Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by intratumoral abundance of neutrophilic/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) which inhibit T-cell function through JAK2/STAT3-regulated arginase activity. To overcome limitations of systemic inhibition of PMN-MDSCs in cancer-bearing patients-i.e., neutropenia and compensatory myelopoietic adaptations-we develop a nanoengineering strategy to target cell-specific signaling exclusively in PMN-MDSCs without provoking neutropenia. We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Cy5.5 dye-loaded CXCR2-NP showed near-exclusive uptake in PMN-MDSCs compared with PDAC tumor-cells, cancer-associated fibroblasts, and macrophages. Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NP Ruxo ) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinib in-vitro and in-vivo . Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.

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.

Correction to "New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance".

[This corrects the article DOI: 10.1021/acscentsci.3c00286.].

New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance.

Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate cancer (PCa) is an example that is resistant to one of the most potent chemotherapeutics, cisplatin. PCa cells survive and proliferate using fatty acid oxidation (FAO), and the dependence on fat utilization increases as the disease progresses toward a resistant form. Using a pool of patient biopsies, we validated the expression of a key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for fat metabolism. We then discovered that a cisplatin prodrug, Platin-L, can inhibit the FAO of PCa cells by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, we documented that the presence of an available carboxylic acid group near the long chain fatty acid linker on the Pt(IV) center is crucial for CPT1A binding. As a result of fat metabolism disruption by Platin-L, PCa cells transition to an adaptive glucose-dependent chemosensitive state. Potential clinical translation of Platin-L will require a delivery vehicle to direct it to the prostate tumor microenvironment. Thus, we incorporated Platin-L in a biodegradable prostate tumor-targeted orally administrable nanoformulation and demonstrated its safety and efficacy. The distinctive FAO inhibitory property of Platin-L can be of potential clinical relevance as it offers the use of cisplatin for otherwise resistant cancer.

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.

Platin-C containing nanoparticles: a recipe for the delivery of curcumin-cisplatin combination chemotherapeutics to mitochondria.

The success story of cisplatin spans over six decades now and yet it continues to be the key player in most chemotherapeutic regimens. Numerous efforts have been made to improve its efficacy, address its shortcomings, and overcome drug resistance. One such strategy is to develop new platinum(IV)-based prodrugs with functionally active ligands to deliver combination therapeutics. This strategy not only enables the drug candidate to access multiple drug targets but also enhances the kinetic inertness of platinum complexes and thereby ensures greater accumulation of active drugs at the target site. We report the synthesis of Platin-C, a platinum(IV)-based cisplatin prodrug tethered to the active component of ancient herbal medicine, curcumin, as one of the axial ligands. This combination complex showed improved chemotherapeutic efficacy in cisplatin resistant A2780/CP70 cell lines compared with the individual components. An amine-terminated biodegradable polymer was suitably functionalized with the triphenylphosphonium (TPP) cation to obtain a mitochondria-directed drug delivery platform. Quantification of Platin-C loading into these NPs using complementary techniques employing curcumin optical properties in high-performance liquid chromatography and platinum-based inductively coupled plasma mass spectrometry evidenced efficacious payload incorporation resulting in functional activities of both the components. Stability studies for a period of one week indicated that the NPs remain stable, enabling substantial loading and controlled release of the prodrug. The targeting nanoparticle (NP) platform was utilized to deliver Platin-C primarily in the mitochondrial network of cancer cells as monitored using confocal microscopy employing the green fluorescence of the curcumin pendant. Our studies showed that amine terminated NPs were relatively less efficient in their ability to target mitochondria despite being positively charged. This re-validated the importance of lipophilic positively charged TPP surface functionalities to successfully target cellular mitochondria. We validated the capabilities of Platin-C and its mitochondria-targeting nanoparticles towards inflicting mitochondria-directed activity in cisplatin-sensitive and cisplatin-resistant cell lines. Furthermore, our studies also demonstrated the effectiveness of Platin-C incorporated targeting NPs in attenuating cellular inflammatory markers by utilizing the curcumin component. This study advances our understanding of the cisplatin prodrug approach to combine chemotherapeutic and inflammatory effects in accessing combinatory pathways.

Biomaterial-targeted precision nanoparticle delivery to the injured spinal cord.

Drug delivery requires precision in timing, location, and dosage to achieve therapeutic benefits. Challenges in addressing all three of these critical criteria result in poor temporal dexterity, widespread accumulation and off-target effects, and high doses with the potential for toxicity. To address these challenges, we have developed the BiomatErial Accumulating Carriers for On-demand Nanotherapy (BEACON) platform that utilizes an implantable biomaterial to serve as a target for systemically delivered nanoparticles (NPs). With the BEACON system, administered NPs are conjugated with a ligand that has high affinity for a receptor in the implanted biomaterial. To test BEACON, an in vivo spinal cord injury (SCI) model was used as it provides an injury model where the three identified criteria can be tested as it is a dynamic and complicated injury model with no currently approved therapies. Through our work, we have demonstrated temporal dexterity in NP administration by injecting 6 days post-SCI, decreased off-target accumulation with a significant drop in liver accumulation, and retention of our NPs in the target biomaterial. The BEACON system can be applied broadly, beyond the nervous system, to improve systemically delivered NP accumulation at an implanted biomaterial target. STATEMENT OF SIGNIFICANCE: Targeted drug delivery approaches have the potential to improve therapeutic regimens for patients on a case-by-case basis. Improved localization of a therapeutic to site of interest can result in increased efficacy and limit the need for repeat dosing. Unfortunately, targeted strategies can fall short when receptors on cells or tissues are too widespread or change over the course of disease or injury progression. The BEACON system developed herein eliminates the need to target a cell or tissue receptor by targeting an implantable biomaterial with location-controllable accumulation and sustained presentation over time. The targeting paradigm presented by BEACON is widely applicable throughout tissue engineering and regenerative medicine without the need to retool for each new application.

Transformation of Amphiphilic Antiviral Drugs into New Dimensional Nanovesicles Structures.

Improved techniques were applied to formulate drugs into dimensional nanostructures, doped "nanovesicles". These nanovesicles are solely composed of self-assembled amphiphilic antiviral agents used for the treatment of viral infections caused by flaviviruses, such as Zika virus. Studies were done to evaluate the effectiveness of the syntheses, formation, and performance under different experimental conditions, and behavior of the drug nanovesicles in vitro and in vivo. These studies demonstrated that assembling the hydrophobic antiviral drug molecules into nanodrugs is a successful technique for the delivery of the therapeutic agents, otherwise difficult to be supplied. Our studies confirmed that this nanodrug preserved and, in many cases, enhanced the embedded cellular activity of the parental free drug molecules, both in vitro and in vivo. This proposed formulation is highly important as it addresses the issue of insolubility and low bioavailabiity of a wide range of highly potent pharmaceutical drugs-not limited to a specific class of antiviral drugs-that are of high demand for the treatment of medical conditions and emerging pathogens.

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.

Recent advances, status, and opportunities of magneto-electric nanocarriers for biomedical applications.

Magneto-electric (ME) materials with core-shell architecture where the core is made of magnetic materials have emerged as an attractive nanomaterial due to the coupling of magnetic and electric properties in the same material and the fact that both fields can be controlled which allows an on-demand, transport and release of loaded cargo. Over the last decade, biomedical engineers and researchers from various interdisciplinary fields have successfully demonstrated promising properties ranging from therapeutic delivery to sensing, and neuromodulation using ME materials. In this review, we systematically summarize developments in various biomedical fields using the nanoforms of these materials. Herein, we also highlight various promising biomedical applications where the ME nanocarriers are encapsulated in other materials such as gels and liposomes and their potential for promising therapeutics and diagnostic applications.

Controlled release nanoplatforms for three commonly used chemotherapeutics.

In order to combat an evolving, multidimensional disease such as cancer, research has been aimed at synthesizing more efficient and effective versions of popular chemotherapeutic drugs. Despite these efforts, there remains a necessity for the development of suitable delivery vehicles that can both harness the chemotherapeutic effects meanwhile reducing some of the known issues when using these drugs such as unwanted side-effects, acquired drug resistance, and associated difficulties with drug delivery. Synthetic drug discovery approaches focusing on modification of the native structure of these chemotherapeutic drugs often face challenges such as loss of efficacy, as well as a potential worsening of side-effects. Synthetic chemists are then left with increasingly narrow choices for possible chemistry they could implement to achieve the desired therapy. The emergence of targeted therapies using controlled-release nanomaterials can provide many opportunities for conventional chemotherapeutic drugs to be delivered to specific target sites, ultimately leading to reduced side-effects and improved efficacy. Logically, it may prove advantageous to consider nano-delivery systems as a likely candidate for circumventing some of the barriers associated with creating viable drug therapies. In this review, we summarize controlled release nanoformulations of the three most widely used and approved chemotherapeutics, doxorubicin, paclitaxel, and cisplatin as an alternative therapeutic approach against different cancer types.

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.

Design of Pd-Decorated SrTiO3/BiOBr Heterojunction Materials for Enhanced Visible-Light-Based Photocatalytic Reactivity.

The development of photocatalytic materials that exploit visible light is imperative for their sustainable application in environmental remediation. While a variety of approaches have been attempted, facile routes to achieve such structures remain limited. In this contribution, a direct route for the production of a SrTiO3/BiOBr/Pd heterojunction is presented that employs a low temperature, sustainable production method. The materials were produced in a two-step process wherein BiOBr nanoplates are fabricated in the presence of the SrTiO3 nanospheres, generating a highly integrated composite material. Pd nanoparticle surface decoration was subsequently employed to facilitate and enhance charge separation lifetimes to optimize reactivity. The structures were fully characterized via a suite of approaches to confirm the final material composition and arrangement. Their reactivity was explored for the degradation of both colored and colorless model environmental pollutants, where the SrTiO3/BiOBr/Pd demonstrated significant reactivity using visible light, leading to substrate degradation in <10 min in some cases. The enhanced reactivity was attributed to the significant integration between materials, facilitating electron transfer. Such studies provide key information for the development of new materials with optimized visible-light-driven photocatalytic reactivity for sustainable environmental remediation.

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.

Nanotechnology in the diagnosis and treatment of stroke.

Increasing developments in the field of nanotechnology have ignited its use in stroke diagnosis and treatment. The benefits of structural modification, ease of synthesis, and biocompatibility support the use of nanomaterials in the clinic. The pathophysiology of stroke is complex, involving different brain regions; hence, therapeutic agents are required to be delivered to specific regions. Nanoparticles (NPs) can be engineered to help improve the delivery and release of therapeutic agents in a localized manner, especially in the penumbra. This contributes not only to therapy, but also to neurosurgery and neuroimaging. Nanomaterials also offer high efficacy with few adverse effects. In this review, we provide a concise summary of the caveats associated with nanotechnology with respect to stroke therapy and diagnosis.

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.

Dual-Targeted Synthetic Nanoparticles for Cardiovascular Diseases.

Atherosclerosis is one of the world's most aggressive diseases, claiming over 17.5 million lives per year. This disease is usually caused by high amounts of lipoproteins circulating in the blood stream, which leads to plaque formation. Ultimately, these plaques can undergo thrombosis and lead to major heart damage. A major contributor to these vulnerable plaques is macrophage apoptosis. Development of nanovehicles that carry contrast and therapeutic agents to the mitochondria within these macrophages is attractive for the diagnosis and treatment of atherosclerosis. Here, we report the design and synthesis of a dual-targeted synthetic nanoparticle (NP) to perform the double duty of diagnosis and therapy in atherosclerosis treatment regime. A library of dual-targeted NPs with an encapsulated iron oxide NP, mito-magneto (MM), with a magnetic resonance imaging (MRI) contrast enhancement capability was elucidated. Relaxivity measurements revealed that there is a substantial enhancement in transverse relaxivities upon the encapsulation of MM inside the dual-targeted NPs, highlighting the MRI contrast-enhancing ability of these NPs. Successful in vivo imaging documenting the distribution of MM-encapsulated dual-targeted NPs in the heart and aorta in mice ensured the diagnostic potential. The presence of mannose receptor targeting ligands and the optimization of the NP composition facilitated its ability to perform therapeutic duty by targeting the macrophages at the plaque. These dual-targeted NPs with the encapsulated MM were able to show therapeutic potential and did not trigger any toxic immunogenic response.