dual-functionalized delivery nanocomplex system for the transport of doxorubicin to cancer cells through the use of AS۱۴۱۱ aptamer and hyaluronic acid polymer that comprised polyethyleneimine and FOXM۱ aptamer

Lung cancer is one of the most common cancers in both genders today. Also Breast cancer is the second rank of malignancy in female mortality. Doxorubicin (DOX) is an antineoplastic medication for various types of cancer. Cardiotoxicity and short half-life in the body make it limited. We conjugated DOX onto nucleolin targeting aptamers (AS۱۴۱۱)-hyaluronic acid polymer (HA)-polyethylenimine (PEI)-FOXM۱ NPs for designing a novel targeted delivery system that can provide antitumor efficacy. The nucleolin-targeting aptamer (AS۱۴۱۱) is located in the nucleus of cells and displayed intensified expression levels within the plasma membrane of malignant cell populations. FOXM۱ Apt, a single-stranded DNA aptamer from the Forkhead family, plays a crucial role in cell carcinogenesis, proliferation and metastasis. Due to its biocompatibility and its ability to target cluster of differentiation-۴۴ (CD۴۴), hyaluronic acid (HA), a linear mucopolysaccharide, is an excellent candidate for drug delivery purposes. methods: The system's core consisted of PEI and the therapeutic FOXM۱ aptamer, which was coated by HA. Next, the AS۱۴۱۱ aptamer was loaded onto the nanocomplex. Afterward, DOX was added to AS۱۴۱۱-HA-PEI-FOXM۱ NP. The loading efficacy of DOX onto the nanoparticles was evaluated through fluorescence spectra and a calibration curve. The Electrophoretic Mobility Shift Assay (EMSA) was executed to establish the binding of AS۱۴۱۱ aptamer with HA-PEI-FOXM۱ NPs. centrifugal devices measured pH-triggered doxorubicin release. Flow cytometry analysis was conducted on A۵۴۹, ۴T۱, and L۹۲۹ cells to investigate cellular uptake. Finally, animal studies were conducted on female BALB/c mice. Biodistribution was determined with ex vivo imaging. Result: The results of characterization demonstrated that the size of spherical nanoparticles was smaller than ۲۰۰ nm which is appropriate for intravenous administration. The Gel Retardation Assay validates the bioconjugation process between each component of nanoparticle surfaces. After the addition of DOX to AS۱۴۱۱-HA-PEI-FOXM۱ NPs, The drug entrapment efficiency for DOX was ۵۳%. The in vitro release profile of DOX in DOX-AS۱۴۱۱-HA-PEI-FOXM۱NPs is controlled. The cell mortality with nano complex in target cancer cells(۴T۱ and A۵۴۹ cells) was considerably increased compared to nontarget cells(L۹۲۹, normal cells). The flow cytometry analysis and fluorescence imaging demonstrated increased cellular absorption of nanocomplex in target cells. The in vivo studies showed that anti-tumor drug accumulated in lung and breast tumor cells specifically. Conclusion : For delivering FOXM۱ aptamer and doxorubicin to A۵۴۹ and ۴T۱ cells (target), a novel targeted delivery system based on PEI, HA, and AS۱۴۱۱ aptamer was formulated.The supreme purpose is an improved targeting technique for more efficient treatment. Some advantages of this formulation can be mentioned, including high DOX loading and enhanced tumor cell sensitivity to DOX, facile design, improved stability of the drug, reduced systemic exposure, and increased cellular uptake.

کلیدواژه ها:

Aptamer ، FOXM۱ ، AS۱۴۱۱ ، Doxorubicin ، cancer