Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity.

INTRODUCTION: The toxic side effects of doxorubicin (DOX) have limited its use in chemotherapy. Neither liposomal DOX nor pegylated liposomal DOX are able to completely resolve this issue. This is a proof-of-concept study testing aptamer-drug conjugate (ApDC) targeted delivery systems for chemotherapeutic drugs. METHODS: Aptamer library targeting human epidermal growth factor receptor 3 (HER3) was screened and affinity was determined by enzyme-linked immunosorbent assay. Specificity was tested in MCF-7HER3-high, BT474HER3-high, and 293THER3-negative cells using flow cytometry and confocal microscopy. We further developed a HER3 aptamer-functionalized liposome encapsulating DOX and the efficiency of this ApDC was detected by cellular uptake analysis and cell viability assay. In MCF-7 tumor-bearing mice, tumor targeting evaluation, efficacy, toxicity and preliminary pharmocokinetic study was performed. RESULTS: The candidate #13 aptamer had highest affinity (Kd =98±9.7 nM) and specificity. ApDC effectively reduces the half maximal inhibitory concentration of DOX compared with lipsome-DOX and free DOX. In vivo imaging and preliminary distribution studies showed that actively targeted nanoparticles, such as Apt-Lip-DOX molecules, could facilitate the delivery of DOX into tumors in MCF-7-bearing mice. This targeted chemotherapy caused greater tumor suppression than other groups and alleviated side effects such as weight loss, low survival rate, and organ (heart and liver) injury demonstrated by H&E staining. CONCLUSION: The results indicate that targeted chemotherapy using the aptamer-drug conjugate format could provide better tolerability and efficacy compared with non-targeted delivery in relatively low-dose toxic drugs.

IL-4Rα aptamer-liposome-CpG oligodeoxynucleotides suppress tumour growth by targeting the tumour microenvironment.

Tumour immunosuppressive microenvironments inhibit antigen-specific cellular responses and interfere with CpG-mediated immunotherapy. Overcoming tumour microenvironment (TME) immunosuppression is an important strategy for effective therapy. This study investigated the ability of a tumour-targeting IL-4Rα aptamer-liposome-CpG ODN delivery system to introduce CpG into tumours and overcome the immunosuppressive TME. The IL-4Rα-liposome-CpG delivery system was prepared. FAM-CpG visualisation was used to demonstrate tumour targeting in vitro and in vivo. Anti-tumour effects of this delivery system were evaluated in CT26 tumour-bearing mice. Mechanisms for conquering the TME were investigated. FAM-CpG was better distributed into the tumours upon treatment with IL-4Rα-liposome-FAM-CpG compared to distribution in the control group in vitro and in vivo. IL-4Rα-aptamer-liposome-CpG treatment inhibited distinct myeloid-derived suppressor cell populations in tumours and bone marrow. Similar profiles were observed for regulatory T cells in tumours. In CT26 tumour-bearing mice, IL-4Rα-liposome-CpG treatment exhibited enhanced anti-tumour activity. Increased mRNA levels of TNF-α, IL-2, and IL-12, and decreased mRNA levels of VEGF, IL-6, IL-10, MMP9, arginase-1, inducible NOS, CXCL9, p-Stat3, and NF-κB were observed in tumours upon IL-4R-liposome-CpG-treatment. The results suggested that pharmacologic targeting by the IL-4R aptamer-liposome-CpG system improves TME therapeutic benefit and provides a rationale for cancer immunotherapies.

[Advances in the study of aptamer-based drug for targeting therapy].

Aptamers are randomly selected from single-stranded oligonucleotide libraries by systematic evolution of ligands technology exponential enrichment(SELEX). They bind to various targets like metal ions, nucleic acids, proteins, small organic compounds, and even entire organisms. Candidate aptamers are predicted to be highly effective in producing targeting effects for certain diseases like cancer, macular degeneration, acute coronary syndrome, von Willebrand factor related disorder disease and so on. Aptamers may also serve as drug-carriers helping drugs to be released in specific regions and tissues. Compared with other types of targeting ligands, aptamers have an array of unique advantageous features, which make them promising to develop aptamer-drug conjugates(ApDCs) for targeted-oriented therapy. Deep investigation into Ap DCs discovery and development may promote the process of biological and biomedical analysis. In this review, we summarize the advances of drug discovery and drug delivery using aptamers in basic and clinical trials in recent years, and meanwhile analyze its advantages and challenges in biomedical studies.