Nanoparticle Drug Delivery Avoids Cancer Cells' Protein Pumps

To prevent these, doctors may limit the amount of Dox given to each patient so that the total amount a patient receives over her or his entire lifetime is 550 milligrams per square meter, or less. Furthermore, the necessity to stop treatment to protect the patient from heart disease may diminish the usefulness of Dox in treating cancer.

A team of investigators at the Houston Methodist Research Institute (TX, USA) reported developing a method to avoid the toxic effects of Dox while delivering it in high concentrations to its target inside tumor cells.

In the March 14, 2016, online edition of the journal Nature Biotechnology they described development of an injectable nanoparticle generator (iNPG), a micrometer-sized porous silicon-based particle loaded with a doxorubicin-poly(L-glutamic acid) conjugate (pDox) that was created using a pH-sensitive cleavable linker. These iNPG particles were injected into mice, and accumulated at tumors due to natural tropism and to the enhanced vascular dynamics at the tumor sites.

Once inside the cancer cell, the acidic pH in the vicinity of the nucleus released the drug conjugate from the nanoparticles. Upon release from iNPG, pDox spontaneously formed nanometer-sized particles in aqueous solution. These pDox nanoparticles were transported to the perinuclear region of the cell and cleaved to free the Dox, which killed the cell. The direct delivery to the nucleus avoided excretion of the Dox by cellular drug efflux protein pumps.

Compared to treatment with its individual components or with current therapeutic formulations, iNPG-pDox showed enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40%–50% of treated mice. These animals remained in remission for at least eight months, which is equivalent to about 24 years of long-term survival following metastatic disease for humans.

"This may sound like science fiction, like we have penetrated and destroyed the Death Star, but what we discovered is transformational. We invented a method that actually makes the nanoparticles inside the cancer and releases the drug particles at the site of the cellular nucleus. With this injectable nanoparticle generator, we were able to do what standard chemotherapy drugs, vaccines, radiation, and other nanoparticles have all failed to do," said contributing author Dr. Mauro Ferrari, CEO of the Houston Methodist Research Institute. "If this research bears out in humans, and we see even a fraction of this survival time, we are still talking about dramatically extending life for many years. That is essentially providing a cure in a patient population that is now being told there is none."

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