Chemotherapy has been the backbone of cancer treatment for decades, but it is notorious for its toxicity to healthy cells, severe side effects, and poor targeting of the intended tumors.
Efforts to improve chemotherapy’s efficacy and tolerability include packaging drugs into nanoparticles, which can protect them from degradation in the body, control their release pattern, and shield the patient from some of the drugs’ side effects.
However, nanoparticles have so far failed to show significant accumulation in target sites, even when they are engineered with surface proteins designed to bind to specific tissues, largely because they are quickly cleared from the blood by the liver and spleen.
Now, a new technique called ELeCt (erythrocyte-leveraged chemotherapy) developed at Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) aims to resolve those problems by using a Trojan horse, smuggling drug-loaded nanoparticles into cancerous lung tissue by mounting them onto the body’s own erythrocytes, commonly called red blood cells. When the red blood cells make their tight squeeze through the lung’s tiny capillaries, the nanoparticles are sheared off and taken up by lung cells with 10-fold greater success than free-floating nanoparticles, and dramatically improve the survival of mice with lung cancer metastasis. The research is reported in Science Advances.
“Thirty to 55 percent of patients with advanced cancer have metastasis to the lung, due to its large number of capillaries, and there is currently no treatment for lung metastasis itself,” said co-first author Zongmin Zhao, postdoctoral fellow in the lab of Samir Mitragotri at the Wyss Institute and SEAS. “ELeCt exploits those same blood vessels to effectively deliver drugs that fight lung metastasis, and has strong potential to be developed into a clinical treatment.”
To create the ELeCt system, Zhao and his collaborators loaded doxorubicin, a common cancer chemotherapy drug, into tiny nanoparticles composed of a biodegradable polymer called PLGA. They then incubated the nanoparticles with both mouse and human erythrocytes, and found that they bound to the cells’ surfaces with high efficiency and without damaging them, allowing the dose of the drug carried by the erythrocytes to be tuned to fit different required dosages.
The team next subjected erythrocyte-bound nanoparticles to lung-corresponding shear stress in vitro to simulate the conditions erythrocytes encounter when squeezing through the lung’s capillaries, and observed that more than 75 percent of the nanoparticles were sheared off of both mouse and human cells. They then injected mouse erythrocytes loaded with the ELeCt construct into the veins of living mice with melanoma that had metastasized to their lungs, and found a remarkable 16-fold higher drug content in the lungs after 20 minutes compared with mice that had received free nanoparticles. A substantial portion of the deposited nanoparticles penetrated deep into the metastatic tumors, suggesting that this method of drug delivery is more precise and effective than existing methods.
“The most serious side effect of doxorubicin in humans is cardiotoxicity, and based on our experiments, ELeCt can ensure that more of the drug ends up in the lungs rather than in the heart,” said co-first author Anvay Ukidve, a Graduate School of Arts and Sciences student in Mitragotri’s lab at SEAS. “This advance could significantly reduce the danger to cancer patients receiving this drug, and increase its effectiveness against lung tumors.”