation compared to free ATRA.
- The nanoparticles effectively released ATRA in response to tumor enzymes, promoting interstitial penetration.
- RNP@ATRA treatment reverted activated PSCs, reduced stromal synthesis, and alleviated vascular compression.
- Combined RNP@ATRA and chemotherapy markedly suppressed tumor growth and metastasis with no added toxicity.
Conclusions:
- The developed RNP@ATRA nanoplatform efficiently delivers ATRA to pancreatic tumors by remodeling the stroma.
- This approach enhances the delivery and efficacy of chemotherapeutics in stroma-rich pancreatic cancer.
- The study presents a promising nanoplatform for treating pancreatic cancer and other tumors with dense stromal components.
