Development of 5-Fluorouracil/pH-Responsive Adjuvant-Embedded Extracellular Vesicles for Targeting αvβ3 Integrin
Jiseung Kim1, Eunsol Lee1, Eun Seong Lee2
1Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si 1462, Gyeonggi-do, Republic of Korea.
Abstract:
To selectively target and treat murine melanoma B16BL6 tumors expressing αvβ3 integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic arginine-glycine-aspartic acid peptide (cRGD, serving as a tumor-targeting ligand), and 5-fluorouracil (5-FU, employed as a model antitumor drug). The pH-responsive adjuvant, essential for modulating drug release, was synthesized by chemically conjugating 3-(diethylamino)propylamine (DEAP) to deoxycholic acid (DOCA, a lipophilic substance capable of integrating into EVs' membranes), denoted as DEAP-DOCA. The DOCA, preactivated using N-(2-aminoethyl)maleimide (AEM), was chemically coupled with the thiol group of the cRGD-DOCA through the thiol-maleimide click reaction, resulting in the formation of cRGD-DOCA. Subsequently, DEAP-DOCA, cRGD-DOCA, and 5-FU were efficiently incorporated into EVs using a sonication method. The resulting tumor-targeting EVs, expressing cRGD ligands, demonstrated enhanced in vitro/in vivo cellular uptake specifically for B16BL6 tumors expressing αvβ3 integrin receptors. The ionization characteristics of the DEAP in DEAP-DOCA induced destabilization of the EVs membrane at pH 6.5 through protonation of the DEAP substance, thereby expediting 5-FU release. Consequently, an improvement in the in vivo antitumor efficacy was observed for B16BL6 tumors. Based on these comprehensive in vitro/in vivo findings, we anticipate that this EV system holds substantial promise as an exceptionally effective platform for antitumor therapeutic delivery.
Insights
Engineered extracellular vesicles (EVs) target melanoma tumors expressing αvβ3 integrin receptors. These novel EVs deliver 5-fluorouracil (5-FU) with pH-triggered release, enhancing antitumor efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Melanoma treatment requires targeted drug delivery to overcome limitations of conventional therapies.
- Extracellular vesicles (EVs) offer a promising platform for drug delivery due to their biocompatibility and targeting capabilities.
- αvβ3 integrin receptors are overexpressed in certain melanoma tumors, presenting a specific therapeutic target.
Purpose of the Study:
- To engineer tumor-specific extracellular vesicles (EVs) for targeted delivery of 5-fluorouracil (5-FU) to melanoma tumors.
- To incorporate a pH-responsive adjuvant for controlled drug release and enhance antitumor efficacy.
- To evaluate the in vitro and in vivo performance of these targeted EVs in a murine melanoma model.
Main Methods:
- Engineered EVs by incorporating a pH-responsive adjuvant (DEAP-DOCA) and a tumor-targeting ligand (cRGD) with 5-FU.
- Utilized a pH-sensitive linker (DEAP) for controlled release of 5-FU at acidic tumor microenvironments (pH 6.5).
- Incorporated cRGD ligands onto EVs to target αvβ3 integrin receptors overexpressed on B16BL6 melanoma cells.
Main Results:
- Engineered EVs demonstrated enhanced in vitro and in vivo cellular uptake in B16BL6 melanoma tumors.
- The pH-responsive adjuvant facilitated triggered release of 5-FU at pH 6.5, enhancing drug delivery.
- Significant improvement in in vivo antitumor efficacy was observed in the murine melanoma model.
Conclusions:
- The developed EV system effectively targets melanoma tumors expressing αvβ3 integrin receptors.
- pH-triggered drug release from EVs enhances therapeutic outcomes.
- This engineered EV platform shows significant potential for advanced antitumor drug delivery.
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