Multidrug resistance, or MDR, is a process in which tumors become impervious to numerous drugs and is a major cause of failure in cancer chemotherapy.
Image Credit: Javier Regueiro/Shutterstock.com
Most often, tumor cells acquire MDR by increasing their production of proteins that pump out medicines from the cell, making the chemotherapies ineffective.
Scientists have now created nanoparticles that discharge bursts of calcium within tumor cells, blocking the pumping of drugs and reversing MDR. The team has reported the study in the ACS’ Nano Letters journal.
P-glycoprotein (P-gp) is a pump protein that usually plays a major role in MDR.It is present in the cell membrane, where it utilizes energy in the form of adenosine triphosphate (ATP) to remove drugs from tumor cells.
Investigators have used various ways in an attempt to inhibit P-gp, for example, by depleting ATP or using small-molecule inhibitors. But the approaches used by scientists to date can lead to side effects, or they are not stable in the body. Certain treatments can be hard to prepare.
Kaixiang Zhang, Zhenzhong Zhang, Jinjin Shi, and collaborators wished to inhibit P-gp using another method. Earlier studies indicated that if the tumor cells are overloaded with calcium ions, it could reduce the production of P-gp and decrease the ATP levels. However, the researchers needed to identify a way to deliver bursts of calcium, together with a chemotherapy drug within the cancer cells.
By loading calcium phosphate nanoparticles with the chemotherapy drug called doxorubicin, the team made a “calcium ion nanogenerator” (TCaNG) and later coated them with molecules that would enable TCaNG to target and penetrate the cancer cells. Once the TCaNGs were inside the cancer cells, they entered an acidic compartment, in which they disintegrated and released doxorubicin as well as bursts of calcium ions.
When the researchers examined the TCaNG on cancer cells in a petri dish in a laboratory setting, the production of both ATP and P-gp dropped, which enabled doxorubicin to destroy the formerly resistant tumor cells.
When tested in tumor-bearing mice, animals treated with TCaNG had considerably smaller tumors following 21 days of treatment when compared to the control group, without any apparent side effects.
Liu, J., et al. (2020) Nanoenabled Intracellular Calcium Bursting for Safe and Efficient Reversal of Drug Resistance in Tumor Cells. Nano Letters. doi.org/10.1021/acs.nanolett.0c03042.