Nature sub-issue: Novel nanoparticles provide innovative cancer chemotherapy immunotherapy

According to a new study, researchers at the University of Pittsburgh have designed cancer-fighting nanoparticles that can deliver chemotherapy drugs and a new immunotherapy
at the same time.

The new immunotherapy approach silences genes found by researchers that are involved in immunosuppression
.
When combined with existing chemotherapy drugs and packaged into tiny nanoparticles, the therapy shrunk tumors
in mouse models of colon and pancreatic cancer.

"There are two innovative aspects of our study: the discovery of a new therapeutic target and a new nanocarrier that is very effective in the selective delivery of immunotherapy and chemotherapy drugs," said
senior author Song Li, professor of pharmacy at the Pitt School of Pharmacy and researcher at UPMC Hillman Cancer Center.
I'm excited about this study because it's highly translatative.

We don't yet know if our approach is effective for patients, but our findings suggest a lot of potential
.
”

Chemotherapy is the backbone of cancer treatment, but residual cancer cells persist and cause tumors to return
.
This process involves a lipid called phosphatidylserine (PS), which is normally found in the inner layers of tumor cell membranes but migrates to the cell surface
under the influence of chemotherapy drugs.
On the surface, PS acts as an immunosuppressant, protecting the remaining cancer cells from damage
by the immune system.

Researchers at the University of Pitt found that treatment with the chemotherapy drugs fluorouracil and auplatin (FuOXP) led to elevated levels of Xkr8, a protein
that controls the distribution of PS on cell membranes.
This finding suggests that blocking Xkr8 prevents cancer cells from shunting PS to the cell surface, allowing immune cells to clear cancer cells
left after chemotherapy.

In a separate study recently published in Cell Reports, Dr.
Yi-Nan Gong, assistant professor of immunology at Pitt University, also identified Xkr8 as a novel therapeutic target to boost the anti-tumor immune response
.

The team designed a piece of genetic code called short interfering RNA (siRNA) that stops the production of a specific protein — in this case, Xkr8
.
After packaging siRNA and FuOXP into double-acting nanoparticles, the next step is to target them to tumors
.

Nanoparticles are often too large to pass through intact blood vessels in healthy tissue, but they can reach cancer cells because tumors are sometimes angiodysplasia and have small holes that allow them to pass through
.
But this approach to targeting tumors is limited because many human tumors don't have pores large enough for nanoparticles to pass through
.

"Like a ferry carrying people from one side of the river to the other, we wanted to develop a mechanism that allows nanoparticles to pass through intact blood vessels without relying on pores," Li said
.

To develop such a ferry, the researchers decorated the surface of
the nanoparticles with chondroitin sulfate and polyethylene glycol.
These compounds extend their residence time in the bloodstream by binding to tumor blood vessels and cell receptors commonly found on tumor cells, helping nanoparticles target tumors and avoid healthy tissue
.

When injected into mice, about 10 percent of the nanoparticles reach the mice's tumors, a significant improvement
over most other nanocarrier platforms.
A previous analysis of published studies found that, on average, only 0.
7% of the nanoparticle dose reached the target
.

Compared to nanoparticles containing the chemical drug FuOXP alone, double-acting nanoparticles significantly reduce the migration
of immunosuppressive PS to the cell surface.

Next, the researchers tested their platform
in mouse models of colon and pancreatic cancer.
Compared to animals receiving placebo or FuOXP doses, animals treated with nanoparticles containing FuOXP and siRNA had a better tumor microenvironment, more anti-cancer T cells and fewer immunosuppressive regulatory T cells
.

As a result, mice that received siRNA-FuOXP nanoparticles significantly reduced tumor size compared to mice that received only one treatment
.

Li said the study also points to the potential
to combine FuOXP-siRNA nanoparticles with another immunotherapy called checkpoint inhibitors.
Immune checkpoints such as PD-1 act like brakes on the immune system, but checkpoint inhibitors work by releasing the brakes to help immune cells fight cancer
.

The researchers found that FuOXP nanoparticles containing or without siRNA increased PD-1 expression
.
But when they added PD-1 inhibitor drugs, the combination therapy showed significant improvements
in tumor growth and survival in mice.

Their goal is to translate their new therapy into the clinic, and the team is now validating their findings with more experiments and further evaluating potential side effects
.