Strengthening Gastric Cancer Therapy by Trastuzumab-Conjugated Nanoparticles with Simultaneous Encapsulation of Anti-MiR-21 and 5-Fluorouridine

Abstract

Background/Aims: MicroRNA-21 is an oncogenic miR (oncomiR) frequently elevated in gastric cancer (GC). Overexpression of miR-21 decreases the sensitivity of GC cells to 5-fluorouridine (5-Fu) and trastuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including anti-miRNA oligonucleotides (AMOs). This study is a continuation of earlier findings involving poly(ε-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target GC with HER2 receptor over-expression using anti-miRNA-21 (AMO-21) and 5-Fu. Methods: HER-PEG-PCL NPs were prepared by one-step carbodiimide coupling using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAc) and Sulfo-NHS in aqueous phase. Covalent coupling of amino groups at the surface of PEG-PCL with the carboxyl groups of trastuzumab was analyzed by X-ray photoelectron spectroscopy (XPS). AMO-21/5-Fu NPs were formulated by a double-emulsion solvent evaporation technique. The cell line specificity, cellular uptake and AMO-21 delivery were investigated through the rhodamine-B-labeled 6-carboxyfluorescein (FAM)-AMO-21-PEG-PCL NPs coated with or without the antibody in both Her2-positive (NUGC4) and negative GC cells (SGC7901) visualized by fluorescence microscopy. The cytotoxicity of the HER-PEG-PCL NPs encapsulating AMO-21 was evaluated by MTT and apoptosis. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to examine miR-21 and phosphatase and tensin homolog (PTEN) and Sprouty2 expression in GC cell lines. The antitumor effects of AMO-21/5-Fu NPs were compared with other groups in xenograft gastric cancer mice. Results: The antibody conjugates significantly enhanced the cellular uptake of NPs. The AMO-21/5-Fu NPs effectively suppressed the target miRNA expression in GC cells, which further up-regulated PTEN and Sprouty2. As a result, the sensitivity of HER2-expressing gastric cancer to trastuzumab and 5-Fu were enhanced both in vitro and in vivo. The approach enhanced the targeting by trastuzumab as well as antibody-dependent cellular cytotoxicity (ADCC) of immune effector cells Conclusions: Taken together, the results provide insight into the biological and clinical potential of targeted AMO-21 and 5-Fu co-delivery using modified trastuzumab for GC treatment.

<p>Research Progress in microRNA-Based Therapy for Gastric Cancer</p>

“…89 Hu's team and Wu's team each introduced PCL-PEG nanoparticles coated with trastuzumab (HER-PEG-PCL NPs) to control the delivery of the inhibitor of miRNA. 12,90 These studies, respectively, verified the inhibitory function of miR-34a, miR-21, miR-542-3p, and miR-200c on GC in vitro or in vivo. Importantly, these strategies involve the use of synthetic nanoparticles and compounds to attempt to solve the problem of improving microRNAs-targeted transport to tumors so as to promote the clinical application of microRNA-based targeted therapies.…”

“…10 In addition, synthetic carriers have been used to deliver the confirmed anti-tumor miRNAs to the precise tumor site so as to directly inhibit GC, such as "PPP", which was constructed by modifying phenylboronic acid onto the surface of a polyamidoamine dendrimer and poly (ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) nanoparticles coated with trastuzumab. 11,12 Indeed, these studies have led to a major advance in the clinical application of miRNAs. Moreover, these findings suggested that in addition to their function as biomarkers, miRNAs can also play roles in the treatment of tumors.…”

Molecular Network Pathway Of ERBB In Diffuse-Type Gastric Cancer, Mesenchymal Stem Cells And Epithelial-Mesenchymal Transition

“…It is also demonstrated that ERBB3 is involved in resistance to EGFR or ERBB2 targeted therapy for cancer [27]. Furthermore, the study of nanoparticles targeting ERBB2 and microRNA21 suggests the importance of ERBB signaling in cancer [28]. These insights indicate the significance of regulation of ERBB2 and ERBB3 signaling in cancer.…”

Synthesis of Biotin-Modified Galactosylated Chitosan Nanoparticles and Their Characteristics in Vitro and in Vivo

“…Furthermore, it also can prevent uracil and orotic acid uptake into RNA to inhibit the effects of RNA, and thus interferes with the biosynthesis of RNA, DNA, and proteins [3,4]. 5-FU has a broad anticancer spectrum and obvious curative effects, and either alone or in combination with other anticancer drugs, it plays an important role in the treatment of most common tumors of the digestive tract such as gastric cancer [5], colorectal carcinoma [6], and hepatoma [7]. To date, it cannot be replaced by other drugs, especially for the treatment of gastrointestinal tumors.…”