Engineered Nanoparticles Research Articles

Primary Human Breast Cancer-Associated Endothelial Cells Favor Interactions with Nanomedicines.

Cancer nanomedicines predominately rely on transport processes controlled by tumor-associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor-associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer-associated endothelial cells exhibit up to ≈2times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super-resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor-associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer-associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cellsin nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor-associated endothelial cell-mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines.

Nanoparticle-enhanced PD-1/PD-L1 targeted combination therapy for triple negative breast cancer.

Breast cancer with triple-negative subtype (TNBC) presents significant challenges with limited treatment options and a poorer prognosis than others. While PD-1/PD-L1 checkpoint inhibitors have shown promise, their efficacy in TNBC remains constrained. In recent years, nanoparticle (NP) technologies offer a novel approach to enhance cancer therapy by optimizing the tumor microenvironment and augmenting chemo- and immunotherapy effects in various preclinical and clinical settings. This review discusses recent investigations in NP strategies for improving PD-1/PD-L1 blockade-based combination therapy for TNBC. Those include single or multi-therapeutic NPs designed to enhance immunogenicity of the tumor, induce immunogenic cell death, and target immunosuppressive elements within the tumor microenvironment. The investigations also include NPs co-loaded with PD-L1 inhibitors and other therapeutic agents, leveraging targeted delivery and synergistic effects to maximize efficacy while minimizing systemic toxicity. Overall, NP approaches represent a promising avenue for enhancing PD-1/PD-L1 checkpoint blockade-based combination therapy in TNBC and encourage further developmental studies.

Viral Delivery of Compact CRISPR-Cas12f for Gene Editing Applications.

Treating human genetic conditions invivo requires efficient delivery of the CRISPR gene editing machinery to the affected cells and organs. The gene editing field has seen clinical advances with ex vivo therapies and with invivo delivery to the liver using lipid nanoparticle technology. Adeno-associated virus (AAV) serotypes have been discovered and engineered to deliver genetic material to nearly every organ in the body. However, the large size of most CRISPR-Cas systems limits packaging into the viral genome and reduces drug development flexibility and manufacturing efficiency. Here, we demonstrate efficient CRISPR gene editing using a miniature CRISPR-Cas12f system with expanded genome targeting packaged into AAV particles. We identified efficient guides for four therapeutic gene targets and encoded the guides and the Cas12f nuclease into a single AAV. We then demonstrate editing in multiple cell lines, patient fibroblasts, and primary hepatocytes. We then screened the cells for off-target editing, demonstrating the safety of the therapeutics. These results represent an important step in applying CRISPR editing to diverse genetic sequences and organs in the body.

Emerging Trends in Hybrid Nanoparticles: Revolutionary Advances and Promising Biomedical Applications.

Modern nanostructures must fulfill a wide range of functions to be valuable, leading to the combination of various nano-objects into hierarchical assemblies. Hybrid Nanoparticles (HNPs), comprised of multiple types of nanoparticles, are emerging as nanoscale structures with versatile applications. HNPs offer enhanced medical benefits compared to basic combinations of distinct components. They address the limitations of traditional nanoparticle delivery systems, such as poor water solubility, nonspecific targeting, and suboptimal therapeutic outcomes. HNPs also facilitate the transition from anatomical to molecular imaging in lung cancer diagnosis, ensuring precision. In clinical settings, the selection of nanoplatforms with superior reproducibility, cost-effectiveness, easy preparation, and advanced functional and structural characteristics is paramount. This study aims toextensively examine hybrid nanoparticles, focusing on their classification, drug delivery mechanisms, properties of hybrid inorganic nanoparticles, advancements in hybrid nanoparticle technology, and their biomedical applications, particularly emphasizing the utilization of smart hybrid nanoparticles. PHNPs enable the delivery of numerous anticancer, anti-leishmanial, and antifungal drugs, enhancing cellular absorption, bioavailability, and targeted drug delivery while reducing toxic side effects.

Assessment of Antiangiogenic and Cytotoxic Effects of Moringa oleifera Silver Nanoparticles Using Cell Lines

Angiogenesis is the physiological process through which new blood vessels are developed from pre-existing vessels. It includes steps like migration, differentiation, and growth of endothelial cells. Furthermore, it plays a critical role in cancer formation and metastasis. Recently, Moringa oleifera (MO) has gained interest due to its properties in various fields, particularly in nanoparticle (NP) technology. This study aims to demonstrate the cytotoxic and antiangiogenic effects of MO silver nanoparticles (MO-AgNPs). Briefly, the cytotoxic effects of MO-AgNPs on Ea. hy 926 and HT 29 cell lines were observed in the Colony Formation Assay. The antiproliferative effects of MO-AgNPs were then further confirmed using MTT assay, in addition to morphological characterization, migration and closure percent calculation. To evaluate the antiangiogenic effect of MO, the chorioallantoic membrane (CAM) assay was done. Fertilized chicken eggs were divided into three groups: MO-AgNPs, MO ethanol extract and negative control. The results showed antiangiogenic effects were observed at 6-12 µg/mL concentration of MO-AgNPs. Whereas the plate efficiency was 45.7 % ± 1%. The surviving fraction at 12, 6, 3, and 1.5 μg/mL was 27.3± 0.5%, 30.1 ± 0.5 %, 41.8 ± 1.5%, and 69.8 ± 2.5 %, respectively. MO-AgNPs showed higher cytotoxic activity than MO ethanol extract on the Ea. hy926 cell line, where the IC50 of MO-AgNPs were 74, 35, and 12 µg/mL for 24, 48 and 72 hours, respectively. On the other hand, the IC50 of MO ethanol extract was above 200, 135 and 11 µg/mL for 24, 48 and 72 hours, respectively. Additionally, significant morphological changes were observed in Ea. hy cells. Whereas the closure percent average of Ea. hy cells at 1.5, 3, 6, and 12 µg/mL were 91.603, 88.507, 84.599, and 63.144%, respectively. Based on the results showed in this study, MO extract shows potential to be an effective anti-angiogenic agent and is a promising therapeutic option in cancer treatment.

Effect of pegagan (Centella asiatica) nanoparticle coated with chitosan on the cytokine profile of chronic diabetic mice.

Diabetes is closely related to immune response problems when it occurs chronically. Pegagan (Centella asiatica) is a medicinal plant with active compounds. Madecassoside is beneficial in treating diabetes, and nanoparticle technology is expected to enhance the medicinal potential and availability of pegagan compounds. The aim of this study was to determine the effect of chitosan-coated pegagan nanoparticles on the cytokine profile of chronic diabetic mice, which included CD4+TNF-α+, CD8+TNF-α+, CD4+IFN-γ+, CD8+IFN-γ+ and IL-6+. An experimental study with a randomized complete block design (CRD) consisting of six treatments with seven replicates was conducted. The groups were: healthy mice as negative control; diabetic mice treated with distilled water as positive control and diabetic mice treated with nanoparticle coated with chitosan (NPC) 20 mg/kg, 30 mg/kg, 40 mg/kg, and metformin 130 mg/kgBW. The data were tested using one-way analysis of variance (ANOVA) with a significance level of 5% and continued with the Duncan's multiple range test. The results showed that pegagan NPC could significantly reduce the relative number of CD4+TNF-α+, CD8+TNF-α+, CD4+IFN-γ+ and CD8+IFN-γ+ and IL-6 in the dose of 20 mg/kg, 30 mg/kg and 40 mg/kg (p<0.05). The treatment dose of 20 mg/kg reduced CD4+TNF-α+, CD8+TNF-α+, CD4+IFN-γ+, CD8+IFN-γ+ to the levels of healthy mice and a dose of 30 mg/kg could reduce IL-6 as in healthy mice. These findings suggest that chitosan-coated pegagan nanoparticles are a promising therapy for diabetes, as they have the potential to modulate the immune response associated with chronic diabetes.

Lipid-based nanoparticles as drug delivery carriers for cancer therapy.

Cancer is a severe disease that results in death in all countries of the world. A nano-based drug delivery approach is the best alternative, directly targeting cancer tumor cells with improved drug cellular uptake. Different types of nanoparticle-based drug carriers are advanced for the treatment of cancer, and to increase the therapeutic effectiveness and safety of cancer therapy, many substances have been looked into as drug carriers. Lipid-based nanoparticles (LBNPs) have significantly attracted interest recently. These natural biomolecules that alternate to other polymers are frequently recycled in medicine due to their amphipathic properties. Lipid nanoparticles typically provide a variety of benefits, including biocompatibility and biodegradability. This review covers different classes of LBNPs, including their characterization and different synthesis technologies. This review discusses the most significant advancements in lipid nanoparticle technology and their use in medicine administration. Moreover, the review also emphasized the applications of lipid nanoparticles that are used in different cancer treatment types.

Molecular mechanisms of resveratrol and its silver nanoparticle conjugate in addressing sepsis-induced lung injury

Sepsis is a life-threatening condition characterized by a systemic inflammatory response to infection. Despite extensive research on its pathophysiology, effective therapeutic approaches remain a challenge. This study investigated the potential of resveratrol (RV) and silver nanoparticle–enhanced resveratrol (AgNP-RV) as treatments for sepsis-induced lung injury using a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). The study focused on evaluating changes in oxidative status (TAS, TOS, and OSI) and the expression of inflammatory and apoptotic markers (IL-1β, TNF-α, P2X7R, TLR4, Caspase-3, and Bcl-2) in lung tissue. Both RV and AgNP-RV demonstrated potential in mitigating oxidative stress, inflammation, and apoptosis, with AgNP-RV exhibiting greater efficacy than RV alone (p < 0.05). These findings were corroborated by histopathological analyses, which revealed reduced tissue damage in the RV- and AgNP-RV-treated groups. Our study highlights the therapeutic potential of RV and, particularly, AgNP-RV in combating sepsis-induced oxidative stress, inflammation, and apoptosis. It also underscores the promise of nanoparticle technology in enhancing therapeutic outcomes. However, further investigations are warranted to fully understand the mechanisms of action, especially concerning the role of the P2X7 receptor in the observed effects. Nonetheless, our research suggests that RV and AgNP-RV hold promise as novel strategies for sepsis management.

Abstract 2123: Validation of novel histone deacetylases (HDAC) specific nanoparticles using HDACs overexpressed human embryonic kidney cells

Abstract Introduction: Histone deacetylase (HDAC) is a major enzyme system that is upregulated in numerous disease conditions including cancer. Harnessing the upregulation of HDAC can be a viable tool to design targeted therapy for these diseases. Nanoparticle technology has emerged as a powerful workhorse to suppress the survival of diseased cells selectively. As such, we aim to design a nanoscale, drug delivery platform that responds to HDAC enzymes to initiate drug release. In this poster, we show the pharmacological evidence that HDAC-sensitive nanoparticles are interacting with HDAC enzymes in vitro in time and concentration dependent pattern. Methods: We synthesized HDAC-responsive nanoparticles via developing a block copolymer composed of a poly (ethylene glycol) block and a poly (L-acetylated lysine) block. Abbreviated as PEG-acPLK, these copolymers self-assemble as nanoparticles with negatively charged surface. Using in vitro culture of HEK 293 cells, we showed that the formed nanoparticles interact and interfere with HDAC enzymes. Cells were grown to 80-90% confluency in DMEM media w/10% FBS prior to experiments. HEK-293 cells were overexpressed with HDAC 7 &amp; HDAC 8 using Lentiviral vectors. Western blot was done to prove the successful overexpression of the HEK cells. Cytotoxicity assay was done by MTT to analyze the efficacy of HDAC specific nanoparticle on control and overexpressed HEK-293 cells. Results: Our work showed that, PEG-acPLK systems form nanoparticles with a hydrodynamic diameter (RH) of 120-150 nm. The particles were negatively charged on their surface, as such did not produce any non-specific toxicity to cells, such as damage of cell membranes. HEK-293 cells were infected with lentivirus vectors for HDAC 7 and HDAC 8. The medium was changed 8 h after infection. Forty-eight hours after infection, the positive cells were selected with 5 µg/mL puromycin. The lentivirus stable transformants of HEK-293 cells were collected and significant overexpression were confirmed by western blot. For the cytotoxicity study, control and overexpressed cells were treated with HDAC-nanoparticle and PEG-acPLKC (5 µg/mL to 70 µg/mL) for 24hrs. Both the HDAC-nanoparticle and PEG-acPLC (free form) showed more than 60% of toxicity at the concentration of 20 µg/mL. Whereas the HDAC 7 and 8 overexpressed HEK-293 cells did not showed any effects with nanoparticle and Ae-peg-PLKC, suggesting compensating effect due to highly available HDAC system in place and confirm the effectiveness of the HDAC nanoparticle. Summary and Conclusion: Overall, these results showed that HDAC specific nanoparticle exhibited effects in HEK-293 HDACs overexpressed cells. Further molecular mechanistic studies will help to delineate how the HDAC-responsive particles can be used for drug delivery. Citation Format: Sahil Lohana, Yogaraj Ramakrishnan, Premanand Balraj, Md Rakib Hasan Khan, Mallik Sanku, Venkatachalem Sathish, Mohiuddin Quadir. Validation of novel histone deacetylases (HDAC) specific nanoparticles using HDACs overexpressed human embryonic kidney cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2123.

Abstract 7117: Convection enhanced delivery of a novel ATR inhibitor synergizes with systemic lomustine for improved treatment of glioblastoma

Abstract Developing effective strategies for treating glioblastoma (GBM), the most common and aggressive form of brain cancer, has been a long-standing challenge. Despite rigorous treatment regimens including surgical resection with concomitant radiotherapy and chemotherapy, the prognosis for this disease remains poor, largely due to tumor recurrence, resistance to conventional therapeutics, pharmacokinetic and brain delivery challenges, and dose-limiting toxicities of existing therapies. The DNA damage response and DNA repair mechanisms such as the ataxia telangiectasia and Rad3-related (ATR) pathway are key mediators of therapeutic responses, and recent studies have shown that targeting DNA repair proteins alongside standard-of-care options is a promising anti-tumor strategy. Here, we employ a combination approach using a next-generation macrocyclic ATR inhibitor, ATRIN-333, to sensitize GBM tumors to alkylators. We establish the potency of ATRIN-333 and report a robust synergistic interaction between it and the alkylator lomustine in GBM cell-based assays and in a murine flank tumor model. This combinatorial treatment was then applied to a mouse intracranial tumor model, where we utilized a convection enhanced delivery (CED) system combined with nanoparticle technology for direct intracranial administration of ATRIN-333. ATRIN-333 was successfully encapsulated into a novel polymeric nanoparticle formulation using poly(ethylene glycol)-co-poly(ethylene brassylate-co-dioxanone) (PEG-EB-co-DO). CED of both free and encapsulated ATRIN-333 potently sensitized intracranial GBM tumors to low-dose (5 mg/kg) systemically-delivered lomustine, reducing tumor size and conferring a substantial survival benefit compared to cohorts treated with lomustine or the ATR inhibitor alone. The combination approach was well tolerated by the mice, with no hematological toxicity observed as assessed by bone marrow analysis and blood cell counts. Our results demonstrate that ATR inhibitor/lomustine combination therapy, used in conjunction with a CED platform, is a powerful avenue for GBM treatment and a viable option for potential clinical implementation. Note: AJ and TL contributed equally to this work. Citation Format: Alexander Josowitz, Teresa Lee, Ranjini K. Sundaram, Jinal Pothupitiya, Eric J. Brown, Amrita Sule, Jason Beckta, Yongheng Wang, Joseph Vacca, Oren Gilad, Ranjit S. Bindra, W Mark Saltzman. Convection enhanced delivery of a novel ATR inhibitor synergizes with systemic lomustine for improved treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7117.

Abstract 5799: Novel nanoparticle technology targets the delivery of polyIC to EGFR overexpressing cancers and induces a multimodal anti-tumor response

Abstract Aberrant activation of epidermal growth factor receptor (EGFR) signaling pathways is associated with tumor growth and progression. EGFR overexpression occurs in various types of solid cancers and correlates with poor outcome. Unfortunately, the clinical benefit from EGFR-targeted therapies is usually short-lived, due to the development of resistance. TargImmune has developed first-in-class Targeted Apoptotic Immunomodulators (TAIMs), which harness the body’s anti-viral responses to treat solid tumors. Our novel nanoparticle platform technology, Ta:RNA , selectively delivers synthetic dsRNA, polyinosinic:polycytidylic acid (polyIC) to tumor cells that overexpress a target receptor. PolyIC and other pattern recognition receptor (PRR) agonists have been used as adjuvants or for intratumoral administration but have limited efficacy as single agents. TargImmune’s platform allows systemic delivery of dsRNA, tailoring the nanoparticles to various solid cancers by simply changing the targeting moiety. Here we describe EGFR-Ta:RNA, which is targeted to tumors that overexpress EGFR. EGFR-Ta:RNA does not inhibit EGFR per se, and therefore activation of alternative or downstream oncogenes is not expected to cause resistance. The mechanism of action of EGFR-targeted Ta:RNA nanoparticles was extensively studied in vitro and in vivo, using confocal imaging, large-scale RNA sequencing studies, Western blot analysis and ELISA assays. In vitro, EGFR-Ta:RNA potency and selectivity were established by comparing cells with high receptor and low receptor expression. Imaging studies showed that the nanoparticles are internalized selectively into EGFR-overexpressing cancer cells by receptor-mediated endocytosis. RNAseq studies revealed: (i) a common transcriptional signature in EGFR-Ta:RNA-treated tumours and cancer cells; (ii) enrichment in pathways related to anti-viral response, inflammation, type I interferon signaling, and NFΚB signaling; (iii) enrichment in genes coding for cytokines. Western blot analysis and ELISA assays confirmed that the mechanism of action of EGFR-Ta:RNA is mediated via the induction of PRR downstream signaling, which results in cytokine secretion, apoptosis and immune cell activation. The efficacy of EGFR-Ta:RNA was demonstrated in multiple animal models, including both xenograft and immunocompetent models. The pharmacodynamic effect, exemplified by target engagement and activation of PRR signaling in tumors, was verified in vivo. In conclusion, TargImmune’s EGFR-Ta:RNA nanoparticles deliver polyIC in a tumor-targeted manner to evoke PRR signaling, inducing targeted tumor cell apoptosis as well as immune cell recruitment and activation against the heterogenous tumor. EGFR-Ta:RNA represents a novel, multimodal treatment approach for EGFR overexpressing cancers. Citation Format: Derrick Broka, Caroline De Feyter, Shoshana Klein, Meera Saxena, Joerg Schreiber, Alexei Shir, Michal Skowicki, Yaakov Benenson, Alexander Levitzki, Cornelia G. Palivan, Esteban Pombo-Villar, Babette Schade, Maya Zigler. Novel nanoparticle technology targets the delivery of polyIC to EGFR overexpressing cancers and induces a multimodal anti-tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5799.

Adapting the in vitro micronucleus assay (OECD Test Guideline No. 487) for testing of manufactured nanomaterials: recommendations for best practices.

The current Organisation for Economic Co-Operation and Development test guideline number 487 (OECD TG No. 487) provides instruction on how to conduct the in vitro micronucleus assay. This assay is one of the gold standard approaches for measuring the mutagenicity of test items; however, it is directed at testing low molecular weight molecules and may not be appropriate for particulate materials (e.g. engineered nanoparticles [ENPs]). This study aimed to adapt the in vitro micronucleus assay for ENP testing and underpins the development of an OECD guidance document. A harmonized, nano-specific protocol was generated and evaluated by two independent laboratories. Cell lines utilized were human lymphoblastoid (TK6) cells, human liver hepatocytes (HepG2) cells, Chinese hamster lung fibroblast (V79) cells, whole blood, and buffy coat cells from healthy human volunteers. These cells were exposed to reference ENPs from the Joint Research Council (JRC): SiO2 (RLS-0102), Au5nm and Au30nm (RLS-03, RLS-010), CeO2 (NM212), and BaSO4 (NM220). Tungsten carbide-cobalt (WC/Co) was used as a trial particulate positive control. The chemical controls were positive in all cell cultures, but WC/Co was only positive in TK6 and buffy coat cells. In TK6 cells, mutagenicity was observed for SiO2- and both Au types. In HepG2 cells, Au5nm and SiO2 showed sub-two-fold increases in micronuclei. In V79 cells, whole blood, and buffy coat cells, no genotoxicity was detected with the test materials. The data confirmed that ENPs could be tested with the harmonized protocol, additionally, concordant data were observed across the two laboratories with V79 cells. WC/Co may be a suitable particulate positive control in the in vitro micronucleus assay when using TK6 and buffy coat cells. Detailed recommendations are therefore provided to adapt OECD TG No. 487 for testing ENP.

The role of nanoparticles of industrial aerosols in the formation of occupational bronchopulmonary pathology

The significant prevalence of industrial aerosols with unintentional nanoparticles and the increasing use of engineering nanoparticles in modern production determine the relevance of research on the patterns of interaction with the human bronchopulmonary system. Unintentional nanoparticles are formed during various production processes: melting and welding of metals, combustion, crushing, grinding of minerals, plasma processing of materials. Engineering nanoparticles are released into the air of the work area during their production or use in any technological processes.&#x0D; The respiratory system, as a barrier organ, is most vulnerable to the effects of adverse environmental factors. At the same time, nanoparticles are the least studied component of industrial aerosols. In order to systematize data on the role of nanoparticles in the development of occupational bronchopulmonary pathology, the authors conducted a literature review.&#x0D; The size determines the features of the physical, chemical and biological properties of nanoparticles. They have high values of the ratio of surface area to volume, total surface area, which leads to an increase in reactogenicity and penetrating power. The pathogenic properties of nanoparticles depend on the chemical composition, shape, curvature of the surface, structure, charge, mass concentration, total surface area of the particles, and exposure time.&#x0D; The multidimensionality of hygienic characteristics determines the complexity of hygienic rationing and monitoring of nanoparticles. To date, safe exposure levels have not been established. When interacting with cells of the respiratory tract, nanoparticles induce the following cellular and molecular mechanisms: oxidative stress, inflammation, violation of the epithelial barrier, autophagy and dysfunction of lysosomes, stress of the endoplasmic reticulum, apoptosis, senescence, fibrosis, endothelial dysfunction, DNA damage. This leads to the development of interstitial pneumonitis, pulmonary fibrosis and obstructive disorders, and an increase in the activity of allergic inflammation. All these mechanisms are present in the pathogenesis of occupational lung diseases. Under the influence of nanoparticles of various chemical compositions, separate phenotypes of occupational chronic obstructive pulmonary disease are formed. There is a lack of epidemiological studies of the possible etiological role of nanoparticles. Nanoparticles of industrial aerosols are a significant factor in the development of occupational diseases of the bronchopulmonary system and have a significant impact on the formation &#x0D; of phenotypes.

Maximizing Aqueous Drug Encapsulation: Small Nanoparticles Formation Enabled by Glycopolymers Combining Glucose and Tyrosine.

Highly potent heterocyclic drugs are frequently poorly water soluble, leading to limited or abandoned further drug development. Nanoparticle technology offers a powerful delivery approach by enhancing the solubility and bioavailability of hydrophobic therapeutics. However, the common usage of organic solvents causes unwanted toxicity and process complexity, therefore limiting the scale-up of nanomedicine technology for clinical translation. Here, we show that an organic-solvent-free methodology for hydrophobic drug encapsulation can be obtained using polymers based on glucose and tyrosine. An aqueous solution based on a tyrosine-containing glycopolymer is able to dissolve solid dasatinib directly without adding an organic solvent, resulting in the formation of very small nanoparticles of around 10 nm loaded with up to 16 wt % of drug. This polymer is observed to function as both a drug solubilizer and a nanocarrier at the same time, offering a simple route for the delivery of insoluble drugs.

Machine learning-based models to predict aquatic ecological risk for engineered nanoparticles: using hazard concentration for 5% of species as an endpoint.

Assessment and prediction for the ecotoxicity of engineered nanoparticles (ENPs) at the community or ecosystem levels represents a critical step toward a comprehensive understanding of the ecological risks of ENPs. Current studies on predicting the ecotoxicity of ENPs primarily focus on the cellular and individual levels, with limited exploration at the community or ecosystem levels. Herein, we present the first of the reports for the direct prediction of aquatic ecological risk for ENPs at the community level using machine learning (ML) approaches in the field of computational toxicology. Specifically, we extensively collected the threshold concentrations of twelve ENPs including metal- and carbon-based nanoparticles for aquatic species, i.e., hazardous concentrations at which 5% of species are harmed (HC5), established by a species sensitivity distribution. Afterwards, we used eight supervised ML methods including Adaboost, artificial neural network, C4.5 decision tree, K-nearest neighbor, logistic regression, Naive Bayes, random forest, and support vector machine to develop nine classification models and four regression models, respectively, for the qualitative and quantitative prediction of HC5. The evaluation of model performance yielded the internal validation accuracy of all classification models ranging from 71.4 to 100%, and the determination coefficient of regression models ranging from 0.702 to 0.999, indicating that the developed models showed good performance. By using a cross-validation method and an application domain characterization, the selected models were further validated to have powerful predictive ability. Furthermore, the incorporation of three nanostructural descriptors (metal oxide sublimation enthalpy, zeta potential, and specific surface area) linked to toxicity mechanisms (the release of metal ions, the stability of dispersions of particles in aqueous suspensions, and the surface properties of the material) effectively enhanced the prediction power and mechanistic interpretability of the selected models. These findings would not only be beneficial in the screening of ENPs with potential high ecological risks that need to be tested as a priority but also contribute to the development of environmental regulations and standards for ENPs.

Mechanisms of Antibiotic Resistance and Developments in Therapeutic Strategies to Combat Klebsiella pneumoniae Infection.

Infections with drug-resistant bacteria have become one of the greatest public health challenges, and K. pneumoniae is among the top six drug-resistant bacteria. K. pneumoniae often causes nosocomial infections, leading to illnesses such as pneumonia, liver abscesses, soft tissue infections, urinary tract infections, bacteremia, and in some cases death. As the pathogen continues to evolve and its multidrug resistance increases, K. pneumoniae poses a direct threat to humans. Drug resistance in K. pneumoniae may occur due to the formation of biofilms, efflux pumps, and the production of β-lactamases. In many cases, resistance is further enhanced by enzymatic modification and loss of porins. Drug resistance to K. pneumoniae has led to a decline in the effectiveness of conventional therapies against this pathogen. Therefore, there is an urgent need to accelerate the development of new antibiotics and explore new therapeutic approaches such as antimicrobial peptides, phages, traditional Chinese medicine, immunotherapy, Antimicrobial nanoparticle technology, antisense oligonucleotides and gene editing technologies. In this review, we discuss the mechanisms of drug resistance in K. pneumoniae and compare several new potential therapeutic strategies to overcome drug resistance in the treatment of K. pneumoniae infections.

Exploring the Potential of Nano Drug Delivery Systems in Non-Small Cell Lung Cancer Treatment: Recent Developments and Perspectives

Abstract: Globally, lung cancer ranks among the most frequent forms of tumor. The survival rate for people suffering from lung tumors after five years is only 20%, despite novel treatment options such as immunotherapy. Current therapies cause severe off-target effects and acquired drug resistance to explain the low survival rate. Identifying and developing new therapeutic approaches for lung cancer patients is crucial to improving the standard of care. As a result of the study, we researched clinical trials and experiments in fundamental research, and new approaches to drug delivery including adenoviruses, nanoparticles, and proteolysis-targeting chimeras (PROTACs). Several approaches can now be applied directly to lung cancer to prevent disease progression, including phosphatases, targeting protein kinases, protein modifications and ubiquitin ligases. In addition, the recent approval of Ribonucleic acid (RNA) based vaccines based on lipid nanoparticle technology has made it possible to improve current lung cancer treatments by combining chemo- and immunotherapies. This review emphasises recent advancements in pharmaceutical research aimed at developing technologies to target post-translational modifications in lung tumorigenesis. Elucidation of various scientific advances in conjunction with encouraging findings concerning therapies available, the future perspectives and challenges of nanocarriers for effective lung cancer are also presented in this article.

Abstract B010: Response to treatment with nab-sirolimus among patients with primary uterine tumors: A subgroup analysis from AMPECT

Abstract Introduction/objective: AMPECT (NCT02494570) is a pivotal study of nab-sirolimus in patients with malignant perivascular epithelioid cell tumors (PEComa). Malignant PEComa is an aggressive, rare sarcoma for which cytotoxic chemotherapies provide limited patient benefit. Inactivation of TSC1 or TSC2 tumor suppressor genes, upstream of mTORC1, is commonly associated with malignant PEComa; these mutations occurred in 56% of patients in AMPECT. nab-Sirolimus is an mTOR inhibitor (mTORi) that utilizes albumin-bound nanoparticle technology to drive higher intratumoral drug levels and more complete pathway suppression than conventional mTORis. nab-Sirolimus is approved in the USA for the treatment of advanced or metastatic malignant PEComa based on the primary analysis results of the AMPECT trial, which showed a confirmed overall response rate (ORR) of 39%, regardless of mutation status. We describe outcomes of a subset of patients with primary uterine PEComa, representing 23% of efficacy-evaluable patients in AMPECT. Methods: AMPECT was an open-label, multicenter, phase 2 registration study in mTORi-naïve adult patients (≥18 years old) with a histologically confirmed diagnosis of malignant PEComa and Eastern Cooperative Oncology Group performance status score ≤1. Patients received nab-sirolimus 100 mg/m2 intravenously on days 1 and 8 of a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was ORR by independent radiology review. Key secondary endpoints included time to response, duration of response (DOR), and safety. Results: A total of 7 patients with uterine PEComa were treated with nab-sirolimus in AMPECT and were evaluable for both safety and efficacy. Mean ± SD age was 60.0 ± 13.4 years, and 71% (5/7) of patients were White. ORR was 43% (3/7 patients); all 3 were confirmed partial responses and were seen in patients with tumors with somatic inactivating alterations in TSC1 or TSC2. Two (29%) patients had best response of stable disease. For the 3 responders, time to response was 1.4, 1.4, and 1.5 months, and DOR was 5.6, 36.0+, and 39.7 months. All 7 patients had ≥1 treatment-related adverse event (TRAE; grade 3, 43%); no grade ≥4 or serious TRAEs occurred. Conclusions: Rates of response to treatment and safety findings in patients with primary uterine PEComa treated with nab-sirolimus in AMPECT were consistent with those previously reported in the overall patient population. Responses were rapid and durable. Notably, all responders had TSC1 or TSC2 alterations; however, there were too few patients in this subset to draw conclusions regarding efficacy in tumors without these alterations. nab-Sirolimus is being further evaluated in a tumor-agnostic trial of patients with TSC1 or TSC2 inactivating alterations (PRECISION I; NCT05103358). Citation Format: Vinod Ravi, Mark A. Dickson, Kristin Ganjoo, Li Ding, Anita N. Schmid, Norma A. Palma, Willis H. Navarro, Andrew J. Wagner. Response to treatment with nab-sirolimus among patients with primary uterine tumors: A subgroup analysis from AMPECT [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B010.

Engineered nanomaterials in plant protection: their controlled, site-directed delivery and phytotoxicity

Engineered nanomaterials (ENMs) are being produced and utilized in certain nanoformulations almost in every sector of development including agriculture. The diverse groups of engineered nanoparticles (ENPs) provide numerous benefits in agriculture, but their bulk and direct delivery pose a serious risk to the plants and ecosystem for a long time. The harmful effects on all the exposed living systems are owing to the variable shape, size, behaviour and toxic properties of ENPs. The accumulated ENMs in plant tissue may lead to biomagnification at a higher trophic level causing severe toxicity. The hazardous effects of these entities can be minimized with their controlled, specified and targeted delivery to the crop plants. Such smart-delivery systems as Ehrlich’s ‘magic bullets’ are being demonstrated for nutrients and growth enhancers, fertilizers, pesticides and weedicides; as well as biomolecules in plant genetic engineering. This review summarizes the benefits of ENMs and ENPs in plant protection to increase crop productivity, their targeted delivery suggesting sustainable utilization, and the available information on phytotoxicity.

Nano Sponge: An Emerging Nano-Technology Based Drug Delivery System

In current scenario medical experts have long struggled with how to deliver medication to targeted location into the body while also controlling the drug release rate to avoid overdosing. This issue may be resolve through the creation of novel, intricate formulation known as nano sponges. Nano sponges are small sponge, all around size virus, that may hold a range of medication. These microscopic sponges can move through the system until they reach the intended target region, where they adhere to surface and start to release the drug in steady and controlled manner. Nano sponges are a network or 3D polyester scaffold that are spontaneously decompose. These polyesters are combined with cross-linkers agent in a solution to create a nano sponge. When loaded nano sponge’s framework breakdown the drug particle is released. They are mostly in solid form and it can be formulated as oral, parenteral, topical, or inhalation dosage form, several studies havebeen conducted on protein, peptide, genes, anti-cancer biomolecules via nano-particle technology which hep to reduce undesirable effect and enhance efficacy.