Nat Nanotech: It turns out that tumors are divided into "cold" and "hot". This nanotechnology that "warms" tumors is expected to become a cancer nemesis!

Immune checkpoint blockade therapy (ICB therapy), as the current "net celebrity" therapy in the field of cancer treatment, is bringing hope to more patients
.

However, it should be noted that only some patients can benefit from it.

Therefore, the medical community is committed to researching ways to transform "immune cold tumors" into "immune hot tumors" to enhance the efficacy of ICB therapy.
In other words, it is to first adopt some therapies to make immunogenic tumors (immune cold tumors) free.
More immune cells gather around, increase the expression of biomarkers, and "transform" into immunogenic tumors (immune fever tumors), and then combine with ICB therapy to achieve a more effective tumor killing effect
.

Among them, immunogenic chemotherapy, as one of the therapies to "heat" tumors, has shown great potential to cooperate with ICB therapy, but due to poor pharmacokinetics and non-specific toxicity to healthy tissues and immune cells, Chemotherapy has been hindered in improving the efficacy of ICB

Recently, a research team from the University of Arizona in the United States published a research article titled "Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy" in Nature Nanotechnology.
The research invented a new type of nanotherapy platform and transmembrane.
As a method of "heating" tumors, transport technology uses the anti-cancer drug camptothecin to cooperate with ICB therapy.
In colorectal cancer and melanoma mouse models, it can not only eradicate most advanced tumors, block tumor metastasis, but also activate Memory immunity prevents cancer recurrence
.

Camptothecin (CPT) is an effective chemotherapeutic drug that can treat a variety of cancers
.

It has the potential to enhance the killing power of cytotoxic T lymphocytes (CTL) to kill tumor cells .

As a result, the researchers synthesized four different SM-CPTs and selected Camptothesome-4 with the highest drug loading, the best stability, and the least side effects
.

After using Camptothesome-4 in CT26 tumor-bearing mice to evaluate the pharmacokinetics and tissue distribution, the test results show that Camptothesome-4 significantly prolongs the circulatory half-life, and through effective CPT release, more The drug is delivered to the tumor with superior safety

The synthesis design process of SM-CPT

The synthetic design process of SM-CPT The synthetic design process of SM-CPT

Next, in order to clarify whether Camptothesome-4 retains the anti-cancer activity of CPT and whether it can be combined with PD-1/PD-L1 and other ICB therapies to enhance the anti-cancer effect, the researchers compared single-dose Camptothesome-4, free CPT and Onivyde (A FDA-approved CPT derivative) for the treatment of CT26 tumor-bearing mice
.

The test results showed that in the tumors treated with Camptothesome-4, the biomarkers PD-L1, PD-1 and IFN-γ were significantly up-regulated.

In addition, after the researchers injected a single dose of Camptothesome-4 intravenously into CT26 tumor-bearing mice plus three intraperitoneal injections of anti-PD-L1 monoclonal antibody, the combination therapy could significantly hinder the development of tumors, and it was effective in one-fifth of the mice.
Eradicate the tumor
.

This effect is also remarkable in the MC38 mouse model.
The combination of blocking PD-L1/PD-1 therapy and Camptothesome-4 can eradicate tumors in five of six mice and significantly prolong the survival of mice.
Rate
.

At the same time, the five surviving mice still had no tumors after receiving MC38 cells again, which means that this combination therapy can activate memory immunity and prevent tumor recurrence

Tumor changes in CT26 tumor-bearing mice after using PD-L1/PD-1 therapy + Camptothesome-4

Tumor changes in CT26 tumor-bearing mice after PD-L1/PD-1 therapy + Camptothesome-4 Tumor changes in CT26 tumor-bearing mice after PD-L1/PD-1 therapy + Camptothesome-4

During the experiment, the researchers discovered the expression of the biomarker IDO1 in CT26 and MC38 colorectal cancer cells.
Therefore, they chose to use DOX (adriamycin) as the transmembrane carrier and use the IDO1 inhibitor IND (indoximod, Indomod) was integrated into Camptothesome-4 to evaluate its anti-cancer potential
.

The test results showed that when combined with PD-L1/PD-1 blockade, DOX-IND/camptothesome-4 eliminated about 400 mm3 tumors in three-fifths of the mice and prolonged the survival time of the mice

The synthetic design process of DOX-IND/camptothesome-4

The synthetic design process of DOX-IND/camptothesome-4 The synthetic design process of DOX-IND/camptothesome-4

The researchers took the experiment a step further and established mouse models of advanced and metastatic in situ colorectal cancer and melanoma, and added folic acid to target them
.

When used together with folic acid targeting, DOX-IND/camptothesome-4 further inhibited tumor growth and eradicated tumors in 33.

Therapeutic effects of various therapies on advanced tumors in mice

Therapeutic effects of various therapies on advanced tumors in mice The therapeutic effects of various therapies on advanced tumors in mice

In short, this experimental study demonstrates the remarkable efficacy of the combination therapy based on this nano-platform in the treatment of early and clinically difficult to treat late metastatic tumors
.
The authors of the study stated that their nanotechnology platform can be used to provide a series of cancer therapies.
At the same time, the use of sphingomyelin lipid carriers approved by the FDA will give this platform an important lead in drug development.
They look forward to The start of early clinical trials
.

Original source:

Original source:

Wang, Z.
, Little, N.
, Chen, J.
et al.
Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy .
Nat.
Nanotechnol.
(2021).
https://doi.
org/10.
1038 /s41565-021-00950-z.

Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy in this message