Self-assisting robot-assisted pulmonary lobectomy has favorable outcome compared to VATS lobectomy.

Background: Open and video-assisted thoracoscopic surgery (VATS) pulmonary lobectomy requires a skilled assistant to complete the operation. A potential benefit of a robot is to allow a surgeon to complete the operation autonomously. We sought to determine the safety of performing robotic-assisted pulmonary lobectomy with self-assistance. Methods: We performed a retrospective analysis of self-assisting robot-assisted lobectomy. We evaluated the intraoperative and postoperative outcomes. We compared the outcome to the propensity matched group of patients who had VATS lobectomy. We also compared them to published outcomes of robot-assisted lobectomy. Results: 95 patients underwent self-assisted lobectomies. The median age was 70 years old, predominately female (57%) and white (85%) with 90% of patients undergoing surgery for cancer. The median of estimated blood loss was 25 mL during the operation with no conversions to open thoracotomies. After the operation, 17% of patients had major postoperative complications with a median length of stay of 2 days. At thirty-day follow-up, the readmission rate was 6.5%, with a mortality of 0%. Compared to the propensity matched VATS lobectomy group, there was significantly less conversion to open surgery (n=0, 0% vs. n=10, 12.2%, P=0.002), less intraoperative blood transfusions (n=0, 0% vs. n=6, 7.3%, P=0.03), less any complications (n=20, 24.4% vs. n=41, 50%, P=0.003), and less median length of stay (2 days, IQR 2, 5 days vs. 4 day, IQR 3, 6 days, P<0.001) in the self-assisting robot lobectomy group. Compared to published outcomes of robot-assisted lobectomy, our series had significantly fewer conversions to open (P=0.03), shorter length of stay (P<0.001), more discharges to home (93.7%) without a difference in procedure time (P=0.38), overall complication rates (P=0.16) and mortality (P=0.62). Conclusions: Self-assistance using the robot technology during pulmonary lobectomy had few technical complications and acceptable morbidity, length of stay, and mortality. This group had favorable outcome compared to VATS lobectomy. The ability to self-assist during pulmonary lobectomy is an additional benefit of the robot technology compared to open and VATS lobectomy.

Intersection of Inorganic Chemistry and Nanotechnology for the Creation of New Cancer Therapies.

Since its discovery in 1965, the inorganic drug cisplatin has become a mainstay of cancer therapies and has inspired many platinum (Pt)-based compounds to solve various issues of toxicity and limitations associated with the original cisplatin. However, many of these drugs/prodrugs continue to be plagued by an array of side effects, limited circulation, and half-life and off-target effects. To solve this issue, we have constructed an array of platinum-based prodrugs on a Pt(IV) skeleton, which provides more favorable geometry and hydrophobicity, easier functionalization, and ultimately better targeting abilities. Each of these Pt(IV) prodrugs aims to either combine cisplatin with other agents for a combination therapeutic effect or improve the targeting of cisplatin itself, all for the more effective treatment of specific cancers. Our developed prodrugs include Platin-A, which combines cisplatin with the anti-inflammatory agent aspirin, Platin-M, which is functionalized with a mitochondria-targeting moiety, and Platin-B and Platin-Cbl, which combine cisplatin with components to combat cellular resistance to chemotherapy. At the same time, however, we recognize the crucial role of nanotechnology in improving the efficacy of cisplatin prodrugs and other inorganic compounds for the treatment of cancers. We describe several key benefits provided by nanomedicine that vastly improve the reach and utility of cisplatin prodrugs, including the ability of biodegradable polymeric nanoparticles (NPs) to deliver these agents with precision to the mitochondria, transport drugs across the blood-brain barrier, and target cisplatin prodrugs to specific cancers using various ligands. In addition, we highlight our progress in the engineering of innovative new polymers to improve the release patterns, pharmacokinetics, and dosages of cancer therapies. In this Account, we aim to describe the growing need for collaboration between the fields of inorganic chemistry and nanotechnology and how new advancements can not only improve on traditional chemotherapeutic agents but also expand their reach to entirely new subsets of cancers. In addition to detailing the design and principles behind our modifications of cisplatin and the efficacy of these new prodrugs against aggressive, cisplatin-resistant, or metastatic cancers, we also shed light on nanotechnology's essential role in protecting inorganic drugs and the human body from one another for more effective disease treatment without the off-target effects with which it is normally associated. We hope that this perspective into the important intersection between inorganic medicinal chemistry and nanotechnology will inspire future research on cisplatin prodrugs and other inorganic agents, innovative polymer and NP design, and the ways in which these two fields can greatly advance cancer treatment.

Blending of Designer Synthetic Polymers to a Dual Targeted Nanoformulation for SARS-CoV-2 Associated Kidney Damage.

As the COVID-19 pandemic has continued to spread, studies have shown that hospitalized COVID-19 patients are at significant risk for developing acute kidney injury (AKI), which can cause increased morbidity, the need for dialysis treatment, chronic kidney diseases, and even death. In this paper, we present a proof-of-concept study for the utilization of combination therapeutic-loaded dual-targeted biodegradable nanoparticles (NPs) to treat concurrent AKI and COVID-19 in patients by delivering the therapeutics across the gut epithelial barrier and to the kidney, in order to lower the viral load as well as reduce the symptoms of AKI. Despite recent vaccination efforts and the end of the COVID-19 pandemic in sight, problems related to the long-term effects of COVID-19 will continue to persist, including impacts on patients suffering from AKI and other chronic renal conditions. Therefore, the dual-targeted blended polymeric NP developed in this study to treat concurrent COVID-19 infection and AKI is a useful proof-of-concept nanoplatform for future treatments of these complications.

Brain-Accumulating Nanoparticles for Assisting Astrocytes to Reduce Human Immunodeficiency Virus and Drug Abuse-Induced Neuroinflammation and Oxidative Stress.

Human neurotropic immunodeficiency virus (HIV) ingress into the brain and its subsequent replication after infection results in viral reservoirs in the brain. The infected cells include microglia, perivascular macrophages, and astrocytes. HIV-associated neurocognitive disorders (HAND) affect glial cells by activating microglia and macrophages through neuroinflammation, as well as astrocytes through mitochondrial dysfunctions and the onset of oxidative stress, impairing the ability of these cells to engage in neuroprotection. Furthermore, the risk of neuroinflammation associated with HAND is magnified by recreational drug use in HIV-positive individuals. Most of the therapeutic options for HIV cannot be used to tackle the virus in the brain and treat HAND due to the inability of currently available combination antiretroviral therapies (ARTs) and neuroprotectants to cross the blood-brain barrier, even if the barrier is partially compromised by infection. Here, we report a strategy to deliver an optimized antiretroviral therapy combined with antioxidant and anti-inflammatory neuroprotectants using biodegradable brain-targeted polymeric nanoparticles to reduce the burden caused by viral reservoirs in the brain and tackle the oxidative stress and inflammation in astrocytes and microglia. Through in vitro coculture studies in human microglia and astrocytes as well as an in vivo efficacy study in an EcoHIV-infected, methamphetamine-exposed animal model, we established a nanoparticle-based therapeutic strategy with the ability to treat HIV infection in the central nervous system in conditions simulating drug use while providing enhanced protection to astrocytes, microglia, and neurons.

Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19.

There is urgent therapeutic need for COVID-19, a disease for which there are currently no widely effective approved treatments and the emergency use authorized drugs do not result in significant and widespread patient improvement. The food and drug administration-approved drug ivermectin has long been shown to be both antihelmintic agent and a potent inhibitor of viruses such as Yellow Fever Virus. In this study, we highlight the potential of ivermectin packaged in an orally administrable nanoparticle that could serve as a vehicle to deliver a more potent therapeutic antiviral dose and demonstrate its efficacy to decrease expression of viral spike protein and its receptor angiotensin-converting enzyme 2 (ACE2), both of which are keys to lowering disease transmission rates. We also report that the targeted nanoparticle delivered ivermectin is able to inhibit the nuclear transport activities mediated through proteins such as importin α/ß1 heterodimer as a possible mechanism of action. This study sheds light on ivermectin-loaded, orally administrable, biodegradable nanoparticles to be a potential treatment option for the novel coronavirus through a multilevel inhibition. As both ACE2 targeting and the presence of spike protein are features shared among this class of virus, this platform technology has the potential to serve as a therapeutic tool not only for COVID-19 but for other coronavirus strains as well.

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.

Orally Administrable Therapeutic Synthetic Nanoparticle for Zika Virus.

The spread of Zika virus (ZIKV) infection across the USA and various countries in the last three years will not only have a direct impact on the U.S. health care system but has caused international concerns as well. The ultimate impact of ZIKV infection remains to be understood. Currently, there are no therapeutic or vaccine options available to protect those infected by ZIKV. The drug ivermectin (IVM) was found to be a viable agent for the prevention of transmission of ZIKV. Ivermectin is unstable in the presence of water and does not remain in adequate concentration in the human bloodstream to be effective in treatment for ZIKV. Biodegradable nanoparticles would aid in the delivery of ivermectin by providing a high enough concentration of drug and ensuring the drug is gradually released to maintain an appropriate level in the body. The overall goal of this study was to develop and optimize an orally administrable nanoformulation of IVM which can circulate in the blood for a long period for efficient delivery. To achieve the goal, we synthesized and optimized a synthetic nanoformulation of IVM for oral use which can cross the intestinal epithelial barrier to enter the bloodstream. Our studies documented that when delivered with the synthetic nanoparticle (NP), IVM can be accumulated in the blood at a higher concentration and preliminary studies highlighted that NP delivered IVM has the ability to target nonstructural 1 protein of ZIKV. For potential clinical relevance, long-term storable formulation of IVM-nanoparticle in dry powder state for inclusion in a capsule form and cryoprotectant containing frozen forms revealed promising findings. Further, our preliminary in vitro studies documented that ivermectin crosses the placental barrier, thus making it unsafe for the pregnant ZIKV population, whereas the ivermectin-loaded nanoparticle did not show any significant placental barrier crossing, thus indicating its potential suitability for such population. We envision that this work will fill a great unmet need by developing safer and more effective therapies for the treatment of viral infections, including ZIKV.