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Sequential Drug Release to Modulate Collagen Synthesis and Promote Micelle Penetration in Tumors
Zhoujiang Chen1,2, Weiping Liu1, Xin Wang1
1Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, 111 North first Section, second Ring Road, Chengdu 610031, P.R. China.
Abstract:
Cancer chemotherapy is confronted with insufficient drug penetration in tumors. "Solid tumor priming" is proposed to modulate the abnormal tumor microenvironment but suffers from limited digestion efficiency and underlying tumor metastasis. Losartan (Los) and telmisartan (Tel) are well-known antihypertensive agents and show capabilities in inhibiting collagen synthesis by cancer-associated fibroblasts. Up to now, no attempt has been made to achieve a local and sustained release of Los and Tel in tumors while alleviating the side effects after systemic administration. In the previous study, micelles were loaded into fiber fragments to achieve high drug accumulation in tumors after intratumoral administration. In the current study, Los and Tel are blend electrospun into fibers to retard the collagen synthesis and promote the tissue penetration of micelles released from fiber fragments. The loading of Los and Tel shows no effect on the micelle release, cellular uptake, and cytotoxicities of micelles released from fiber fragments. Because of the hydrophilicity, Los is almost released out after 5 day in pH 6.8 buffers, while hydrophobic Tel is gradually released for 30 days. Thus, fiber fragments with loaded Los and Tel are combined to achieve a sustained remodeling of collagen levels in tumors, and the combination with a ratio of 1/2 showed the most significant and consistent reductions of collagen I levels in tumors, as determined via Western blotting, Masson's trichrome, and immunofluorescence staining. A wide distribution of micelles is observed in the tumor tissues, as well as strong fluorescence in the distal sections of tumors during 14 days. Compared with pristine fiber fragments, the sequential release of Los and Tel induces stronger inhibition of tumor growth, lower expression of hypoxia-inducible factor-α (HIF-α), and fewer tumor metastases to lungs. Thus, this study demonstrates a feasible strategy to enhance the local retention and even distribution of chemotherapeutic agents in tumors in favor of therapeutic efficacy.
Insights
This study developed blend electrospun fibers releasing losartan and telmisartan to improve chemotherapy drug delivery in solid tumors. The sequential drug release enhanced micelle distribution, reduced tumor growth, and inhibited metastasis.
Area of Science:
- Biomedical Engineering
- Materials Science
- Oncology
Background:
- Chemotherapy faces challenges with poor drug penetration in solid tumors, limiting treatment efficacy.
- Existing strategies like "solid tumor priming" have limitations in digestion efficiency and can promote tumor metastasis.
- Losartan (Los) and telmisartan (Tel), antihypertensive drugs, show potential in inhibiting cancer-associated fibroblast collagen synthesis.
Purpose of the Study:
- To develop a local and sustained release system for Losartan and Telmisartan within tumors.
- To investigate the effect of blend electrospun fibers on collagen synthesis and micelle penetration in tumor tissues.
- To evaluate the therapeutic efficacy of sequential drug release on tumor growth and metastasis.
Main Methods:
- Blend electrospinning of Losartan and Telmisartan into fiber fragments loaded with micelles.
- In vitro assessment of micelle release kinetics, cellular uptake, and cytotoxicity.
- In vivo evaluation of collagen level reduction, micelle distribution, tumor growth inhibition, and lung metastasis in tumor-bearing models.
Main Results:
- Blend electrospun fibers achieved sustained release of Losartan (5 days) and Telmisartan (30 days) at pH 6.8.
- The sequential release of Los and Tel significantly reduced collagen I levels in tumors.
- Micelles showed wide distribution in tumor tissues, enhanced local retention, and reduced tumor growth and lung metastasis.
- The 1/2 ratio of Los/Tel demonstrated the most effective collagen reduction.
Conclusions:
- Blend electrospun fibers provide a feasible strategy for sustained local delivery of Losartan and Telmisartan in tumors.
- This approach enhances the penetration and distribution of chemotherapeutic agents, improving therapeutic outcomes.
- The developed system effectively remodels the tumor microenvironment, inhibits tumor progression, and reduces metastasis.
