Croda Pharma ’s Post

Enhancing bone-repair using LNP-mRNA: Chelsea Bahney, Nicole Ehrhart at Colorado State University and collaborators enhanced a delivery platform for a mRNA-based therapeutic encoding β-catenin by leveraging recent advances in liposomal technologies, using two FDA-approved ionizable phospholipids (MC3 and SM-102) to create unique ionizable lipid nanoparticle formulations. These LNPs were subsequently tested for transfection efficacy both in vitro and in a murine tibia fracture model https://lnkd.in/eYSMSvhY SM-102 LNPs demonstrated superior transfection efficacy in vitro and provided prolonged transfection in vivo, with minimal interference in fracture healing and no localized inflammatory response, outperforming MC3 LNPs. An article also authored by Anna Laura Nelson, Chiara Mancino, PhD, Xueqin Gao, Joshua C., Laura Chubb, Katherine Williams, Molly Czachor, Ralph Marcucio, Francesca Taraballi, John Cooke and Johnny Huard #LNP #mRNA #drugdelivery #targeteddelivery #genetherapy #Vesiculab

Unveiling the secrets of CIL-LNPs! Structural transitions and enhanced endosomal release are two parameters more interlinked than we thought! Unlocking the power of mRNA-based therapies depends on understanding the intricate mechanisms of lipid nanoparticles (LNPs). This study dives deep into the pH-dependent response of three cationic ionizable lipids (CILs) used in LNP construction, revealing crucial insights into their effectiveness. Key findings: 1) CIL type significantly impacts endosomal release: MC3 and KC2 outperform DD in terms of eGFP protein expression, despite similar mRNA delivery. 2) pH-driven structural transitions are crucial -synchrotron X-ray scattering reveals distinct sequences of ordered phases for each CIL, with a critical transition from inverse micellar to inverse hexagonal structure. 3) Excess lipid behavior matters -the addition of polyadenylic acid highlights differences in next-neighbor distances within the excess lipid phase, suggesting a link to release efficiency. These findings propose a refined understanding of CIL-LNPs in which not structure alone, but structural transitions govern fusogenic activity. Moreover, differences in these transitions between CILs explain their varied efficacy, with the Fd3m-H II transition emerging as a key determinant of release efficiency. This work opens the door to tailoring CIL design for optimal LNP performance and the chance of developing more effective mRNA-based therapeutics. If you want to learn more: https://lnkd.in/ercw7YUu #mRNATherapy #Nanotechnology #BiomedicalResearch #MolecularBiology #InnovationInScience

QK is a peptide derived from the 17-25 helical region of vascular endothelial growth factor (VEGF), which is the region of VEGF involved when binding to its receptor Flt-1 (VEGFR-1),  QK acts as a VEGF mimetic and agonist and can reproduce the biological activity of VEGF while retaining its bioactivity much longer in vivo than the full-length protein. QK promotes proliferation and angiogenic differentiation of endothelial cells and can promote microvascularization in vitro and in vivo. QK can be used as a VEGF mimetic agent in reparative angiogenesis and has been synthesised as a nanoparticle for enhanced stability, in this form it has been used to prevent the occurrence of bisphosphonate-related osteonecrosis of the jaw (BRONJ). https://lnkd.in/ezNXeYg7 #peptides #peptide #biochemistry

VMAT structures reveal exciting targets for drug development Vesicular monoamine transporter (VMAT)-2 has a crucial role in the neurotransmission of biogenic amines. Recently, Dalton et al., Pidathala et al., Wu et al., and Wang et al. individually reported cryo-electron microscopy (EM) structures of human VMAT2, offering opportunities for developing improved therapeutics and deep insights into the functioning of this protein. VMATs actively remove monoamines, such as serotonin, dopamine, histamine, adrenaline, and noradrenaline, from the cytosol. These monoamines are stored in synaptic vesicles at nerve terminals or storage organelles found in platelets, enterochromaffin, chromaffin, and other similar cells. This storage process is essential for regulating the release of neurotransmitters into the synaptic cleft or to appropriate targets throughout the human body. In humans, mutations in VMATs can lead to developmental delay, dystonia, parkinsonism, and increased mortality, highlighting the importance of these transporters in neurotransmission. VMATs are also a target for treating hypertension, psychotic agitation, psychostimulant abuse, and hyperkinetic movement disorders, such as Huntington's disease-related chorea. Despite their physiological and pharmacological significance, the structural basis for substrate recognition and inhibition by different drugs was unknown until recently. Four publications reported cryo-EM structures of VMAT2 in different conformations, bound to substrates and inhibitors. https://lnkd.in/dN3EM4yv

🔬Citation Break!📖 This citation investigates Beta-Amyloid aggregation and the role of Aβ in neuronal cell death and in the progression of AD. Specifically, this article studies the KLVFF fragment of the 1-42 peptide and its effects on the aggregation propensity of the Beta-Amyloid. rPeptide Beta-Amyloid (1-42) HFIP (Cat# A-1163) was successfully aggregated and used in neurotoxicity assays with neuroblastoma cells to further the authors’ research. Paper: https://t.ly/cKTll Beta-Amyloid (1-42): https://t.ly/ul-4V #Research #Development #rPeptide #BetaAmyloid #Citation

Pharmacological inhibitor protects nerve cells in ALS disease A research team examined a neuroprotective molecule that belongs to a novel drug class. It is able to inhibit the interactions of certain proteins and has been successfully tested in a mouse model of ALS and in brain organoids of ALS patients. The FP802 molecule the scientists used in the study belongs to a new pharmacological class of drugs. These are “TwinF interface inhibitors”, and these inhibitors disrupt the physical interactions of two ion channel proteins, with the names NMDA receptor and TRPM4, which, due to a so-called protein pocket named “TwinF” by the scientists, form a protein-protein complex. The neuroprotective molecule FP802 binds to the TwinF protein pocket of TRPM4, blocks the contact areas of the interacting proteins, and thereby disrupts the fatal complex of NMDA receptors and TRPM4. The scientists have studied this new drug principle using an ALS mouse model as well as brain organoids of ALS patients. “ #ScienceMission #sciencenewshighlights https://lnkd.in/gqZVYfyN

Engineering targeted extracellular vesicles loaded with TGF-β inhibitors: in their latest work, Xiaoqian Dang at Xi'an Jiaotong University and collaborators assessed the stability, cytotoxicity, and bone-targeting capability of the BT-EV-G platform, which consists of macrophage-derived extracellular vesicles decorated with targeting peptides and loaded with Galunisertib, a TGF-β inhibitor https://lnkd.in/gVBdzY29 Their findings revealed that BT-EV-G exhibited low toxicity and excellent bone-targeting ability in both in vitro and in vivo studies. An article co-authored by Zhaopu Jing, Guangyang Zhang, Yuanqing Cai, Jialin Liang and Leifeng Lv #extracellularvesicles #exosomes #bioengineering #osteoarthritis #drugdelivery #Vesiculab

Mimicking “The Hercules Hold” of #coagulation #factor-VIII An inherent dysfunction of blood #coagulation #factor VIII leads to Hemophilia A. Prophylactic usage of exogenous #FVIII is of limited use because of frequent IV administrations, short plasma half-life, and development of inhibitory antibodies.   To meet this, a novel antibody-based modality was invented: #Asymmetric #Bispecific IgG #Antibody called #Emicizumab. FIXa recognising arm called Q-chain FX recognising arm called J-chain. In this masterpiece work #Zenjiro #Sampei et al walks us through an evolution of #Emicizumab. The work describes therapeutic development, optimization of the #bispecific antibody by #molecular #engineering to enable large-scale manufacturing of the #bispecific #antibody at clinical grade through following steps,   Identification of Lead #Anti-FIXa/#FX BsAb #Humanization of Lead Chimeric BsAb Improving FVIII-mimetic Activity of BsAb Improving #Pharmacokinetics #Isoelectric Point #Engineering to Facilitate Purification Removing Deamidation Site in the #CDR #Deimmunization of Humanized BsAb by Removing #T-cell #Epitopes   Citation: #Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, et al. (2013) Identification and Multidimensional Optimization of an Asymmetric Bispecific IgG Antibody Mimicking the Function of Factor VIII Cofactor Activity. PLoS ONE 8(2): e57479. doi:10.1371/journal.pone.0057479

I am excited to share the publication of the #crystal #structure of #Bimekizumab Fab fragment bound to IL-17F. A collaborative effort from the Bunick lab and UCB, this article provides #dermatologists and the #medical and #scientific community a #molecular basis for how and why bimekizumab binds to and inhibits IL-17A and IL-17F. This dual inhibition has made a remarkable impact on the #treatment of plaque #psoriasis, and is poised for #FDAapproval for psoriatic #arthritis and #hidradenitis suppurativa in the coming months. Please dive into the molecular differentiation of Bimekizumab from other IL-17 targeted biologics! Another victory for molecular and structural #science, and more importantly, for the #patients who will benefit from this #therapy! https://lnkd.in/eeaeYe-V

"Magnetic nanoparticles (MNPs) as a fascinating area of research in the context of targeted drug delivery systems for cancer treatment" #MNPs are tiny particles, typically made of iron oxide, that can be controlled using magnetic fields. Their small #size allows them to navigate through the body and reach specific sites, such as #tumors. #Biopolymers are natural polymers that are #biocompatible and #biodegradable. When used in drug delivery, they can #encapsulate #drugs, protecting them from #degradation and ensuring they're released at the right time and place. The combination of MNPs with biopolymers creates a #targeted #drug_delivery_system. The MNPs can be directed to cancerous sites using an #external #magnetic_field, and the biopolymers can #release the drug in a controlled manner. This #method of drug delivery is highly advantageous because it minimizes the #side_effects of #chemotherapy by targeting only the cancer cells and sparing healthy tissue. It also allows for the drug to be delivered in higher concentrations at the tumor site. Researchers are exploring various #coatings for MNPs to improve their #biocompatibility and #functionality. They're also investigating different methods of drug loading and release, as well as the overall #pharmacokinetics and toxicity of these systems in the body. This targeted approach is a significant step forward in cancer treatment, offering a more efficient and less harmful alternative to traditional chemotherapy. The field is rapidly evolving, with ongoing research aimed at improving the effectiveness and safety of these #nanomedicines. More details: https://lnkd.in/d6FZGHBZ https://lnkd.in/dK3E8EvV ***** The figure was created and powered by DALL·E 3. *****