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Published on: November 1, 2017
Hypoxia-Responsive Golgi-Targeted Prodrug Assembled with Anthracycline for Improved Antitumor and Antimetastasis
Chenqi Guo1,2, Mengying Wu2, Zhaofei Guo2
1Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China.
Abstract:
Tumor metastasis is an intricate multistep process regulated via various proteins and enzymes modified and secreted by swollen Golgi apparatus in tumor cells. Thus, Golgi complex is considered as an important target for the remedy of metastasis. Currently, Golgi targeting technologies are mostly employed in Golgi-specific fluorescent probes for diagnosis, but their applications in therapy are rarely reported. Herein, we proposed a prodrug (INR) that can target and destroy the Golgi apparatus, which consisted of indomethacin (IMC) as the Golgi targeting moiety and retinoic acid (RA), a Golgi disrupting agent. The linker between IMC and RA was designed as a hypoxia-responsive nitroaromatic structure, which ensured the release of the prototype drugs in the hypoxic tumor microenvironment. Furthermore, INR could be assembled with pirarubicin (THP), an anthracycline, to form a carrier-free nanoparticle (NP) by emulsion-solvent evaporation method. A small amount of mPEG2000-DSPE was added to shield the positive charges and improve the stability of the nanoparticle to obtain PEG-modified nanoparticle (PNP). It was proved that INR released the prototype drugs in tumor cells and hypoxia promoted the release. The Golgi destructive effect of RA in INR was amplified owing to the Golgi targeting ability of IMC, and IMC also inhibited the protumor COX-2/PGE2 signaling. Finally, PNP exhibited excellent curative efficacy on 4T1 primary tumor and its pulmonary and hepatic metastasis. The small molecular therapeutic prodrug targeting Golgi apparatus could be adapted to multifarious drug delivery systems and disease models, which expanded the application of Golgi targeting tactics in disease treatment.
Insights
This study introduces a novel prodrug that targets the Golgi apparatus to treat cancer metastasis. This Golgi-targeting strategy shows promise for developing new anti-metastasis therapies.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Drug Delivery
Background:
- Tumor metastasis is a complex process involving Golgi apparatus dysfunction in cancer cells.
- Current Golgi-targeting strategies primarily focus on diagnostic probes, with limited therapeutic applications.
- The Golgi complex presents a promising therapeutic target for combating cancer metastasis.
Purpose of the Study:
- To develop a novel prodrug (INR) that targets and disrupts the Golgi apparatus for cancer therapy.
- To create a hypoxia-responsive drug delivery system for enhanced therapeutic efficacy in the tumor microenvironment.
- To evaluate the anti-metastatic potential of the developed nanoparticle formulation (PNP).
Main Methods:
- Design of a prodrug (INR) comprising indomethacin (IMC) for Golgi targeting and retinoic acid (RA) for Golgi disruption, linked by a hypoxia-responsive moiety.
- Formulation of INR into a carrier-free nanoparticle (PNP) using emulsion-solvent evaporation, with PEGylation for stability.
- In vitro and in vivo evaluation of drug release, Golgi disruption, anti-metastatic activity, and therapeutic efficacy against primary tumors and metastases.
Main Results:
- INR effectively released prototype drugs (IMC and RA) in tumor cells, with hypoxia enhancing this release.
- Indomethacin (IMC) enhanced the Golgi-disrupting effect of retinoic acid (RA) and inhibited protumor COX-2/PGE2 signaling.
- The PEGylated nanoparticle formulation (PNP) demonstrated significant efficacy against 4T1 primary tumors and their pulmonary and hepatic metastases.
Conclusions:
- A novel small-molecule therapeutic prodrug targeting the Golgi apparatus was successfully developed.
- The Golgi-targeting prodrug strategy, integrated into a nanoparticle delivery system, offers a promising approach for treating cancer metastasis.
- This work expands the application of Golgi-targeting tactics in disease treatment and can be adapted for various drug delivery systems and models.
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