Scientists believe they’ve devised a way to use antimiRs as anticancer drugs by showing that a specific antimiR could treat diffuse large B-cell lymphoma (DLBCL) in mice.
In a letter to Nature, the group explained that microRNAs known as oncomiRs can play a causal role in the onset and maintenance of cancer when they are overexpressed.
So inhibiting oncomiRs using antisense oligomers, or antimiRs, has seemed a promising therapeutic strategy. But physiological and cellular barriers have prevented targeted delivery.
Frank Slack, PhD, of Beth Israel Deaconess Medical Center in Boston, Massachusetts, and his colleagues have devised a new antimiR delivery platform and shown that it can inhibit DLBCL growth in vivo.
The team created a mouse model to study miR-155, an oncomiR that, when overexpressed, leads to DLBCL.
“We hypothesized that we could inhibit the function of miR-155 by way of an antisense molecule that would bind to miR-155,” Dr Slack said. “[However,] there are a number of significant obstacles to reaching the tumor cell target. Some roadblocks are clearance through the kidneys and accumulation in the liver, which absorbs any systemically injected agent.”
“Furthermore, even if you are able to reach your targeted cells, the molecules must cross cell membranes and escape degradation from a process known as endocytosis. If you can picture our antisense molecule being a warhead, we had to find the right ‘rocket’ to actually transport it to its target.”
The “rocket” turned out to be a peptide with a low-pH induced transmembrane structure (pHLIP), meaning it inserts into cell membranes only when cells are low in pH. And tumor cells provided the ideal environment.
“When we attached our antisense warhead to the pHLIP peptide, not only did it successfully insert itself into the tumor cell, but it also dragged the antisense molecule itself into the cell,” Dr Slack said. “Now the ‘warhead’ could deploy and actually inhibit microRNA function and control cancer growth.”
In the miR-155/DLBCL mouse models, pHLIP-anti155 slowed tumor growth, suppressed the metastatic spread of neoplastic lymphocytes to other organs, reduced the onset of splenomegaly, and delayed the development of conspicuous lymphadenopathy, when compared to control mice.
Responses with pHLIP-anti155 were similar to those observed in mice that received doxorubicin or CHOP, but pHLIP-anti155 proved less toxic than the other treatments.
“With this delivery platform, we should also be able to transform other RNAs into druggable targets,” Dr Slack said, adding that low pH is also an issue in kidney disease, myocardial infarction, stroke, and infection, among other conditions. So this type of therapy could have wide applications.
