Scientists at the University of Alabama at Birmingham (UAB) have just developed a multilayer polymer capsule for fighting cancer that should bring the promise of guided drug delivery closer to preclinical testing. The findings from this new study were published recently in ACS Nano through an article entitled “Theranostic Multilayer Capsules for Ultrasound Imaging and Guided Drug Delivery.”
The new multilayer capsules have three traits that have been difficult to achieve in a single entity. The research team has called the new capsules a triple-threat cancer-fighting agent. Since they have good imaging contrast that allows detection with low-power ultrasound, they can stably and efficiently encapsulate the cancer drug doxorubicin, and both a low- and higher-power dose of ultrasound can trigger the release of that cargo.
“We envision an entirely different approach to treating solid human tumors of numerous pathologic subtypes, including common metastatic malignancies such as breast, melanoma, colon, prostate, and lung, utilizing these capsules as a delivery platform,” explained senior study investigator Eugenia Kharlampieva, Ph.D., associate professor in the department of chemistry at the UAB College of Arts and Sciences. “These capsules can protect encapsulated therapeutics from degradation or clearance prior to reaching the target and have ultrasound contrast as a means of visualizing the drug release. They can release their encapsulated drug cargo in specific locations via externally applied ultrasound exposure.”
The triple features developed for the new capsules creates a guided drug delivery system to target solid tumors. Therapeutic efficacy can be further improved through surface modifications to boost targeting capabilities. Diagnostic low-power ultrasound then could visualize the nanocapsules as they concentrated in a tumor, and therapeutic higher-dose ultrasound would release the drug at ground zero, sparing the rest of the body from dose-limiting toxicity. The UAB investigators are optimistic that these precise controls of when and where doxorubicin or other cancer drugs are released could offer a noninvasive alternative to cancer surgery or systemic chemotherapy.
In the current study, the UAB team used alternating layers of biocompatible tannic acid and poly(N-vinylpyrrolidone), or TA/PVPON, to build their microcarriers. The layers are formed around a sacrificial core of solid silica or porous calcium carbonate that is dissolved after the layers are complete.
Interestingly, by varying the number of layers, the molecular weight of PVPON or the ratio of shell thickness to capsule diameter, the researchers were able to alter the physical traits of the capsules and their sensitivity to diagnostic ultrasound, at power levels below the FDA maximum for clinical imaging and diagnosis.
For instance, one-fourth of empty microcapsules made with four layers of TA/low-molecular weight PVPON were ruptured by three minutes of ultrasound, while capsules made of 15 layers of TA/low-molecular weight PVPON or capsules made from four layers of TA/high-molecular weight PVPON showed no rupture. The ruptured capsules had a lower mechanical rigidity that made them more sensitive to ultrasound pressure changes. Experiments showed that the ratio of the thickness of the capsule wall to the diameter of the capsule is a key variable for sensitivity to rupture.
To test the ultrasound imaging contrast of the microcapsules, the research team created capsules that were 5 micrometers wide or about two times wider than the capsules used in the rupture experiments. This size is small enough to still pass through capillaries in the lung, while a larger size for various microparticles is known to improve ultrasound contrast greatly. Red blood cells, for a size comparison, have a diameter of about 6 to 8 micrometers.
The researchers found that 5-micrometer-wide, empty capsules that were made with eight layers of TA/low-molecular weight PVPON showed an ultrasound contrast comparable to the commercially available microsphere contrast agent Definity. When the UAB capsules were loaded with doxorubicin, the ultrasound imaging contrast increased two- to eightfold compared to empty capsules, depending on the mode of ultrasound imaging used.
A therapeutic dose of ultrasound was able to rupture 50% of the 5-micrometer, doxorubicin-loaded microcapsules, releasing enough doxorubicin to induce 97% cytotoxicity in human breast adenocarcinoma cells in culture. Adenocarcinoma cells that were incubated with intact doxorubicin-loaded microcapsules remained viable.
Based on their results the researchers feel that the TA/PVPON capsules have strong potential as “theranostic” agents—nanoparticles or microcapsules that can double as diagnostic imaging agents and as therapeutic drug delivery carriers. Animal model studies using the microcapsules are set to begin soon.