Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.

Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Solitary Isolated Oropharyngeal Neurofibroma Presenting With Dysphagia in the Setting of Von Recklinghausen's Disease.

A 24-year-old man with von Recklinghausen's disease presented with complaints of difficulty in swallowing for 6 months and change of voice for 3 months. He also had recent-onset difficulty in breathing. Telelaryngoscopy and subsequent contrast-enhanced computed tomography scan revealed a well-defined, smooth submucosal mass in the oropharynx (attached to the posterior pharyngeal wall, superior to the level of left aryepiglottic fold), obscuring the ipsilateral pyriform fossa, and nearly blocking the pharyngeal lumen. The mass was removed with endoscopic coblation-assisted laryngeal surgery, and subsequent histopathology revealed it to be neurofibroma. Neurofibromas are rare neoplasms to be encountered in the oropharynx. However, in the setting of von Recklinghausen's disease (neurofibromatosis type 1), one or more well-demarcated, submucosal nodular lesions in the upper aerodigestive tract may be considered as neurofibromas, and workup and treatment should be directed accordingly based on this clinical presumption. Endoscopic coblation during laryngeal surgery can effectively be used as a surgical tool to excise such lesions. It provides a relatively bloodless field compared to the conventional cold steel excision, and reduces the risk of complications at surgery and during the follow-up period. This clinical record illustrates the presentation and management of a solitary, isolated oropharyngeal neurofibroma in a man suffering from von Recklinghausen's disease. It further emphasizes the role of endoscopic coblation-assisted laryngeal surgery in this setup, and the need to maintain a low threshold of suspicion in having a provisional clinical diagnosis of such lesions.

All-in-One Pyruvate Dehydrogenase Kinase Inhibitor for Tracking, Targeting, and Enhanced Efficacy.

The metabolic preference of cells toward glycolysis often indicates a diseased state ranging from cancer to other dysfunctions. When a particular cell type utilizes glycolysis as a major energy production pathway, their mitochondria become impaired resulting a cascade of events which eventually contributes to resistance toward therapies to tackle such diseases. In abnormal tissues such as seen in the tumor microenvironment, when cancer cells utilize glycolysis, other cell types such as the immune cells switch their metabolism and prefer such glycolysis. As a result, utilization of therapies to destroy glycolytic preferences by cancer cells results in destruction of immune cells contributing toward an immunosuppressive phenotype. Thus, development of targeted, trackable, comparatively stable glycolysis inhibitors is urgently needed to manage diseases where glycolysis is preferred for disease progression. No glycolysis inhibitor exists which can be tracked and packaged in a delivery vehicle for efficient targeted deployment. Here, we report synthesis, characterization, and formulation of an all-in-one glycolysis inhibitor and document the therapeutic potential along with trackability and glycolysis inhibition of this inhibitor by utilizing an in vivo breast cancer model.

Turning the Tide for Academic Women in STEM: A Postpandemic Vision for Supporting Female Scientists.

The "leaky pipeline" of women in science, technology, engineering, and mathematics (STEM), which is especially acute for academic mothers, continues to be problematic as women face continuous cycles of barriers and obstacles to advancing further in their fields. The severity and prevalence of the COVID-19 pandemic both highlighted and exacerbated the unique challenges faced by female graduate students, postdocs, research staff, and principal investigators because of lockdowns, quarantines, school closures, lack of external childcare, and heightened family responsibilities, on top of professional responsibilities. This perspective provides recommendations of specific policies and practices that combat stigmas faced by women in STEM and can help them retain their careers. We discuss actions that can be taken to support women within academic institutions, journals, government/federal centers, university-level departments, and individual research groups. These recommendations are based on prior initiatives that have been successful in having a positive impact on gender equity─a central tenet of our postpandemic vision for the STEM workforce.

Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration.

Cancer cells are known to be glycolytic, driving increased glucose consumption and its conversion to lactate. This process modulates the tumor microenvironment (TME). In the TME, glycolytically activated immune cells often become anergic, leading to an increase in immune checkpoint proteins such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Most glycolytic inhibitors not only inhibit glycolysis of cancer but also of immune cells. Therefore, using a nanoparticle-delivered agent to preferentially inhibit glycolysis in tumor cells, and not in immune cells, has the potential to attenuate the expression of checkpoint proteins. Pyruvate dehydrogenase kinase 1 (PDK1) can be an important target to achieve tumor specific glycolysis inhibition. We report TME modulation by a mitochondrion-targeted nanoparticle (NP) containing a prodrug of dichloroacetate (DCA), a PDK1 inhibitor. We demonstrated that the targeted NP alters the TME which results in increased immunological activation against cancer cells, causing a decrease in mean tumor volume. Here, we also show findings that when Mito-DCA, a prodrug of DCA, was combined with anti-PD-1, a checkpoint inhibitor, results from in vivo syngeneic models showed an upregulation in the number of tumor infiltrating lymphocytes. This work provides a platform to bring therapeutic efficacy by selectively inhibiting glycolysis of cancer cells.

A designer bow-tie combination therapeutic platform: An approach to resistant cancer treatment by simultaneous delivery of cytotoxic and anti-inflammatory agents and radiation.

Multimodal therapies are used to treat advanced cancers including castration-resistant prostate cancer to manage the biological characteristics of the tumors like inflammation, bone metastases, and participation of metabolically altered cancer stem cells (CSCs) that have integral roles in disease dissemination and progression. We developed a multifunctional polymer-based self-assembled technology to deliver a predefined stoichiometric combination of a chemotherapy and an anti-inflammatory agent in a stimuli responsive manner, to complement and improve the currently established treatment methods of prostate cancer. We combined clinically applicable fractionated radiation therapy (XRT) to further sensitize the activity of this targeted multifunctional platform towards prostate-specific membrane antigen (PSMA) expressing advanced prostate cancer. After irradiation, our PSMA-targeted self-assembly system could modulate the mitochondrial metabolism, cellular respiration and the overall radiation-induced DNA damage process. We report the synthesis of this advanced multifunctional platform and describe its unique properties that allow the ability to load multiple FDA approved drugs with a predefined stoichiometric ratio for targeted co-delivery of chemotherapeutics and anti-inflammatory agents. The efficacy of this platform was demonstrated using several in vitro and in vivo studies, in a unique bilateral PSMA expressing prostate cancer tumor model, and in patient derived CSCs.