Non-specific Toxicity Research Articles

Applications of Novel Microscale and Nanoscale Materials for Theranostics: From Design to Clinical Translation.

The growing global prevalence of chronic diseases has highlighted the limitations of conventional drug delivery methods, which often suffer from non-specific distribution, systemic toxicity, and poor bioavailability. Microscale and nanoscale materials have emerged as innovative solutions, offering enhanced targeting, controlled release, and the convergence of therapeutic and diagnostic functions, referred to as theranostics. This review explores the design principles, mechanisms of action, and clinical applications of various novel micro- and nanomaterials in diseases such as cancer, cardiovascular disorders, and infectious diseases. These materials enable real-time monitoring of therapeutic responses and facilitate precision medicine approaches. Additionally, this paper addresses the significant challenges hindering clinical translation, including biocompatibility, potential toxicity, and regulatory issues. Ongoing clinical trials demonstrate the potential of nanomaterials in theranostic applications, but further research is needed to overcome the barriers to widespread clinical adoption. This work aims to contribute to the acceleration of integrating nanomedicine into clinical practice, ultimately enhancing the efficacy and safety of therapeutic interventions.

A Facile Strategy for PEGylated Nanoprodrug of Bortezomib with Improved Stability, Enhanced Biocompatibility, pH-Controlled Disassembly, and Release.

The therapeutic efficacy of bortezomib (BTZ) is often limited due to low solubility, poor stability in vivo and nonspecific toxicity. Herein, a kind of catechol-functionalized polyethylene glycol (mPEG-CA) is first synthesized and then mPEG-CA is readily used to conjugate with BTZ by the formation of dynamic boronate bonds to obtain PEGlyated BTZ prodrug (mPEG-CA-BTZ) with the ability of pH-controlled disassembly and drug release. The structure and morphology, physicochemical characteristics, drug loading, and release as well as in vitro cytotoxicity of mPEG-CA-BTZ nanoparticles are investigated in detail. The results demonstrated that mPEG-CA-BTZ can not only self-assemble into nanostructures with uniform size and stable dispersion in physiological pH condition (pH 7.4) but also respond to the tumor acid microenvironment and achieve pH-controlled BTZ release by acid-triggered cleavage of boronate bonds, decomposition of mPEG-CA-BTZ and thus disassembly of mPEG-CA-BTZ nanoparticles. mPEG-CA-BTZ nanoparticles are expected to have great potential as a promising nanoplatform for pharmaceutical formulations of BTZ to increase therapeutic efficacy and decrease side effects of BTZ. Considering the easily available and biocompatible excipients and simple preparation process, the strategy designed herein provides a facile and promising approach to synergistically integrate the function of PEGylation and pH-sensitiveness into boronic acid-containing small molecule pharmaceutical agents.

Therapeutic Efficacy of Nanocarrier‐Mediated Inhalable Gene Transfection for Lung Cancer

AbstractLung cancer is now the leading cause of cancer‐related mortality, eclipsing all other cancer forms, and of all lung malignancies, non‐small cell lung cancer (NSCLC) makes up around 85%. Recently, the use of vectors in gene therapy besides chemotherapy to treat malignancies brought on by gene mutations has gained prominence. Therapeutic molecule inhalation is a direct approach to lung‐targeted medication delivery with low nonspecific toxicity and limited drug exposure. Treatment for lung cancer with chemotherapy and immunotherapy can be aided by inhalable nanomedicine through advanced mechanisms. Viral and nonviral vectors, such as lipid‐based nanoparticles, polymeric nanoparticles, and inorganic nanoparticles, have all drawn a lot of interest for their ability to increase effects and decrease side effects. Nanocarriers have a significant impact on targeted gene delivery, bioavailability, stability, and residence in target areas. The inhaled pulmonary gene delivery approach, when combined with nanomedicine, will offer a noninvasive and successful way to treat lung cancer by taking use of the physiological properties of the lung. The authors have majorly used data from PubMed and Google Scholar to obtain the relevant information required for the article. In general, this review concentrates on the usage of various inhalable nanocarriers, which might serve as an inspiration for the creation and deployment of more potent genetic therapy for the treatment of lung cancer.

Hypoxia-Inducible Factor-1α-Activated Protein Switch Based on Allosteric Self-Splicing Reduces Nonspecific Cytotoxicity of Pharmaceutical Drugs.

Protein-based therapeutic agents currently used for targeted tumor therapy exhibit limited penetrability, nonspecific toxicity, and a short circulation half-life. Although targeting cell surface receptors improves cancer selectivity, the receptors are also slightly expressed in normal cells; consequently, the nonspecific toxicity of recombinant protein-based therapeutic agents has not been eliminated. In this study, an allosteric-regulated protein switch was designed that achieved cytoplasmic reorganization of engineered immunotoxins in tumor cells via interactions between allosteric self-splicing elements and cancer markers. It can target the accumulated HIF-1α in hypoxic cancer cells and undergo allosteric activation, and the splicing products were present in hypoxic cancer cells but were absent in normoxic cells, selectively killing tumor cells and reducing nonspecific toxicity to normal cells. The engineered pro-protein provides a platform for targeted therapy of tumors while offering a novel universal strategy for combining the activation of therapeutic functions with specific cancer markers. The allosteric self-splicing element is a powerful tool that significantly reduces the nonspecific cytotoxicity of therapeutic proteins.

Chemo-Enzymatic Functionalization of Bovine Milk Exosomes with an EGFR Nanobody for Target-specific Drug Delivery.

Bovine milk exosomes (BmExo) have been identified as versatile nanovesicles for anti-cancer drugs delivery due to their natural availability and biocompatibility. However, tumor-specific delivery based on BmExo often requires post-isolation modifications of the membrane surface with active-targeting ligands. In this study, we report an alternative approach to functionalize BmExo with nanobody combining facile chemical modification and Sortase A-mediated site-specific ligation, as demonstrated by the development of an epidermal growth factor receptor (EGFR)-targeted drug delivery system. The BmExo membrane was first coated with a diglycine-containing amphiphile molecule, NH2-GG-PEG2000-DSPE, by hydrophobic insertion. The diglycine as nucleophiles displayed on the membrane enabled the subsequent ligation of the EGFR nanobody (7D12) by Sortase A (SrtA)-mediated site-specific transpeptidation. The successful construction of BmExo-7D12 was confirmed by Western blotting analysis, electron microscopy, and dynamic light scattering (DLS). As a demonstration model, BmExo-7D12 loaded with the chemotherapeutic drug doxorubicin (Dox) was shown to be able to deliver Dox to cancer cells in response to the expression of EGFR as manifested by immunocytochemistry and flow cytometry analysis. Finally, the cytotoxicity assay showed that BmExo-7D12-Dox was more effective in killing tumor cells with high EGFR expression while significantly reduced the non-specific toxicity to EGFR negative cells. In conclusion, these results demonstrate that 7D12-functionalized BmExo can serve as a target-specific delivery system for Dox to selectively kill EGFR-expressing tumor cells. This approach should prove to be versatile and efficient for the generation of protein-ligands modified BmExo.

Green-synthesized Metal Nanoparticles for Cancer Diagnosis and Treatment: A Critical Review

: The utilization of chemotherapy remains an established therapeutic strategy in the ongoing fight against cancer. Nevertheless, it has been impeded by the occurrence of several fatal adverse reactions caused by non-specific toxicity often associated with chemotherapy. Nanotechnology is an emerging field of research that is experiencing rapid growth and is widely recognized as a highly promising approach for advanced cancer therapy. Biosynthesized green nanomaterials are emerging as promising tools for cancer treatment and diagnosis. Metal nanoparticles have been developed for use in several applications, including magnetically sensitive medication delivery, photothermal treatment, and photoimaging. Nanomaterials containing metals, such as iron, cobalt, and silver, which are generated from various bio-sources, have been described. The boundless capabilities of nanoparticles have already had a profound impact on human existence. Nevertheless, the potential adverse effects of nanoparticles on human health have consistently instilled apprehension. A thorough investigation of the toxicity and intricate nature of nanomaterials has facilitated the emergence of nanotoxicology, a field that examines the fundamental origins of these problems. The introduction of green chemistry principles has aimed to provide safer techniques for the production and management of nanomaterials, resulting in the emergence of green nanotechnology. This review article highlights the potential uses of green nanotechnology for the detection and management of tumors, including the challenges they face in reaching clinical trials.

Nanoencapsulation of etoposide promotes increased long-term DNA damage, greater induction of senescence and reduces population regrowth of lung cancer cells

Lung cancer is the most common type of cancer and the leading cause of cancer-related deaths worldwide. The nanoencapsulation of etoposide, a topoisomerase II inhibitor and widely used chemotherapeutic drug, may overcome the limitations related to low aqueous solubility and non-specific toxicity, in addition to enabling a sustained release of etoposide and promoting long-term effects. Here we developed etoposide-loaded lipid-core nanocapsules (ETO NC) having unimodal particle size (∼150 nm), drug content of 0.5 mg mL−1 and encapsulation efficiency of ∼99 %. The formulation remained stable for 28 days at 5 °C. The release experiment showed 70 % of drug dialyzed from ETO NC within 72h in a biexponential curve characterized by a burst phase (60 %, t½ = 1.3 h) followed by a sustained phase (33 %, t½ = 173.2 h). Exposure of A549 lung adenocarcinoma cells to 10 μmol L−1 of drug (ETO NC) produced a threefold reduction in cell viability after 48h. Etoposide (ETO or ETO NC) produced DNA double-strand breaks, as indicated by nuclear foci in A549 cells stably expressing 53BP1-mApple. However, ETO NC significantly promoted nuclear damage over the long-term (20 days), consequently enhancing the induction of senescence and significantly reducing the proliferative subpopulation compared to etoposide in solution. Our findings reveal that ETO NC can enhance the long-term effects of etoposide in inducing DNA damage and inducing senescence, being an innovative strategy to overcome the limitations of this treatment, and strongly encouraging future investigations in in vivo models.

Synergistic cytotoxicity of olive leaf extract-loaded lipid nanocarriers combined with Newcastle disease virus against cervical cancer cells.

Despite recent medical progress, cervical cancer remains a major global health concern for women. Current standard treatments have limitations such as non-specific toxicity that necessitate development of safer and more effective therapeutic strategies. This research evaluated the combinatorial effects of olive leaf extract (OLE), rich in anti-cancer polyphenols, and the oncolytic Newcastle disease virus (NDV) against human cervical cancer cells. OLE was efficiently encapsulated (>94% loading) within MF59 lipid nanoparticles and nanostructured lipid carriers (NLCs; contains Precirol as NLC-P, contains Lecithin as NLC-L) to enhance stability, bioavailability, and targeted delivery. Physicochemical analysis confirmed successful encapsulation of OLE within nanoparticles smaller than 150 nm. In vitro cytotoxicity assays demonstrated significantly higher toxicity of the OLE-loaded nanoparticle formulations on HeLa cancer cells versus HDF normal cells (P<0.05). MF59 achieved the highest encapsulation efficiency, while NLC-P had the best drug release profile. NDV selectively infected and killed HeLa cells versus HDF cells. Notably, combining NDV with OLE-loaded nanoparticles led to significantly enhanced synergistic cytotoxicity against cancer cells (P<0.05), with NLC-P (OLE) and NDV producing the strongest effects. Apoptosis and cell cycle analyses confirmed the increased anti-cancer activity of the combinatorial treatment, which induced cell cycle arrest. This study provides evidence that co-delivery of OLE-loaded lipid nanoparticles and NDV potentiates anti-cancer activity against cervical cancer cells in vitro through a synergistic mechanism, warranting further development as a promising alternative cervical cancer therapy.

Delivery of 5-fluorouracil for cancer therapy using aptamer-based nonlinear hybridization chain reaction

5-Fluorouracil (5-FU) is a conventional nucleotide analogue used for cancer treatment. However, its clinical application faces challenges such as low stability and non-specific toxicity. With the remarkable advancements in DNA nanotechnology, DNA-based self-assembled nanocarriers have emerged as powerful tools for delivering nucleotide drugs. In this study, we have designed a non-linear hybrid chain reaction involving a fuel strand with AS1411 aptamer sequence to construct a dendritic structure capable of carrying 5-FU. This structure specifically targets cancer cells with overexpressed nucleolin on their surface, allowing the 5-FU to exert its anticancer effects and achieve therapeutic outcomes. Furthermore, we have also investigated the mechanistic action of this drug delivery system, aiming to establish a novel therapeutic platform for 5-FU treatment.

Recent Advances in Photodynamic Therapy: Metal-Based Nanoparticles as Tools to Improve Cancer Therapy.

Cancer remains a significant global health challenge, with traditional therapies like surgery, chemotherapy, and radiation often accompanied by systemic toxicity and damage to healthy tissues. Despite progress in treatment, these approaches have limitations such as non-specific targeting, systemic toxicity, and resistance development in cancer cells. In recent years, nanotechnology has emerged as a revolutionary frontier in cancer therapy, offering potential solutions to these challenges. Nanoparticles, due to their unique physical and chemical properties, can carry therapeutic payloads, navigate biological barriers, and selectively target cancer cells. Metal-based nanoparticles, in particular, offer unique properties suitable for various therapeutic applications. Recent advancements have focused on the integration of metal-based nanoparticles to enhance the efficacy and precision of photodynamic therapy. Integrating nanotechnology into cancer therapy represents a paradigm shift, enabling the development of strategies with enhanced specificity and reduced off-target effects. This review aims to provide a comprehensive understanding of the pivotal role of metal-based nanoparticles in photodynamic therapy. We explore the mechanisms, biocompatibility, and applications of metal-based nanoparticles in photodynamic therapy, highlighting the challenges and the limitations in their use, as well as the combining of metal-based nanoparticles/photodynamic therapy with other strategies as a synergistic therapeutic approach for cancer treatment.

Cucurbitacin: Unveiling its Role as Phytomolecule in Health Benefits

Abstract: In recent scientific studies, a variety of phytochemicals, including carotenoids, polyphenols, isoprenoids, phytosterols, saponins, and dietetic fibers, besides polysaccharides, have been linked to beneficial health effects, which include reducing the risk of diabetes, obesity, and cancer, cardiovascular diseases, and other conditions. Squash, pumpkin, cucumber, and melons are just a few examples of the Cucurbitaceae family plants that contain cucurbitacins, highly oxygenated tetracyclic triterpenes. Since ancient times, various traditional remedies have been made from plants that contain cucurbitacins. Several cucurbitacins (A, B, C, D, E, F, G, I, J, K, L, O, P, Q, R, S) have an extensive assortment of bioactivities, including hepatoprotective activity, liver protection, anticancer, anti-inflammatory, antiviral, and anti-diabetic properties. Cucurbitacins, for instance, have a well-known anticancer effect. Specific reports suggest that cucurbitacins stimulate apoptosis via the JAK/STAT3 pathway. Through cyclin inhibition, cucurbitacins may inhibit the cell cycle. Besides, they expedite autophagy while preventing cancer cells from migrating and infecting other tissues. Cucurbitacins have been categorized as signal transducers and activators of transcription. It is soundly acknowledged that the plant-based compound cucurbitacin B (CuB) has insecticidal and repellent properties. CuB has been shown to have non-specific toxicity and limited bioavailability in studies evaluating its toxicity and pharmacokinetic characteristics. Hence, we aimed to concentrate on the numerous properties of cucurbitacins in this article, including their chemistry, an analysis of biosynthesis, several types of bioactivities, and studies on their toxicity.

A small molecular “albumin hitchhiking” deferoxamine conjugate improved iron clearance efficacy

Deferoxamine (DFO), the first FDA-approved iron chelator, showed multifaceted potential in the treatment of iron accumulation-related diseases. However, the extremely short half-life of DFO leads to low patient compliance, and required high doses result in nonspecific toxicity. To overcome these obstacles, a new conjugate 2-sulfo-9-fluorenylmethoxycarbonyl-deferoxamine (FMS-DFO) was developed, which could be leveraged to hand-in-hand associate with the albumin in plasma to bypass the rapid elimination and reduce the related toxicities. FMS-DFO was observed in comparable albumin binding capacity as the amphiphilic modular “albumin hitchhiking” DSPE-PEG2000-DFO and maintained identical iron chelating potency of DFO. As compared with DSPE-PEG2000-DFO (t1/2–1.30 h), FMS-DFO (t1/2–4.49 h) remarkably more prolonged the exposure circulation of marketed DFO (t1/2–0.08 h) in mice. FMS-DFO could spare the dosing frequency from 5 times to 3 times weekly in iron overload therapy, which can improve patient compliance and reduce the difficulty of clinical usage. Additionally, the combined utilization of 5-ALA and FMS-DFO demonstrated excellent anti-cancer efficacy in synergistic photodynamic therapy model, broadening the clinical potential of the developed iron chelators. The strategy of “albumin hitchhiking” FMS-DFO is thus of great clinical interest and merits further exploration for treating iron accumulation-related diseases.

QbD Enabled Development and Evaluation of Pazopanib Loaded Nanoliposomes for PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7nm and 182.0nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.

Multifunctional nano-in-microparticles for targeted lung cancer cells: Synthesis, characterization and efficacy assessment

Non-small cell lung cancer is the leading cause of cancer-related deaths worldwide. Gemcitabine (GEM) is an effective chemotherapeutic agent for treating this and other cancers. However, the non-specific toxicity of GEM has prompted a search for novel chemotherapeutic strategies. The main objective of this work was to obtain microencapsulated systems loaded with GEM, nanomagnetite and microzeolite in chitosan matrix by spray drying in order to characterise them and test their activity on lung cancer cells. Capsule characterizations showed spherical nano-in-microparticles measuring 1.91 μm on average with a rough surface and characteristic signs of material interaction by TEM and FESEM-EDS. The interaction and loading of nano- and microparticles in the chitosan matrix was evidenced by FT-IR. % E.E. were obtained. greater than 99.00 % in all microencapsules and the release of the GEM was slow and controlled at pH 7.4 and 5.0 up to 24 h. Magnetic mobility was dependent on the concentration of nanomagnetite in the formulation and cell viability was lower than the pure GEM control (1 mg/mL) in both cell lines (A549 and H1299). Nano-in-microencapsulated systems show great potential for inhaled delivery of GEMs for the treatment of non-small cell lung cancer.

Multimodal Imaging-Guided Synergistic Photodynamic Therapy Using Carbonized Zn/Co Metal-Organic Framework Loaded with Cytotoxin Against Liver Cancer.

The study aimed to address the non-specific toxicity of cytotoxins (CTX) in liver cancer treatment and explore their combined application with the photosensitizer Ce6, co-loaded into carbonized Zn/Co bimetallic organic frameworks. The goal was to achieve controlled CTX release and synergistic photodynamic therapy, with a focus on evaluating anti-tumor activity against human liver cancer cell lines (Hep G2). Purified cobra cytotoxin (CTX) and photosensitizer Ce6 were co-loaded into carbonized Zn/Co bimetallic organic frameworks, resulting in RGD-PDA@C-ZIF@(CTX+Ce6). The formulation was designed with surface-functionalization using polydopamine and tumor-penetrating peptide RGD. This approach aimed to facilitate controlled CTX release and enhance the synergistic effect of photodynamic therapy. The accumulation of RGD-PDA@C-ZIF@(CTX+Ce6) at tumor sites was achieved through RGD's active targeting and the enhanced permeability and retention (EPR) effect. In the acidic tumor microenvironment, the porous structure of the metal-organic framework disintegrated, releasing CTX and Ce6 into tumor cells. Experiments demonstrated that RGD-PDA@C-ZIF@(CTX+Ce6) nanoparticles, combined with near-infrared laser irradiation, exhibited optimal anti-tumor effects against human liver cancer cells. The formulation showcased heightened anti-tumor activity without discernible systemic toxicity. The study underscores the potential of utilizing metal-organic frameworks as an efficient nanoplatform for co-loading cytotoxins and photodynamic therapy in liver cancer treatment. The developed formulation, RGD-PDA@C-ZIF@(CTX+Ce6), offers a promising avenue for advancing the clinical application of cytotoxins in oncology, providing a solid theoretical foundation for future research and development.

Micro-environment-triggered chemodynamic treatment for boosting bacteria elimination at low-temperature by synergistic effect of photothermal treatment and nanozyme catalysis

An injectable hydrogel dressing, Zr/Fc-MOF@CuO2@FH, was constructed by combing acid-triggered chemodynamic treatment (CDT) with low-temperature photothermal treatment (LT-PTT) to effectively eliminate bacteria without harming the surrounding normal tissues. The Zr/Fc-MOF acts as both photothermal reagent and nanozyme to generate reactive oxygen species (ROS). The CuO2 nanolayer can be decomposed by the acidic microenvironment of the bacterial infection to release Cu2+ and H2O2, which not only induces Fenton-like reaction but also enhances the catalytic capability of the Zr/Fc-MOF. The generated heat augments ROS production, resulting in highly efficient bacterial elimination at low temperature. Precisely, injectable hydrogel dressing can match irregular wound sites, which shortens the distance of heat dissipation and ROS diffusion to bacteria, thus improving sterilization efficacy and decreasing non-specific systemic toxicity. Both in vitro and in vivo experiments validated the predominant sterilization efficiency of drug-resistant methicillin-resistant Staphylococcus aureus (MRSA) and kanamycin-resistant Escherichia coli (KREC), presenting great potential for application in clinical therapy.

Regrettable substitution? Comparative study of the effect profile of bisphenol A and eleven analogues in an in vitro test battery

BackgroundBisphenol A (BPA) is currently one of the most widely used synthetic chemicals in the production of a wide range of plastics. Due to its diverse endocrine disrupting potential alternative bisphenols, also referred to as analogues, have been developed. Although the toxicity of BPA is well studied, the (eco)toxicological effects of the bisphenol analogues are largely unknown. The similar molecular structure of the analogues suggests comparable toxicological effects. This study aims to extend the (eco)toxicological knowledge on the bisphenol analogues by evaluating eleven bisphenol analogues compared to the reference substance BPA in in vitro bioassays. The examined endpoints are endocrine potential on three nuclear receptors in recombinant yeast cells of Saccharomyces cerevisiae, baseline toxicity (also referred to as non-specific toxicity, describing the minimal toxicity of a chemical) in the luminescent bacterium Aliivibrio fischeri, and mutagenicity in two strains of Salmonella typhimurium.ResultsBisphenol A showed estrogenic and anti-androgenic activity at EC50 concentrations of 0.516 mg/L (2.26 × 10–6 M) and 1.06 mg/L (4.63 × 10–6 M), respectively. The assays confirmed notable estrogenic and anti-androgenic activity for the vast majority of analogues in comparable, and often higher, efficacies to BPA. Some analogues showed anti-estrogenic instead of estrogenic activity in a range from 0.789 mg/L (1.45 × 10–6 M; TBBPA) to 2.69 mg/L (2.46 × 10–6 M; BADGE). The baseline toxicity of the analogues revealed a similar tendency of comparable to more prominent effects compared to BPA, ranging from 5.81 mg/L (1.73 × 10–5 M; BPAF) to 39.1 mg/L (1.56 × 10–4 M; BPS). There was no evidence of mutagenicity found.ConclusionThe examined bisphenol analogues prove to be equally, if not more, problematic in endocrine activities than the reference bisphenol A. Based on these results, the tested bisphenols cannot be regarded as safer alternatives and reinforce the notion of bisphenol analogues being considered as regrettable substitutions.

Recent Therapy to Treat Various Types of Cancer: An Overview

Cancer is a fatal condition brought on by unchecked cellular growth. One of the gravest dangers to people worldwide is this. Both the incidence and mortality of cancer are rising. With their great benefits, particularly in the treatment of cancer, nanoparticles have revolutionized the globe. Conventional chemotherapy used to be the main treatment option for patients. Chemotherapeutics, however, also have several pharmacological drawbacks, including drug resistance, drug-drug interactions, water solubility, and stability. Reciprocally, dose-limiting toxicity is important, with non-specific toxicity to healthy cells, appetite loss, hair loss, peripheral neuropathy, vomiting, fatigued muscles, and diarrheal being the usual side effects. Drug delivery systems employ nanocarriers such as gold nanoparticles, high-density lipoprotein nanostructures, polymer nanoparticles, dendrimers, quantum dots, and nanodiamonds.&#x0D; Keywords: Nanotechnology, Cancer, Drug delivery

Abstract 480: Nanotherapeutic strategies to improve targeted radionuclide therapy

Abstract Cancer is a leading cause of death worldwide. Several multidisciplinary approaches exist for cancer treatment, including radiotherapy and chemotherapy. Radiotherapy uses high-energy radiation to kill cancer cells; chemotherapy inhibits cancer cell proliferation and often kills cells by targeting the cell cycle. Resistance to radiotherapy and chemotherapy is a key determining factor in the outcome of therapeutic efficacy. Conventional nontargeted radiotherapy also affects distant nonirradiated cells, leading to DNA damage and changes in the cell cycle that are often linked to secondary carcinogenesis in patients. In recent years, targeted radionuclide therapy (TRT) has emerged as a promising personalized treatment strategy that delivers cytotoxic levels of radiation directly and specifically to cancer cells. Among radioisotopes,225Ac exhibits desirable properties for TRT: multiple α-particle emission and high cytotoxicity. One of the challenges with 225Ac is the nonspecific toxicity caused by the release and relocation of its decay daughters. Different approaches have been proposed to prevent the relocation of decay daughters, including nanoparticles. Nanoparticles have been pursued as a promising delivery vehicle of α-emitting radioisotopes to the tumor site. Here, we show specific targeting of Her2-positive breast cancer cells with 225Ac-radiolabeled lanthanum orthovanadate (LaVO4) nanoparticles. Nanoparticles’ surfaces were functionalized to improve biocompatibility and conjugated to target cancer cells, respectively. Cellular uptake and localization of these engineered nanoparticles were analyzed by a Confocal microscope and IncuCyte live cell analysis system. Results confirm its localization in the nucleus following the endolysosomal path, enhancing the nanoparticles’ effectiveness as a delivery vehicle for α-emitting radioisotopes with the potential of increased treatment efficacy. Upon addition of cancer-targeting ligands, these nanoparticles can achieve higher efficiency by delivering the radioisotope to the tumor cells with a potential of safe encapsulation of all α-emitters in the decay chain. The anticancer efficiency of 225Ac-radiolabeled nanoparticles was demonstrated by a dose-dependent effective killing of 3D breast cancer spheroids using both IncuCyte live imaging and the cell survival assays. Ultimately, the results of this study will be crucial in determining the future use of targeted radiolabeled nanoparticle-based delivery systems as an approach for more efficacious cancer treatment. Citation Format: Debjani Pal, Miguel Toro Gonzáleza, Amber N. Bibleb, Brian Sanders, Anna Plechaty, Owee Kirpekar, Mircea Podar, Sandra M. Davern. Nanotherapeutic strategies to improve targeted radionuclide therapy [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 480.

Abstract 1913: KD5005: HER-2 dependent strong potent anti-tumor activity of an anti-HER-2 mAb-TNFaimmunocytokine

Abstract Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with diverse biological functions, including apoptosis, cell survival, inflammation, and immunity. While recombinant human TNFα has demonstrated therapeutic efficacy in isolated limb perfusion for soft tissue sarcoma and melanoma, its systemic administration is limited by severe toxicities, including hypotension. Tumor-specific targeting and enhancement of TNFα's tumor cell killing activity hold promise for improving its therapeutic index. To address these challenges, we developed KD5005, a novel HER-2-targeted immunocytokine fusion protein comprising an anti-HER-2 IgG1 monoclonal antibody (trastuzumab) and human TNFα. Tissue distribution studies revealed that KD5005 specifically accumulated in HER-2-expressing tumors, demonstrating its tumor-targeting capability. In vitro, KD5005 exhibited reduced TNFα-mediated apoptosis in L929 cells compared to recombinant TNFα, indicating its lower non-specific toxicity. Notably, KD5005 induced apoptosis of HER-2-positive human gastric cancer NCI-N87 cells at significantly lower concentrations than trastuzumab, TNFα, or their combination, demonstrating its enhanced tumor cell killing activity. The potent apoptotic activity of KD5005 was HER-2-dependent, as it did not show increased apoptotic activity in WT mouse forestomach carcinoma (MFC) cells and had similar apoptotic activity compared to the combination of trastuzumab and TNFα. This HER-2 dependency further supports the tumor-specific targeting of KD5005.In vivo, KD5005 demonstrated superior anti-tumor efficacy compared to the combination of trastuzumab and TNFα in syngeneic tumor models using CT26 tumor cells transfected with the human HER-2 gene. KD5005 induced robust tumor regression and durable cure in 7 of 8 mice, while the combination of trastuzumab and TNFα elicited weaker therapeutic responses, resulting in tumor rejection in only 3 of 8 mice. Pharmacokinetic and toxicity studies of KD5005 were conducted in cynomolgus monkeys. KD5005 exhibited a significantly prolonged in vivo half-life compared to TNFα, indicating its improved pharmacokinetic profile. KD5005 was administered intravenously every two weeks to the same animal in a dose-escalation study at 0.3 mg/kg, 1.0 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg. The toxicity study results showed that the maximum tolerated dose for KD5005 in cynomolgus monkeys is 10 mg/kg, indicating its favorable toxicity profile. In summary, we have developed KD5005, a HER-2-targeted immunocytokine fusion protein with enhanced tumor-killing activity, improved pharmacokinetic properties, and a favorable toxicity profile. These preclinical findings support the further clinical development of KD5005 as a promising therapeutic agent for HER-2-positive cancers. Citation Format: YI CHEN, PENG LI, GUOBO FANG, HENG WU, CHI ZHANG, ZELING CAI. KD5005: HER-2 dependent strong potent anti-tumor activity of an anti-HER-2 mAb-TNFaimmunocytokine [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 1913.