A quick description of New Cancer detection, tumor fighting, and metastatic fighting cancer cures.

There are several techniques recently developed that allow for the detection, selective cell-destroying, and eventually, cure for Metastasis in early trials in the last 5 years.  These are breakthrough technologies, if released to the public, could greatly lengthen human lifespans. 

The first technology that will be discussed is the ability to screen for cancer.  Imaging techniques of in-vivo tumors have several techniques.  This fluophore in the first paper discussed is a targetable “activatable” fluophore that can be controlled to only fluoresce when a current target molecule: “fluorophores could be controlled and predicted precisely by using the concept of intramolecular photoinduced electron transfer”[1].  Several fluophores were created DPAX and DMAX for singlet oxygen, DAF, DAMBO and DACals for nitric oxide. HPF, APF and APC for highly reactive oxygen, NiSPYs for peroxynitrite, DNAT-Me for glutathione S-transferase, TG-BetalGal for Beta-galactosidase and some more.

These fluophores are specifically targeted for specific ions and compounds known in cancer cells.  The reactions of each to determine which fluophore for which molecule is beyond my skill in metallo-organic chemistry.  Here is the table.

In-vivo cancer visualization is created by making targeted activatable fluorescent imagine probes.  Novel acidic pH-activatable probes based on the BODIPY fluophore were developed using the PeT – based rational design strategies, and conjugated them to a cancer-targeting monoclonal antibody.  This agent is activated after endocytotic internalization by sensing the pH change in the lysosome.  Here is a chart of the functioning of the fluorescence dye.

This reaction occurs within 1 minute after being applied.  Tiny tumors less than 1 mm size were successfully detected based on the concept of signal activation by using cancer-specific antibodies labeled with acidic-pH activatable fluorescence probes.

After the cancer is detected there is a lot of research into which drugs to use to kill the cancer.  A programmed drug-delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment.  Herein, a core–shell-based “nanodepot” consisting of a liposomal core and a crosslinked-gel shell (designated Gelipo) is developed for the sequential and site-specific delivery (SSSD) of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and doxorubicin (Dox). As a small-molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half-maximal inhibitory concentration (IC 50 ) of TRAIL and Dox co-loaded Gelipo (TRAIL/Dox-Gelipo) toward human breast cancer (MDA-MB-231) cells is 83 ng mL –1 (Dox concentration), which presents a 5.9-fold increase in the cytotoxicity compared to 569 ng mL –1 of Dox-loaded Gelipo (Dox-Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA-MB-231 xenograft tumor animal model.[2]

The conventional chemotherapeutic drugs attack the tumors by interrupting processes or inhibiting substances essential for the replication and proliferation of the tumor cells. For example, co-delivery of doxorubicin (Dox) and paclitaxel (Ptx) by a polymeric nanoparticle could release both drugs simultaneously and efficiently within the cells. The released Ptx inhibits the intracytoplasmic microtubules disassembly that is required for cell proliferation, while Dox intercalates into the nuclear DNA and induced cell apoptosis. For the cancer gene therapy, siRNA for silencing the target genes in cancer cells and pDNA for implanting corrective genetic material into the cells, have been applied to coordinate with small-molecule drugs. A typical example involves a micellar nanocarrier for co-delivery of MDR-1 siRNA and Dox, the released siRNA in the cells downregulates the P-glycoprotein expression to improve the efficacy of Dox in the multi-drug resistant

cancer cells. [2]

Here is the results of the drugs administered to the tumor and the testing of various drugs. [C]  In vitro cytotoxicity of TRAIL-Gelipo, Dox-Gelipo and TRAIL/Dox-Gelipo after 30 min

of HAase pre-treatment toward MDA-MB-231 cells for 24 h.

As you can see, the chemical cocktail has a dramatic effect on the tumor after 14 days.  A further problem with tumors is the metastatic ability to grow in regions far away from the original tumor.  A recent technology was developed at Duke University to combat this.  Metastatic spread is the mechanism in more than 90% of cancer deaths, and current chemical options, such as systemic chemotherapy, are often ineffective.  This paper is about Synergistic Immuno Photothermal Therapy (SYMPHONY).    Immune checkpoint inhibition is a promising immunotherapy that aims to reverse signals from immunosuppressive tumor microenvironment. Programmed death-ligand 1 (PD-L1), a

protein overexpressed by many cancers, contributes to the suppression of the immune system and cancer immune evasion. PD-L1 binds to its receptor, PD-1 found on activated T cells, and inhibits

cytotoxic T-cell function, thus escaping the immune response. To reverse tumor-mediated immunosuppression, therapeutic anti-PD-1/PD-L1 antibodies have been designed to block the PD-L1/PD-1 interaction.  nanoparticle (NP)-mediated thermal therapy has recently demonstrated the potential to combine the advantages of precise cancer cell ablation with benefits of mild HT in tumor microenvironments. NPs have a natural propensity to extravasate from the tumor vascular network and accumulate in and around cancer cells due to the enhanced permeability and retention (EPR) effect. Among various types of nanoparticles, gold nanostars (GNS), whose sharp branches create a “lightning rod” effect that dramatically enhances the local electromagnetic (EM) field, are the most effective in converting light into heat for photothermal therapy (PTT).  The unique tip-enhanced plasmonics property of GNS can be optimally tuned in the near infrared (NIR) tissue optical window, where photons can travel further in healthy tissue to be ‘captured’ and converted into heat by GNS taken up preferentially in cancer cells. We have investigated the PEGylated GNS bio-distribution in mice as well as GNS uptake at both macroscopic and microscopic scales by using radiolabeling, CT and optical imaging methods. In addition, a recent toxicity study of aptamer-loaded GNS found no signs of acute toxicity.

In this experiment, only 1 tumor was treated, and the other tumor was not.  It was found that using the GNS+Laser+Anti-PD-L1 had the only group of mice that survived the cancer at all.  It is shown that this cocktail has the only chance of survival in bladder cancer tumors for any mice at all.

Hopefully, these cancer treatments will assist in the future for detecting, treating, and then treating metastatic cancer in the future and can be applied to human use.  Unfortunately, even in experiments, the survival rate is not very high at this point for cancer cures, but some chance of survival is better than no chance of survival.  It appears that Phototherapy, in addition with chemical cocktails gives the best chance of survival.

[1] Urano, Yasuteru. “Novel Live Imaging Techniques of Cellular Functions and in Vivo Tumors Based on Precise Design of Small Molecule-Based ‘Activatable’ Fluorescence Probes.” Current Opinion in Chemical Biology, vol. 16, no. 5-6, 2012, pp. 602–608., doi:10.1016/j.cbpa.2012.10.023.

[2] Jiang, Tianyue, et al. “Gel-Liposome-Mediated Co-Delivery of Anticancer Membrane-Associated Proteins and Small-Molecule Drugs for Enhanced Therapeutic Efficacy.” Advanced Functional Materials, vol. 24, no. 16, 2014, pp. 2295–2304., doi:10.1002/adfm.201303222.

Liu, Yang, et al. “Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) for the Treatment of Unresectable and Metastatic Cancers.” Scientific Reports, vol. 7, no. 1, 2017, doi:10.1038/s41598-017-09116-1.