BiomaterialsSouth China University of Technology's team Youyong Yuan has developed a reactive oxygen species wake-up self-amplifying degradable polymer for enhancing cancer immunotherapy

iNature

While stimulus-responsive polymers have become a promising strategy for smart cancer treatment, limited polymer degradation and insufficient drug release remain a challenge
.
On September 12, 2022, Yuan Youyong's team at South China University of Technology published an online article titled "Cinnamaldehyde-based poly(thioacetal): A ROS-awakened self-amplifying degradable polymer for enhanced cancer immunotherapy" at Biomaterials (IF=15).
Research paper that developed a ROS-wake self-amplifying degradable cinnamaldehyde (CA)-based poly (sulfur acetal) polymer
for enhancing cancer immunotherapy.

The polymer consists
of a sulfuric acetal (TA) group in response to ROS and a CA as a ROS generating agent.

Endogenous ROS induces TA group cracking to interpret the release of CA, which in turn triggers the degradation process of self-amplifying polymers, and after CA release, more ROS generation is promoted by mitochondrial dysfunction, resulting in large
polymer degradation.

What's more, polythioacetal itself triggers immunogenic cell death (ICD) of tumor cells, and its side chains can bind to indolemine 2,3-dioxygenase 1 (IDO-1) inhibitors, reversing the immunosuppressive tumor microenvironment and enabling synergistic tumor immunotherapy
.

The self-amplific degradable polysulfide developed in this work provides insights
for the development of novel stimulus-responsive polymer-enhanced cancer immunotherapies.

In recent years, the tremendous development of stimulus-reactive polymers has witnessed the targeted delivery and site-specific release
of various therapeutic agents.

These polymers can trigger reactions
by using external (light, magnetic field, or ultrasonic) or internal (pH, temperature, enzyme, or redox potential) stimulation.

For traditional stimulus-responsive polymers, a stimulus reacts with a sensitive bond, causing the polymer to degrade
.

However, the degradation rate of these polymers may remain the same and even decrease
after the stimulus dissipates.

In contrast, much attention has been paid to the study of cascading degradable polymers that utilize a self-destruct reaction triggered by the lysis of a single sensitive covering agent, resulting in a cascading degradation reaction
.

Since the self-destruct reaction occurs only when the capping agent is removed, the polymer may undergo incomplete degradation
due to the stoichiometric imbalance between the amount of stimulation relative to the capping agent.

To solve this problem, researchers recently developed innovative self-amplifying degradable polymers
.

In these polymers, polymer degradation is triggered by specific triggers, which in turn generate more triggers during polymer degradation, leading to polymer degradation autoamplification
.

While much progress has been made in this area, there have been no reports
of the development of novel self-amplifying degradable polymers with therapeutic effects.

Levels of reactive oxygen species (ROS) are one of the unique markers of cancer because levels in cancer cells (50-100 × 10-6 M) are much higher than in normal tissues (≈20 × ^10-9 M
).

Therefore, intracellular ROS can be used as a stimulus for drug delivery in cancer cells
.

A variety of ROS-responsive units, such as aryl borates, thioulactones, and selenium-containing bonds, are used to develop ROS-responsive polymers
.

However, endogenous intracellular ROS levels are not sufficient to effectively trigger degradation of sensitive bonds, so increasing intracellular ROS levels
are often required.

Therefore, there is an urgent need to develop new ROS-responsive polymers with self-amplification degradation capabilities for efficient drug delivery
.

A recent study of the mechanistic pattern map (figure from Biomaterials) reported that disruption of intracellular homeostasis by ROS-induced elevated oxidative stress promotes immunogenic cell death (ICD
).

ICD is the backbone of cancer immunotherapy, which stimulates anti-cancer immunity by promoting tumor infiltration through cytotoxic T lymphocytes (CTLs
).

Unfortunately, less than 1% of available cancer drugs, including doxorubicin (DOX), oxaliplatin, and several ruthenium complexes, are able to induce ICD
.

There are currently no reports of stimulus-responsive polymers capable of inducing ICD, so there is an urgent need to develop novel drugs
capable of inducing ICD.

In this study, the authors developed a novel reactive oxygen species (ROS) wake-up cinnamaldehyde (CA)-based self-amplifying degradable polythioacetal polymer
.

The polymer consists of the ROS-reactive thioacetal (TA) group and CA as a ROS generator and can be used in synergistic cancer immunotherapy
.

CA is a (FDA)-approved food additive isolated from cinnamon that is known to boost intracellular ROS
through mitochondrial dysfunction.

Thus, endogenous ROS within cancer cells releases CA by cutting TA groups, triggering a series of cascading events
.

CA induces more ROS production through mitochondrial dysfunction, resulting in large
polymer degradation.

What's more, the self-amplifying degradable polymer triggers the ICD
of tumor cells.

The side chain of the polymer can bind to the indolemine 2,3-bioxygenase 1 (IDO-1) inhibitor 1-methyl-lDL-tryptophan (1-MT), thereby reversing the immunosuppressive tumor microenvironment and polyethylene glycol (PEG) to obtain a bipro-ROS-responsive polymer PEG-PTA_1-MT
.

PEG-PTA_{1-MT can self-assemble} into nanoparticles in an aqueous solution, which accumulates
in tumor tissue after administration by systemic injection.

After being uptaken by cancer cells, the poly (thioacetal) backbone of the polymer has a high-density thioacetal group that reacts strongly to a small amount of endogenous ROS to release CA, and the released CA is induced by mitochondrial dysfunction to produce more ROS
.

The resulting ROS, in turn, amplifies polymer degradation, inducing ICDs of tumor cells for use in cancer immunotherapy
.

In addition, 1-MT released from polymer side chains can reverse the immunosuppressive tumor microenvironment
by inhibiting IDO-1-mediated tryptophan (Trp) degradation and CTL failure.

These events work together to enhance cancer immunotherapy
.
Original link: https://doi.
org/10.
1016/j.
biomaterials.
2022.
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