Design, synthesis, and biological evaluation of novel bifunctional thyrointegrin antagonists for neuroblastoma.

Receptor-mediated cancer therapy has received much attention in the last few decades. Neuroblastoma and other cancers of the sympathetic nervous system highly express norepinephrine transporter (NET) and cell plasma membrane integrin αvß3. Dual targeting of the NET and integrin αvß3 receptors using a Drug-Drug Conjugate (DDC) might provide effective treatment strategy in the fight against neuroblastoma and other neuroendocrine tumors. In this work, we synthesized three dual-targeting BG-P400-TAT derivatives, dI-BG-P400-TAT, dM-BG-P400-TAT, and BG-P400-PAT containing di-iodobenzene, di-methoxybenzene, and piperazine groups, respectively. These derivatives utilize to norepinephrine transporter (NET) and the integrin αvß3 receptor to simultaneously modulate both targets based on evaluation in a neuroblastoma animal model using the neuroblastoma SK-N-F1 cell line. Among the three synthesized agents, the piperazine substituted BG-P400-PAT exhibited potent integrin αvß3 antagonism and reduced neuroblastoma tumor growth and cancer cell viability by >90%. In conclusion, BG-P400-PAT and derivatives represent a potential therapeutic approach in the management of neuroblastoma.

Correction: Karakus et al. Development of Triiodothyronine Polymeric Nanoparticles for Targeted Delivery in the Cardioprotection against Ischemic Insult. Biomedicines 2021, 9, 1713.

In the published manuscript [...].

Norepinephrine transporter analog benzylguanidine-conjugated nanoparticles for the delivery of paclitaxel in neuroblastoma.

Aim: We previously synthesized a polyethylene glycol-based norepinephrine transporter-targeted agent, BG-P-TAT, which has a benzylguanidine and a triazolyl-tetrac group. This targeted conjugate showed suppression of neuroblastoma tumor progression. In this study we aimed to synthesize nanoparticles to encapsulate the chemotherapeutic agent paclitaxel for targeting neuroblastoma tumors by using benzylguanidine so that it can compete with norepinephrine for uptake by neuroendocrine cells. Methods: Biocompatible poly(lactide-co-glycolic acid)-polyethylene glycol was chosen to prepare targeted nanoparticles for safe delivery of the chemotherapy agent paclitaxel. Result: Paclitaxel concentration was 60% higher in neuroblastoma tumors of mice treated with paclitaxel encapsulated in targeted nanoparticles than with non-targeted nanoparticles. Conclusion: These findings support the targeted delivery of paclitaxel as a chemotherapeutic agent for neuroblastoma.

New Thyrointegrin αvß3 Antagonist with a Scalable Synthesis, Brain Penetration, and Potent Activity against Glioblastoma Multiforme.

We have previously reported that the αvß3 inhibitor P-bi-TAT, a bifunctional version of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) conjugated to polyethylene glycol (PEG) MW 4000, has excellent efficacy in a glioblastoma multiforme (GBM) mouse model. However, bioanalysis problems due to PEG polydispersity and large-scale synthesis issues led to a search for new molecules, culminating in the discovery of fb-PMT, a conjugate of tetrac and monodisperse PEG36, with a lipophilic 4-fluorobenzyl group at the opposite end of the PEG chain. fb-PMT reduces GBM tumor growth and viability by up to 98%, is suitable for large-scale synthesis, and is amenable to bioanalysis using mass spectrometry-based detection. We also showed that changes in lipophilicity at the opposite end of the PEG chain from the active tetrac component affected the proton NMR chemical shift of the tetrac moiety in D20 and brain levels of the compound after subcutaneous dosing.

Development of Triiodothyronine Polymeric Nanoparticles for Targeted Delivery in the Cardioprotection against Ischemic Insult.

Ischemic heart disease is the main cause of death globally. Cardioprotection is the process whereby mechanisms that reduce myocardial damage, and activate protective factors, contribute to the preservation of the heart. Targeting these processes could be a new strategy in the treatment of post-ischemic heart failure (HF). Triiodothyronine (T3) and thyroxine (T4), which have multiple effects on the heart, prevent myocardial damage. This study describes the formulation, and characterization, of chemically modified polymeric nanoparticles incorporating T3, to target the thyroid hormone receptors. Modified T3 was conjugated to polylactide-co-glycolide (PLGA) to facilitate T3 delivery and restrict its nuclear translocation. Modified T3 and PLGA-T3 was characterized with 1H-NMR. The protective role of synthesized phosphocreatine (PCr) encapsulated PLGA-T3 nanoparticles (PLGA-T3/PCr NPs) and PLGA-T3 nanoparticles (PLGA-T3 NPs) in hypoxia-mediated cardiac cell insults was investigated. The results showed that PLGA-T3/PCr NPs represent a potentially new therapeutic agent for the control of tissue damage in cardiac ischemia and resuscitation.

Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvß3 Receptors in the Treatment of Neuroblastoma.

Therapeutic targeting of the norepinephrine transporter (NET) function with benzylguanidine (BG), conjugated with the high-affinity thyrointegrin αvß3 antagonist triazole tetraiodothyroacetic acid, TAT, via noncleavable bonding to poly(ethylene glycol) (PEG400) (P) might allow for effective treatment options in neuroblastoma. BG-P-TAT is a dual-targeting agent, targeting the NET function and the thyrointegrin αvß3 receptors that are overexpressed in neuroblastoma and other neuroendocrine tumors. Various cancer cells and actively dividing tumor-endothelial cells express the thyrointegrin αvß3 receptors. In this work, the novel compound BG-P-TAT was synthesized and evaluated in the neuroblastoma SK-N-FI cell line for improved targeting and to offer a new strategy for patients with neuroblastoma. BG-P-TAT demonstrated significant suppression of neuroblastoma tumor progression, growth, and viability in a dose-dependent manner. In conclusion, BG-P-TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.

Synthesis and structure elucidation of 25,26,27,28-tetramethylcalix[4]arene tetraketone using 1D and 2D NMR spectroscopies.

The (1)H and (13)C NMR spectra of the new calix[4]arene-based tetraketone were completely assigned by one- and two-dimensional homo- and heteronuclear experiments ((1)H-(1)H COSY, (1)H-(13)C HMQC, and HMBC) at 400 and 100MHz, respectively, at 25 degrees C standard pulse sequence. (1)H and (13)C spectra were measured at room temperature for 25,26,27,28-tetramethylcalix[4]arene tetraketone (1). (13)C[(1)H], DEPT and NMR techniques were used to distinguish the methyl, methylene and methine carbon resonance signals of calix[4]arene 1. Correlation of 1D ((1)H, (13)C[(1)H], DEPT) and 2D (HMQC and HMBC) NMR data was used to completely assign various overlapping and broad signals of calix[4]arene 1. Heteronuclear multibond correlation (HMBC) studies were used to completely assign various carbon resonances. Our results show that the conformation of calix[4]arene 1 in the solution is very similar to the cone conformation reported in the literature.