The conventional anticancer strategies of chemotherapy and radiotherapy are highly effective at killing cancer cells but they lack target specificity and can also kill healthy noncancerous cells, resulting in unwanted side effects. Recently, targeted cancer therapies such as monoclonal antibodies have been designed to reduce potential toxicity and achieve a higher therapeutic index. However, limitations such as high production costs and low penetration of solid tumours has encouraged the development of cheaper and more effective targeted therapies.
Nucleic acid aptamers are short single‑stranded oligonucleotides that fold into unique three‑dimensional structures. They can bind to a wide range of targets, including proteins, small molecules, metal ions, viruses, bacteria and whole cells. They serve as “chemical antibodies” because of their high affinity and specificity for their targets. Aptamers also have advantages compared to antibodies such as rapid in vitro selection, cell‑free chemical synthesis, low immunogenicity and superior tissue penetration because of their smaller size.
Nucleic acid aptamers are generated from nucleic acid random‑sequence using a systematic evolution of ligands by exponential enrichment (SELEX) technology. SELEX is a process of effectively selecting aptamers for different targets. To date, SELEX technology has successfully generated thousands of aptamers some of which can bind to various surface molecules and tumour‑associated membrane proteins on cancer cells. Furthermore, after target‑specific aptamers have been identified they can be chemically synthesised, modified and optimised for clinical applications. Therefore, aptamers are promising agents for biomarker discovery, early diagnosis and targeted cancer therapy.
Theranostics is a strategy that combines multiple functions such as targeting, stimulus‑responsive drug release and diagnostic imaging into a single platform often with the aim of developing personalised medicine to avoid unwanted side effects.
In a paper by Zhao et al they used an 8‑mer peptide aptamer as a ligand targeting heat shock protein 70 (Hsp70). This aptamer was covalently bound to the periphery of nanoparticles to achieve both targeting and potential chemosensitisation functionality against Hsp70. Doxorubicin was also bound to the polymeric carrier as a model chemotherapeutic drug through a degradable hydrazone bond, enabling pH‑controlled release under mildly acid conditions that mimics the environment in endosomes/lysosomes of tumour cells. Furthermore, in order to track the nanoparticles, cyanine‑5 (Cy5) was incorporated into the polymer as an optical imaging agent.
Zhao et al. demonstrated:
Controlled release of Doxorubicin in vitro was achieved via the pH sensitive hydrazone bond, which is relatively stable at physiological conditions (pH 7.4) but could effectively be cleaved under mildly acidic conditions (pH 5), which mimic those found in endosomal and lysosomal environments.
A greater cellular uptake of the Hsp70 aptamer targeted polymer compared to the untargeted analogue.
The targeted polymer was shown to accumulate in vesicles and therapeutic release was observed in live MDA‑MB‑468 breast cancer cells using confocal microscopy.
Incorporation of the Hsp70 targeted aptamer onto the polymer provided significantly enhanced accumulation within xenograft breast tumours compared to the untargeted analogue, visualised using in vivo optical imaging.
The in vivo study suggested that the Hsp70 aptamer targeted polymer also had longer retention at the site of the tumour presumably because of the ligand‑receptor interaction.
Overall, these results indicate that this polymeric carrier shows promise as a cancer theranostic for breast cancer and potentially other solid tumour types. The 8‑mer peptide aptamer allowed for active targeting to tumour cells in vitro and in vivo with simultaneous drug release.