INTELLECTUAL MERIT: One of the current challenges in using polymers for drug delivery is the ability to trigger the release of the drug at a specific site. Preventing premature or uncontrolled drug release is a key design requirement. The PI and his group are designing, synthesizing, and evaluating a new type of polymeric nanoparticle (NP) for drug delivery that is initially hydrophobic, but upon cellular internalization and a lowering of local pH, transforms into a hydrophilic structure - namely a hydrogel particle. This hydrophobic-to-hydrophilic transformation results in release of the encapsulated drug and swelling with a change in volume of >300 fold. Building upon the initial published results with these NP used successfully in vitro and in vivo, the PI proposes a detailed mechanistic study to characterize and understand the polymer chemistry and biomaterials principles at work. Specifically, he and his group will encapsulate paclitaxel (Pax) within the nanoparticles and identify the key molecular and nanoscale characteristics that affect nanoparticle size, swelling rate, pH responsiveness, volume change, paclitaxel release, uptake by tumor cells, intracellular particle trafficking, endosomal release, and cytotoxicity. These studies address two hypotheses: (1) that paclitaxel will only release upon this hydrophobic to hydrophilic transition; and (2) that the paclitaxel loaded expansile nanoparticles (Pax eNPs) will afford a higher intracellular concentration of paclitaxel than nonexpansile (Pax neNP), conventional Pax PLGA NP formulations, paclitaxel albumin-bound particles (Abraxane), or free paclitaxel/Cremophor. The results of this research will have a significant impact by affording a detailed mechanistic understanding of this delivery method as well as knowledge for the development of new polymer carriers and biomaterials.
BROADER IMPACTS: The broader impacts of the proposed activities are as follows: (1) The PI is committed to education and has developed a new two-semester course, related to this topic, entitled Biomaterials I and II that is cross-listed in Boston University's School of Engineering and the College of Arts and Sciences. The PI and his graduate students have also been involved in outreach programs, including the Boston Urban Fellow NSF GK12 Program which provides co-instructors for high school science courses in those Boston Public School systems where a majority of the students are underrepresented minorities or economically disadvantaged; (2) The PI will continue to provide research opportunities to high school students through the BU Research Internship Program for Science and Engineering and Project SEED programs; (3) NSF funding will be used to support one BU undergraduate student in the summer, illustrating the PI's continued commitment to undergraduates. The PI is also participating in two summer research programs (NSF-REU and NSF-PROgram in STem Academic Retention and Success), which target undergraduate women or underrepresented minority students; (4) NSF funding for this project will be used to support one engineering and one chemistry graduate student who will benefit from an interdisciplinary educational experience that encompasses training in synthetic organic chemistry, applied polymer research, and biomaterials research. The students will work side-by-side in the laboratory where they will exchange ideas and learn from each other, as well as receive training on a variety of analytical instruments. Students trained in the Grinstaff Laboratory are encouraged to think independently and creatively while recognizing the importance of working collaboratively with other experts; and (5) The PI and his students will continue to publish results in peer-reviewed journals and attend national meetings to present their research. The PI will also develop a polymer synthesis protocol database describing the current and past polymer syntheses that will be accessible to the public from the Web.
Polymeric expansile nanoparticles (eNPs) respond to a mildly acidic environment by swelling with water and expanding 2-10 X in diameter. The pH- and time-dependence of eNP swelling is a key property responsible for the observed performance and differentiation from conventional nanoparticles. Results demonstrate a significant change in eNP volume (>350 X) at pH 5.0 as seen using: scanning electron microscopy (SEM), conventional transmission electron microscopy (TEM), freeze-fracture transmission electron microscopy (ff-TEM), fluorescence microscopy, and a new nanopore based characterization technology, the qNano, which measures both individual particle size as well as overall particle concentration in situ using tunable resistive pulse sensing. eNP swelling occurs in a continuous and yet heterogeneous manner over several days and is pH dependent. Finally, paclitaxel-loaded-eNPs are cytotoxic against a number of human-derived cancer cell lines (MDA-MB-213 – breast, A549 – lung, Panc-1 – pancreatic, MSTO-211H – mesothelioma) while unloaded-eNPs do not demonstrate cytotoxicity. The results from this work will serve to further development of new materials and approaches for improving the delivery of anti-cancer compounds. Lastly, our results led to: 1) 13 peer-review publications; 2) three additional manuscripts in preparation; 3) 12 poster presentations by students at conferences; and 4) 36 oral presentations by the PI and students at conferences.
