Systemic Toxicity Research Articles

MicroRNA‐Triggered Programmable DNA‐Encoded Pre‐PROTACs for Cell‐Selective and Controlled Protein Degradation

Proteolysis‐targeting chimeras (PROTACs) have accelerated drug development; however, some challenges still exist owing to their lack of tumor selectivity and on‐demand protein degradation. Here, we developed a miRNA‐initiated assembled pre‐PROTAC (miRiaTAC) platform that enables the on‐demand activation and termination of target degradation in a cell type‐specific manner. Using miRNA‐21 as a model, we engineered DNA hairpins labeled with JQ‐1 and pomalidomide and facilitated the modular assembly of DNA‐encoded pre‐PROTACs through a hybridization chain reaction. This configuration promoted the selective polyubiquitination and degradation of BRD4 upon miR‐21 initiation, highlighting significant tumor selectivity and minimal systemic toxicity. Furthermore, the platform incorporates photolabile groups, enabling the precise optical control of pre‐PROTACs during DNA assembly/disassembly, mitigating the risk of excessive protein degradation. Additionally, by introducing a secondary ligand targeting CDK6, these pre‐PROTACs were used as a modular scaffold for the programmable assembly of active miRiaTACs containing two different warheads in exact stoichiometry, enabling orthogonal multitarget degradation. The integration of near‐infrared light‐mediated photodynamic therapy through an upconversion nanosystem further enhanced the efficacy of the platform with potent in vivo anticancer activity. We anticipate that miRiaTAC represents a significant intersection between dynamic DNA nanotechnology and PROTAC, potentially expanding the versatility of PROTAC toolkit for cancer therapy.

Combinational delivery of berbamine and 5-fluorouracil in cerium oxide nanoparticles for colon cancer therapy: Insights from in vitro and in silico studies

Colon cancer is traditionally treated by an antimetabolite drug 5-fluorouracil (5FU) but has been linked to several drawbacks and systemic toxicity. To overcome drug associated toxicity, combination therapy is a promising strategy that synergistically enhances the therapeutic effects of co-delivered drugs while minimizing administration doses. Therefore, the current study aims to investigate the anti-colon cancer potency of 5FU co-delivered with a phytochemical i.e., berbamine (BERB) in a Cerium oxide nanoparticles (CONPs) delivery system. CONPs loaded 5FU (5FU-CONPs) and BERB (BERB-CONPs) were prepared and characterized using different analytical techniques. Successful entrapment of both drugs into CONPs formulations was detected under X-ray diffraction (XRD) observations. Drug-loaded CONPs in combination showed effective anti-oxidant activity by preventing reactive oxygen species (ROS) generations and had superior cytotoxic effects on HT-29 cell lines compared to treatment with native drugs singly or in combination. They also triggered apoptosis through p21, p53, Bax upregulation, and Bcl-2 downregulation, as confirmed by Western blot studies. Additionally, in silico analysis was performed using molecular docking and molecular dynamics simulation (MDS) to validate the in vitro results. Results of the study suggest that 5FU and BERB CONPs in combination could be taken as a possible therapeutic approach for colon cancer treatment.

Two-Dimensional Biodegradable l-Cysteine-Iodine Nanosheets for Computed Tomography-Guided Cancer Synergistic Sonodynamic Therapy and Chemotherapy.

Biodegradable versatile inorganic nanomaterials are highly desirable in the field of nanomedicine. Here, for the first time, we report a kind of novel two-dimensional biodegradable l-cysteine-iodine (l-Cys-I) nanosheet with high computed tomography (CT) imaging ability and sonosensitization efficacy. Such l-Cys-I nanosheets consist of iodine molecules and l-Cys, where the iodine molecules are coordinated and stabilized by l-Cys and cross-linked to form nanosheets through disulfide bonds. The large and convenient functional surface is further modified with targeting moieties DSPE-PEG-RGD and cancer drug doxorubicin (DOX) to construct a nanotheranostic nanoplatform (CIRD). Under ultrasound irradiation, the CIRD nanosheets assist in tremendous reactive oxygen species generation and controllable DOX release, leading to remarkable anticancer performance both in vitro and in vivo due to the synergistic sonodynamic therapy (SDT) and chemotherapy. Our results validate that the CIRD nanosheets enable effective body excretion and negligible systemic toxicity owing to the biodegradation properties. The CIRD nanosheets, with biodegradability, biocompatibility, and versatility, hold great promise in nanotheranostics.

Advancing Proteolysis Targeting Chimera (PROTAC) Nanotechnology in Protein Homeostasis Reprograming for Disease Treatment.

Proteolysis targeting chimeras (PROTACs) represent a transformative class of therapeutic agents that leverage the intrinsic protein degradation machinery to modulate the hemostasis of key disease-associated proteins selectively. Although several PROTACs have been approved for clinical application, suboptimal therapeutic efficacy and potential adverse side effects remain challenging. Benefiting from the enhanced targeted delivery, reduced systemic toxicity, and improved bioavailability, nanomedicines can be tailored with precision to integrate with PROTACs which hold significant potential to facilitate PROTAC nanomedicines (nano-PROTACs) for clinical translation with enhanced efficacy and reduced side effects. In this review, we provide an overview of the recent progress in the convergence of nanotechnology with PROTAC design, leveraging the inherent properties of nanomaterials, such as lipids, polymers, inorganic nanoparticles, nanohydrogels, proteins, and nucleic acids, for precise PROTAC delivery. Additionally, we discuss the various categories of PROTAC targets and provide insights into their clinical translational potential, alongside the challenges that need to be addressed.

Phthalocyanine derivative attenuates TNF-α production in macrophage culture and prevents alveolar bone loss in experimental periodontitis.

This study investigated the activity and mechanism of action of the iron tetracarboxyphthalocyanine (FeTcPc) on tumor necrosis factor alpha (TNF-α) production and its impact on experimental periodontitis. RAW 264.7 macrophages were treated with FeTcPc, activated with lipopolysaccharide (LPS) at 10 ng/mL, and the TNF-α levels were measured, as well as the nuclear factor kappa B (NF-κB) activation. Subsequently, a mouth gel containing 1% FeTcPc was topically administered to the gingival tissue of mice with periodontitis-induced ligatures. Bone loss and the gene expression of Tnfα, p65 (NF-κB), and receptor-activating nuclear factor kappa B ligand (Rankl) were quantified in gingival tissue. Finally, the systemic toxicity of FeTcPc was estimated in Galleria mellonella larvae. In an activated RAW 264.7 macrophage culture, 100 μM FeTcPc reduced TNF-α release and NF-κB activation. Regarding experimental periodontitis, topical application of mouth gel containing 1% FeTcPc blocked alveolar bone loss. Additionally, 1% FeTcPc reduced the expression of Tnfα, p65 (NF-κB), and Rankl in gingival tissue. Finally, administration FeTcPc at doses ranging from 1 to 1000 mg/kg did not cause acute systemic toxicity in G. mellonella. Overall, we demonstrated the potential of mouth gel containing FeTcPc as a therapeutic strategy for managing osteolytic inflammatory disorders, such as periodontitis.

Preclinical immunogenicity and safety of hemagglutinin-encoding modRNA influenza vaccines

Seasonal epidemics of influenza viruses are responsible for a significant global public health burden. Vaccination remains the most effective way to prevent infection; however, due to the persistence of antigenic drift, vaccines must be updated annually. The selection of vaccine strains occurs months in advance of the influenza season to allow adequate time for production in eggs. RNA vaccines offer the potential to accelerate production and improve efficacy of influenza vaccines. We leveraged the nucleoside-modified RNA (modRNA) platform technology and lipid nanoparticle formulation process of the COVID-19 mRNA vaccine (BNT162b2; Comirnaty®) to create modRNA vaccines encoding hemagglutinin (HA) (modRNA-HA) for seasonal human influenza strains and evaluated their preclinical immunogenicity and toxicity. In mice, a monovalent modRNA vaccine encoding an H1 HA demonstrated robust antibody responses, HA-specific Th1-type CD4+ T cell responses, and HA-specific CD8+ T cell responses. In rhesus and cynomolgus macaques, the vaccine exhibited durable functional antibody responses and HA-specific IFN-γ+ CD4+ T cell responses. Immunization of mice with monovalent, trivalent, and quadrivalent modRNA-HA vaccines generated functional antibody responses targeting the seasonal influenza virus(es) encoded in the vaccines that were greater than, or similar to, those of a licensed quadrivalent influenza vaccine. Monovalent and quadrivalent modRNA-HA vaccines were well-tolerated by Wistar Han rats, with no evidence of systemic toxicity. These nonclinical immunogenicity and safety data support further evaluation of the modRNA-HA vaccines in clinical studies.

Hematological and Systemic Toxicity of in ovo Flubendiamide Exposure in Newly Hatched Domestic Chicks

Hematological and Systemic Toxicity of in ovo Flubendiamide Exposure in Newly Hatched Domestic Chicks

Microbial Therapeutics in Oncology: A Comprehensive Review of Bacterial Role in Cancer Treatment.

Conventional cancer therapies, including chemotherapy, radiotherapy, and immunotherapy, have significantly advanced cancer treatment. However, these modalities often face limitations such as systemic toxicity, lack of specificity, and the emergence of resistance. Recent advancements in genetic engineering and synthetic biology have rekindled interest in using bacteria as a novel therapeutic approach in oncology. This comprehensive review explores the potential of microbial therapeutics, particularly bacterial therapies, in the treatment of cancer. Bacterial therapies offer several unique advantages, such as the ability to selectively target and colonize hypoxic and necrotic regions of tumors, areas typically resistant to conventional treatments. The review delves into the mechanisms through which bacteria exert antitumor effects, including direct tumor cell lysis, modulation of the immune response, and delivery of therapeutic agents like cytotoxins and enzymes. Various bacterial species, such as Salmonella, Clostridium, Lactobacillus, and Listeria, have shown promise in preclinical and clinical studies, demonstrating diverse mechanisms of action and therapeutic potential. Moreover, the review discusses the challenges associated with bacterial therapies, such as safety concerns, immune evasion, and the need for precise targeting, and how recent advances in genetic engineering are being used to overcome these hurdles. Current clinical trials and combination strategies with conventional therapies are also highlighted to provide a comprehensive overview of the ongoing developments in this field. In conclusion, while bacterial therapeutics present a novel and promising avenue in cancer treatment, further research and clinical validation is required to fully realize their potential. This review aims to inspire further exploration into microbial oncology, paving the way for innovative and more effective cancer therapies.

Tumoricidal Activity and Side Effects of Radiolabeled Anti-NCAM [131I]-Iodine-ERIC1 in Neuroblastoma-Bearing Mice.

Preliminary studies on a radioactive antibody against the neural cell adhesion molecule (NCAM) demonstrated a significant accumulation of [131I]I-ERIC1 in neuroblastoma tumor cells in mice. This study aims to validate the therapeutic efficacy and potential adverse effects of these radioactive immunoconjugates (RICs) in neuroblastoma-bearing mice. To determine the highest tolerated dose, healthy SCID mice received 1 to 22 MBq of [131I]I-ERIC1, with the survival time measured. Tumor response was evaluated by administering 0.8 to 22 MBq of [131I]I-ERIC1 to neuroblastoma-bearing mice and assessing tumor size and systemic toxicity through body weight, blood counts, and survival. It was observed that doses up to approximately 3 MBq per animal (150 MBq/kg) were well tolerated, whereas higher doses resulted in systemic toxicity and death. The neuroblastomas exhibited a dose-dependent response, with optimal therapeutic efficacy achieved at 1.8-2.5 MBq per animal (90-125 MBq/kg), significantly extending survival by a factor of five. The antibody ERIC1 is a promising vehicle for the transport of beta emitters into NCAM-positive tumor tissue. An optimal dosage of the [131I]I-ERIC1 antibody can be established with a balance of tumor-static effects and adverse effects, resulting in a marked extension of survival time.

Evaluation of the functional activity and specificity of the <i>hSLPI</i> gene promoter

BACKGROUND: One of the main problems of modern oncotherapy is the lack of selectivity of the antitumor drugs, leading to their systemic toxicity on the body. Targeted expression of therapeutic genes represents a new approach in cancer gene therapy. One of the ways to achieve the selectivity of action of the therapeutic genes towards tumor cells is the use of promoters that are active only in tumor cells, but not in normal cells. AIM: To evaluate the functional activity and specificity of the promoter of the human secretory leukocyte protease inhibitor hSLPI. MATERIALS AND METHODS: The promoter of the hSLPI gene was cloned into the promotorless vector pTurboGFP-PRL. The functional activity and specificity of the promoter were assessed by the expression of the mRNA of the TurboGFP reporter gene and the intensity of its luminescence in A549, MCF-7, HeLa tumor cells and WI-38 normal cells using real-time polymerase chain reaction with reverse transcription and fluorescence analysis, respectively. RESULTS: Despite the literature data, the promoter of the hSLPIa gene demonstrated high transcriptional activity only against HeLa cervical cancer tumor cells. At the same time, in the cells of lung adenocarcinoma A549 and breast cancer MCF-7, as in normal WI-38 cells, a reduced level of promoter activity was observed. CONCLUSION: The data obtained confirm the need for a preliminary assessment of the functional activity of tumor-specific promoters in relation to tumor and normal cells.

Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.79 vs. 64.41). Further investigation indicated that 7i dose-dependently inhibited P-gp function, without affecting its expression. CETSA results illustrated that 7i could obviously improve P-gp stability, suggesting its high affinity with P-gp. Molecular docking analysis revealed that 7i fit well into P-gp's binding pocket, thus displaying potent reversal effect on P-gp-mediated tumor MDR Optical properties evaluation confirmed that azo-containing 7i can undergo reversible changes in the cis and trans configurations under the irradiation of 365 nm and 520 nm wavelength of light. Notably, the configuration change of azo might affect the MDR-reversal potency, and cis-7i has a lower RF value than trans-7i (122.70 vs. 142.79), suggesting that development of photoswitchable P-gp inhibitors might be a novel strategy to reduce the systemic toxicity caused by indiscriminate inhibition of P-gp by traditional inhibitors. Collectively, 7i, as a novel P-gp inhibitor, warranted further investigation.

Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA

PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a–14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.

Liposomal Nanoformulation-encapsulated Paclitaxel for Reducing Chemotherapy Side Effects in Lung Cancer Treatments: Recent Advances and Future Outlooks.

Paclitaxel is one notable chemotherapy drug that is used to treat a number of cancers, including lung cancer. Nevertheless, it has drawbacks such as toxicity, low solubility in water, and the emergence of multidrug resistance (MDR). This article reviews the use of liposomal formulations to improve paclitaxel administration and efficacy for lung cancer therapy. Paclitaxel's pharmacological characteristics can be improved by liposomes through increased solubility, extended circulation, passive tumor targeting through leaky vasculature, and decreased side effects. Recent developments in paclitaxel liposomal formulations, including as cationic liposomes, conventional liposomes, targeted liposomes with particular ligands, and liposome-loaded microorganisms, are outlined in this article. In comparison to free paclitaxel, these nanoformulations exhibit enhanced cytotoxicity, cellular uptake, apoptosis, tumor growth suppression, and anticancer effects in lung cancer cell lines and animal models. One efficient way to get around the drawbacks of paclitaxel is to alter its size, makeup, and surface characteristics. This will let the medication accumulate and penetrate tumors more easily, avoid multidrug resistance, and cause less systemic toxicity. The article explores clinical studies showcasing the safety and therapeutic efficacy of liposomal paclitaxel for individuals afflicted with lung cancer. In its entirety, the document provides an in-depth examination of the potential enhancement in paclitaxel's dispersion and anti-tumor impacts through the utilization of liposomal technology when addressing diverse manifestations of lung cancer.

Biocompatibility analysis of titanium bone wedges coated by antibacterial ceramic-polymer layer

This paper presents the surface treatment results of titanium, veterinary bone wedges. The functional coating is composed of a porous oxide layer (formed by a plasma electrolytic oxidation process) and a polymer poly(sebacic anhydride) (PSBA) layer loaded with amoxicillin (formed by dip coatings). The coatings were porous and composed of Ca (4.16%-6.54%) and P (7.64%-9.89% determined by scanning electron microscopy with EDX) in the upper part of the implant. The titanium bone wedges were hydrophilic (54° water contact angle) and rough (surface area (Sa):1.16 μm) The surface tension determined using diiodomethane was 68.6 ± 2.0° for the anodized implant and was similar for hybrid coatings: 60.7 ± 2.2°. 12.87 ± 0.91 µg/mL of amoxicillin was released from the implants during the first 30 min after immersion in the phosphate-buffered saline (PBS) solution. This concentration was enough to inhibit the Staphylococcus aureus ATCC 25923, and Staphylococcus epidermidis ATCC12228 growth. The obtained inhibition zones were between 27.3 ± 2.1 mm–30.7 ± 0.6 mm when implant extract after 1 h or 4 h immersion in PBS was collected. Various implant biocompatibility analyses were performed under in vivo conditions, including pyrogen test (3 rabbits), intracutaneous reactivity (3 rabbits, 5 places by side), acute systemic toxicity (20 house mice), and local lymph node assay (LLNA) (20 house mice). The extracts from implants were collected in polar and non-polar solutions, and the tests were conducted according to ISO 10993 standards. The results from the in vivo tests showed, that the implant’s extracts are not toxic (mass body change below 5%), not sensitizing (SI < 1.6), and do not show the pyrogen effect (changes in the temperature 0.15ºC). The biocompatibility tests were performed in a certificated laboratory with a good laboratory practice certificate after all the necessary permissions.

Cetuximab functionalized chitosan/hyaluronic acid-based nanoparticles loaded with cabazitaxel enhances anti-tumor efficacy in DMBA-induced breast cancer model in rats through spatial targeting

The article discusses the ionic gelation of cationic chitosan (CS) with anionic hyaluronic acid (HA) sodium salt to form nanoparticles in the range of 125 nm. The particles were further functionalized with cetuximab to endow it with the ability to spatially target the tumor over-expressing EGFR. Solid-state characterization of the particles using XRD, FTIR, and DSC revealed the formation of stable nanoparticles with Cabazitaxel loaded in the amorphous nanostructure. XPS study used to assess the surface characteristics indicated that the cetuximab was successfully anchored on the surface of the particle. The prepared CS-HA-Cmab-NP elicited a pH-responsive drug release behavior due to the presence of CS in the matrix. In vitro performance of the nanoparticles was evaluated on MDA-MB-231 breast cancer cell lines showed overall increase in efficacy. In vivo pharmacokinetic and anti-tumor effect evaluated in female Sprague Dawley rats indicated that the Cmab-conjugated nanoparticles improved half-life of cabazitaxel and tumor reduction capability with higher survival rate and lower reduction in body weight. The results indicate that CS/HA nanoparticles anchored with cetuximab show enhanced efficacy in reducing the breast cancer tumor in DMBA-induced breast tumor model through spatial targeting, consequently reducing the systemic toxicity.

In Vivo Biocompatibility of Synechococcus sp. PCC 7002-Integrated Scaffolds for Skin Regeneration.

Cyanobacteria, commonly known as blue-green algae, are prevalent in freshwater systems and have gained interest for their potential in medical applications, particularly in skin regeneration. Among these, Synechococcus sp. strain PCC 7002 stands out because of its rapid proliferation and capacity to be genetically modified to produce growth factors. This study investigates the safety of Synechococcus sp. PCC 7002 when used in scaffolds for skin regeneration, focusing on systemic inflammatory responses in a murine model. We evaluated the following three groups: scaffolds colonized with genetically engineered bacteria producing hyaluronic acid, scaffolds with wild-type bacteria, and control scaffolds without bacteria. After seven days, we assessed systemic inflammation by measuring changes in cytokine profiles and lymphatic organ sizes. The results showed no significant differences in spleen, thymus, and lymph node weights, indicating a lack of overt systemic toxicity. Blood cytokine analysis revealed elevated levels of IL-6 and IL-1β in scaffolds with bacteria, suggesting a systemic inflammatory response, while TNF-α levels remained unaffected. Proteome profiling identified distinct cytokine patterns associated with bacterial colonization, including elevated inflammatory proteins and products, indicative of acute inflammation. Conversely, control scaffolds exhibited protein profiles suggestive of a rejection response, characterized by increased levels of cytokines involved in T and B cell activation. Our findings suggest that Synechococcus sp. PCC 7002 does not appear to cause significant systemic toxicity, supporting its potential use in biomedical applications. Further research is necessary to explore the long-term effects and clinical implications of these responses.

An updated landscape on nanopharmaceutical delivery for mitigation of colon cancer.

Globally, colorectal cancer (CRC) continues to rank among the leading causes of cancer-related death. Systemic toxicity, multidrug resistance, and nonspecific targeting often pose challenges to conventional therapy for CRC. Because it is a complex disease with a complex genetic and environmental pathophysiology, advanced therapeutic strategies are needed. Nanotechnology presents a potential solution that may maximize therapeutic efficacy while minimizing negative effects by enabling personalized delivery of anticancer drugs. This review focuses on recent developments in colorectal drug delivery systems based on nanotechnology. Numerous nanomaterials, including liposomes, dendrimers, micelles, exosomes, and gold nanoparticles, are developed and used. Distinctive characteristics of mentioned nanocarriers are discussed along with strategies that can be employed for enhancing the delivery of drugs to colorectal cancer cells. The review also quotes the most relevant preclinical and clinical studies that show how these nanomaterials improve drug solubility, stability, and targeted delivery while overcoming the shortcomings of conventional therapies. Nanotechnology has made CRC treatment very efficient and advanced, which has opened up new possibilities for targeted drug delivery. Preclinical and clinical studies have also proved that the use of nano-formulations in colon-specific delivery systems have significant results, indicating potential for better patient outcomes. Future research can be done in order to overcome the hurdles regarding biocompatibility, expansion, and regulatory challenges. Large-scale clinical trials and nanomaterial formulation optimization should be the main goals of future research to confirm the efficacy and safety of these novel treatments.

Long in vivo circulating nanomicelles formed by sharp-contrast Janus star polymers derived from β-cyclodextrin grafted with lipids and polyzwitterions

Amphiphilic block polymers have the ability to self-assemble and form nanomicelles, which have been extensively studied as nanocarriers for improving the bioavailability and biodistribution of chemotherapeutic drugs while reducing systemic toxicity. However, polymer micelles often face issues with poor stability in the bloodstream, leading to a short circulation time and leakage of the payload. Here, this work reports a rational design of a sharp-contrast Janus star polymer (SJSP) consisting of multiple arms of superhydrophobic lipid moieties and superhydrophilic polyzwitterion chains attached to a β-cyclodextrin core. The SJSP polymer forms nanomicelles possessing a stable core and a controllable and dense stealth shell that effectively protects them in the bloodstream, preventing payload leakage and blood protein adsorption. It is demonstrated that the hydrophobic/hydrophilic balance can be optimized to achieve strong micellar assembly by adjusting the number of lipid and polyzwitterion arms. The SJSP micelle system shows significantly longer blood circulation time in vivo compared to linear counterparts and other available amphiphilic block copolymer micelle systems. Therefore, the SJSP micelle design offers a promising strategy for developing nanocarriers with potential for translational applications in vivo.

Local Sustained Dinutuximab Delivery and Release From Methacrylated Chondroitin Sulfate.

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. High-risk NB is a subset of the disease that has poor prognosis and requires multimodal treatment regimens, with a 50% rate of recurrence despite intervention. There is a need for improved treatment strategies to reduce high-risk patient mortality. Dinutuximab is an anti-GD2 antibody ideal for targeting GD2 expressing NB cells, but binding of the antibody to peripheral nerve fibers leads to severe pain during systemic administration. Intratumoral delivery of the anti-GD2 antibody would allow for increased local antibody concentration, without increasing systemic toxicity. Chondroitin Sulfate (CS) is a biocompatible glycosaminoglycan that can be methacrylated to form CSMA, a photocrosslinkable hydrogel that can be loaded with therapeutic agents. The methacrylation reaction time can be varied to achieve different degrees of substitution, resulting in different release and degradation profiles. In this work, 4 and 24 h reacted CSMA was used to create hydrogels at 10% and 20% CSMA. Sustained in vitro release of dinutuximab from these formulations was observed over a 24-day period, and 4 h reacted 10% CSMA hydrogels had the highest overall dinutuximab release over time. An orthotropic mouse model was used to evaluate in vivo response to dinutuximab loaded 4 h methacrylated 10% CSMA hydrogels as compared to bolus tail vein injections. Tumor growth was monitored, and there was a statistically significant increase in the days to reach specific tumor size for tumors treated with intratumoral dinutuximab-loaded hydrogel compared to those treated with dinutuximab solution through tail vein injection. This supports the concept that locally delivering dinutuximab within the hydrogel formulation slowed tumor growth. The CSMA hydrogel-only treatment slowed tumor growth as well, an interesting effect that may indicate interactions between the CSMA and cell adhesion molecules in the tumor microenvironment. These findings demonstrate a potential avenue for local sustained delivery of dinutuximab for improved anti-tumoral response in high-risk NB.

Design, Synthesis, and Characterization of HBP-Vectorized Methotrexate Prodrug Molecule 1102-39: Evaluation of In Vitro Cytotoxicity Activity in Cell Culture Models, Preliminary In Vivo Safety and Efficacy Results in Rodents.

A novel bone-targeted prodrug, 1102-39, is discussed with the aim of enhancing the therapeutic effects of methotrexate (MTX) within bone tissues while minimizing systemic toxicity. Within the 1102-39 molecule, the central linker part forms a cleavable ester group, with MTX being also linked by a stable imine bond to the specially designed hydroxybisphosphonic (HBP) vector. Synthesized through a convergent approach starting from MTX, this prodrug advantageously modulates MTX's activity by selective esterification of its α-carboxyl group. In vitro tests revealed a 10-fold reduction in cytotoxicity compared to standard MTX, in alignment with prodrug behavior and correlated with gradual MTX release. In vivo in rodents, 1102-39 displayed preliminary encouraging antitumor effects on orthotopic osteosarcoma. Furthermore, various aspects of designing molecules for selective therapy in bone tissue based on bisphosphonate molecules as vectors for delivering active compounds to the bone are discussed. The 1102-39 molecule exhibits strong affinity for hydroxyapatite and a progressive release of MTX in aqueous environments, enhancing the safety and efficacy of bone-specific treatments and enabling sustained activity within bone and bone joints in the therapy of tumor and inflammation.