A Convergent Synthetic Platform for Single-Nanoparticle Combination Cancer Therapy: Ratiometric Loading and Controlled Release of Cisplatin, Doxorubicin, and Camptothecin

The synthesis of polymer therapeutics capable of controlled loading and synchronized release of multiple therapeutic agents remains a formidable challenge in drug delivery and synthetic polymer chemistry. Herein, we report the synthesis of polymer nanoparticles (NPs) that carry precise molar ratios of doxorubicin, camptothecin, and cisplatin. To our knowledge, this work provides the first example of orthogonally triggered release of three drugs from single NPs. The highly convergent synthetic approach opens the door to new NP-based combination therapies for cancer.MIT Research Support CommitteeLincoln Laboratory. Advanced Concepts CommitteeUnited States. Dept. of Defense (Ovarian Cancer Research Program Teal Innovator Award)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01)Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)Natural Sciences and Engineering Research Council of Canada (Graduate Fellowship)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051

Chemistry, photophysics, and biomedical applications of gold nanotechnologies

Gold nanoparticles exhibit a combination of physical, chemical, optical, and electronic properties unique from all other nanotechnologies. These structures can provide a highly multifunctional platform with which to diagnose and treat diseases and can dramatically enhance a variety of photonic and electronic processes and devices. The work herein highlights some newly emerging applications of these phenomena as they relate to the targeted diagnosis and treatment of cancer, improved charge carrier generation in photovoltaic device materials, and strategies for enhanced spectrochemical analysis and detection. Chapter 1 introduces the reader to the design, synthesis, and molecular functionalization of gold nanotechnologies, and provides a framework from which to discuss the unique photophysical properties and applications of these nanoscale materials and their physiological interactions in Chapter 2. Chapter 3 discusses ongoing preclinical research in our lab investigating the use of near-infrared absorbing gold nanorods as photothermal contrast agents for laser ablation therapy of solid tumors. In Chapter 4, we present recent work developing a novel strategy for the targeted treatment of hormone-dependent breast and prostate tumors using multivalent gold nanoparticles that function as highly selective and potent endocrine receptor antagonist chemotherapeutics. In Chapter 5, we discuss a newly-emerging tumor-targeting strategy for nanoscale drug carriers which relies on their selective delivery to immune cells that exhibit high accumulation and infiltration into breast and brain tumors. Using this platform, we further investigate the interactions of nanoscale drug carriers and imaging agents to a transmembrane protein considered to be the single most prevalent and single most important contributor to drug resistance and the failure of chemotherapy. Chapter 6 presents work from a series of studies exploring enhanced charge carrier generation and relaxation in a hybrid electronic system exhibiting resonant interactions between photovoltaic device materials and plasmonic gold nanoparticles. Chapter 7 concludes by presenting studies investigating the contributions from so-called “dark” plasmon modes to the spectrochemical diagnostic method known as surface enhanced Raman scattering.Ph.D

Periodic-shRNA molecules are capable of gene silencing, cytotoxicity and innate immune activation in cancer cells

Large dsRNA molecules can cause potent cytotoxic and immunostimulatory effects through the activation of pattern recognition receptors; however, synthetic versions of these molecules are mostly limited to simple sequences like poly-I:C and poly-A:U. Here we show that large RNA molecules generated by rolling circle transcription fold into periodic-shRNA (p-shRNA) structures and cause potent cytotoxicity and gene silencing when delivered to cancer cells. We determined structural requirements for the dumbbell templates used to synthesize p-shRNA, and showed that these molecules likely adopt a co-transcriptionally folded structure. The cytotoxicity of p-shRNA was robustly observed across four different cancer cell lines using two different delivery systems. Despite having a considerably different folded structure than conventional dsRNA, the cytotoxicity of p-shRNA was either equal to or substantially greater than that of poly-I:C depending on the delivery vehicle. Furthermore, p-shRNA caused greater NF-κB activation in SKOV3 cells compared to poly-I:C, indicating that it is a powerful activator of innate immunity. The tuneable sequence and combined gene silencing, immunostimulatory and cytotoxic capacity of p-shRNA make it an attractive platform for cancer immunotherapy.United States. Dept. of Defense (Teal Innovator Award)Natural Sciences and Engineering Research Council of Canada (Graduate Research Fellowship)National Institutes of Health (U.S.) (NIBIB 1F32EB017614-02)National Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051