University of Arizona researchers have developed a breakthrough nanoparticle formulation of the chemotherapy drug paclitaxel that significantly improves tumor targeting while reducing damage to healthy tissues. The new delivery system, called Paclitaxome, outperformed standard paclitaxel formulations in preclinical studies of triple-negative breast cancer and advanced pancreatic cancer, according to research published in Nature Cancer.
Enhanced Drug Delivery Through Nanovesicle Technology
The research team, led by Jianqin Lu, PhD, the John A. and Frances P. Ware endowed associate professor in the University of Arizona R. Ken Coit College of Pharmacy, addressed a fundamental challenge in cancer chemotherapy. "Paclitaxel is potent and kills cancer cells, but to unleash its full therapeutic potential, we have to address its toxicity," Lu explained. "That means finding a better way to get it to tumor cells while also making it stay around longer."
The innovative approach involves chemically attaching paclitaxel to sphingomyelin, a type of fat found in cell membranes, to form nanovesicles. These tiny, fatty bubbles enable the drug to "have better tumor delivery and stay in circulation longer, accumulating in the tumor site and less so into healthy tissue," according to Lu.
Superior Performance in Preclinical Studies
In mouse models, Paclitaxome demonstrated superior efficacy compared to existing paclitaxel formulations Taxol and Abraxane. The researchers further enhanced the system by engineering an improved version called CD47p/AZE-Paclitaxome, which resulted in reduced tumor growth and longer survival in test animals.
Study co-author Aaron Scott, MD, an associate professor of medicine at the University of Arizona College of Medicine and oncologist, emphasized the clinical significance: "Paclitaxome is clinically promising because the system delivers the drug at the tumor site and will prevent side effects. The drug isn't cleared from the system as quickly. All of this improves its efficacy."
Combination Therapy Applications
The nanovesicle platform also showed promise for delivering drug combinations. Researchers tested paclitaxel combined with gemcitabine by inserting gemcitabine inside the nanovesicle core. "We screened different drug ratios and then loaded the best one into the nanovesicle," Lu noted. "The combination outperformed the co-administration of gemcitabine plus Taxol as well as the combination of Abraxane and gemcitabine."
In additional experiments, the team combined the modified paclitaxel with carboplatin to prevent triple-negative breast cancer recurrence in mice while eliminating metastatic disease.
Fluorescent Targeting System
Complementing this work, researchers at the Indian Association for the Cultivation of Science in Kolkata developed fluorescent nanoparticles that both deliver paclitaxel and illuminate cancer cells. The team, led by biologists Prasanta Kumar Das and Afreen Zaman, synthesized particles from naphthalene diimide that self-assemble into spherical nanoparticles emitting bright orange light.
These nanoparticles were coated with transferrin, a protein that binds to transferrin receptors overexpressed in various cancer cells. The system released more than 90% of the drug over two days at pH levels between 7.4 and 5.5 in cell cultures, killing cancer cells through apoptosis while sparing healthy cells.
"The nano-formulation, which is stable in biological conditions, made the drug more toxic to the cancer cells than to healthy cells and more effective than free paclitaxel," Das reported.
Broad Therapeutic Potential
The University of Arizona team demonstrated the versatility of their nanovesicle approach by successfully applying it to another chemotherapy drug, camptothecin, which worked effectively in a colon cancer mouse model. "This strategy can be applied to other drugs and also other diseases," Lu said, highlighting the platform's potential for treating various conditions beyond the initially tested cancers.
Lu envisions combining chemotherapy drugs with immunotherapies using this delivery system, potentially harnessing the immune system against cancer more effectively. The research team is currently gathering additional preclinical data to better understand the platform's applications.
Path to Clinical Translation
Both research teams are working toward clinical translation of their technologies. "Our goal is the take this into first-in-human clinical trials," Scott stated. "This platform can span a variety of tumor types for patients who desperately need better therapies."
The University of Arizona work was supported by the National Institute of General Medical Sciences and the National Cancer Institute, both divisions of the National Institutes of Health, under multiple award numbers including R35GM147002, R01CA272487, and K08CA276137.
