Nanoparticle drug delivery vehicles that maintain potency yet diminish toxicity of maytansinoids as cancer therapeutics.
- Reduces cancer metastasis and could be used as a prophylactic treatment.
- Acts as a delivery vehicle for maytansinoids that simultaneously maintain potency, increase efficacy, and diminish toxicity.
- Shows reduced side effects of maytansinoids and increased drug circulation time in the blood.
The plant-derived maytansine and its derivatives, maytansinoids, have significant anti-tumorigenic effects. Maytansinoids inhibit tubulin polymerization and were over 1000-fold more potent than the chemotherapeutic, paclitaxel, in vitro. However clinical trials resulted in a lack of tumor specificity, no substantial clinical benefits, and severe side effects that ultimately led tothe termination of the trials. In order to take advantage of the benefits of maytansinoids, research has focused on antibody-drug conjugates. These conjugates show improved pharmacokinetics and pharmacodynamics. Several antibody matyansinoid conjugates are currently in clinical trials, including trastuzumab-DM1 for the treatment of HER-2 positive metastatic breast cancer. This class of drugs, however, involves a complicated antibody manufacturing and conjugating process and may be improved with better drug delivery vehicles.
Increasing evidence indicates that the selective delivery of anti-cancer drugs into a tumor mass by nanoparticles can minimize toxicity to normal tissues and maximize bioavailability and cell killing effects. Ideally, nanocarriers for the drug delivery should stay intact during the blood circulation, but once they reach the tumor sites, the payload should be released promptly. Emory researchers have developed pH sensitive polymeric nanoparticles for the delivery of maytansinoids and other highly potent drugs to tumors. The nanoparticles are stable at a neutral environment similar to blood (pH = 7.4) and rapidly disassociate under acidic conditions (pH < 5) like those found in the tumor microenvironments and inside intracellular organelles. These self-assembled nanoparticles significantly increased drug circulation time in the blood and improved the efficacy of maytansinoids in vivo. In addition, the same study showed that side effects were dramatically reduced when compared to standard maytansinoids.
Compound shows increased efficacy and reduced toxicity in vivo.