Polymer-bile salts interaction and its impact on the solubilisation and intestinal uptake of poorly water-soluble drugs

I would like to thank my primary supervisor Dr. Sheng Qi for the invaluable support and encouragement received during my PhD time at UEA. Thanks also to my supervisors Prof. Peter Wilde and Prof. Duncan Craig for their help. I would also like to express my gratitude to Prof. Pete Belton, Dr. Francesca Baldelli Bombelli from the UEA School of Pharmacy for their precious scientific collaboration. Thanks to Dr. Patrick Gunning, Dr. Nicola Woodwards and Mr. Andrew Kirby, Dr. Paul Kroon and Mr. Mark Winterbone from the Institute of Food Research for their help with Nanosight, pendant drop and biological experiments. I would like to thank all the friends that have been part of my life in Norwich, for the happy times together and for being supportive when I mostly needed. A special thanks goes to Yohan for being a good friend and taking care of me as a brother. Thanks to my housemates Desirè and Hanae, for their friendship and their constant support. Thanks to Francesca and Alberto for all the laughes and their invaluable help and care. Thanks to Lorina, Elisabetta, Marcello, Antonella and Tiziana for being good friends during these years. Thanks to all the other friends from the schools of Pharmacy and Chemistry. I would also like to thank my friends from Italy, in particular Ilaria for being a constant presence and support in my life. Finally I would like to thank my family, my outstanding parents for their love, their encouragement and support. Thanks to my sister Flavia, for being the special sister she is

Probing the Molecular Interactions between Pharmaceutical Polymeric Carriers and Bile Salts in Simulated Gastrointestinal Fluids using NMR Spectroscopy

The number of poorly soluble new drugs is increasing and one of the effective ways to deliver such pharmaceutically active molecules is using hydrophilic polymers to form a solid dispersion. Bile salts play an important role in the solubilisation of poorly soluble compounds in the gut prior to absorption. When a poorly water-soluble drug is delivered using a hydrophilic polymer based solid dispersion oral formulation, it is still unclear whether there are any polymer-bile salt interactions, which may influence the drug dissolution and solubilisation. This study, using two widely used hydrophilic model polymers, Hydroxypropyl methylcellulose (HPMC) and polyvynilpirrolidone (PVP), and sodium taurocholate (NaTC) as the model bile salt, aims to investigate the interactions between the polymers and bile salts in simulated fed state (FeSSIF) and fasted state (FaSSIF) gut fluids. The nature of the interactions was characterised using a range of NMR techniques. The results revealed that the aggregation behaviour of NaTC in FaSSIF and FeSSIF is much more complex than in water. The addition of hydrophilic polymers led to the occurrences of NaTC-HPMC and NaTC-PVP aggregation. For both systems, pH and ionic strength strongly influenced the aggregation behavior, while the ion type played a less significant role. The outcome of this study enriched the understanding of the aggregation behaviour of bile salts and typical hydrophilic pharmaceutical polymers in bio-relevant media. Due to the highly surface-active behaviour of the bile salts, such aggregation behaviour is expected to play a role in drug solubilisation in the gut when the drug is delivered by hydrophilic polymer based dispersions

Self-Assembled Peptide–Inorganic Nanoparticle Superstructures: From Component Design to Applications

[Abstract] Peptides have become excellent platforms for the design of peptide–nanoparticle hybrid superstructures, owing to their self-assembly and binding/recognition capabilities. Morover, peptide sequences can be encoded and modified to finely tune the structure of the hybrid systems and pursue functionalities that hold promise in an array of high-end applications. This feature article summarizes the different methodologies that have been developed to obtain self-assembled peptide–inorganic nanoparticle hybrid architectures, and discusses how the proper encoding of the peptide sequences can be used for tailoring the architecture and/or functionality of the final systems. We also describe the applications of these hybrid superstructures in different fields, with a brief look at future possibilities towards the development of new functional hybrid materials.We are thankful for the funding received from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 851179), the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) (CTQ2016-75629-P), the Agencia Estatal de Investigación and FEDER (CTQ2017-89166-R) and the Consellería de Educación, Universidade e Formación Profesional, Xunta de Galicia (ED431C 2018/39). E. P. thanks the UDC-Inditex InTalent Programme for her research contract and funding and the Xunta de Galicia for the Oportunius ProgrammeXunta de Galicia; ED431C 2018/3

Halogenation dictates the architecture of amyloid peptide nanostructures

Amyloid peptides yield a plethora of interesting nanostructures though difficult to control. Here we report that depending on the number, position, and nature of the halogen atoms introduced into either one or both phenylalanine benzene rings of the amyloid β peptide-derived core-sequence KLVFF, four different architectures were obtained in a controlled manner. Our findings demonstrate that halogenation may develop as a general strategy to engineer amyloidal peptide self-assembly and obtain new amyloidal nanostructures

Impact of doxorubicin-loaded ferritin nanocages (FerOX) vs. free doxorubicin on T lymphocytes: a translational clinical study on breast cancer patients undergoing neoadjuvant chemotherapy

Despite the advent of numerous targeted therapies in clinical practice, anthracyclines, including doxorubicin (DOX), continue to play a pivotal role in breast cancer (BC) treatment. DOX directly disrupts DNA replication, demonstrating remarkable efficacy against BC cells. However, its non-specificity toward cancer cells leads to significant side effects, limiting its clinical utility. Interestingly, DOX can also enhance the antitumor immune response by promoting immunogenic cell death in BC cells, thereby facilitating the presentation of tumor antigens to the adaptive immune system. However, the generation of an adaptive immune response involves highly proliferative processes, which may be adversely affected by DOX-induced cytotoxicity. Therefore, understanding the impact of DOX on dividing T cells becomes crucial, to deepen our understanding and potentially devise strategies to shield anti-tumor immunity from DOX-induced toxicity. Our investigation focused on studying DOX uptake and its effects on human lymphocytes. We collected lymphocytes from healthy donors and BC patients undergoing neoadjuvant chemotherapy (NAC). Notably, patient-derived peripheral blood mononuclear cells (PBMC) promptly internalized DOX when incubated in vitro or isolated immediately after NAC. These DOX-treated PBMCs exhibited significant proliferative impairment compared to untreated cells or those isolated before treatment initiation. Intriguingly, among diverse lymphocyte sub-populations, CD8 + T cells exhibited the highest uptake of DOX. To address this concern, we explored a novel DOX formulation encapsulated in ferritin nanocages (FerOX). FerOX specifically targets tumors and effectively eradicates BC both in vitro and in vivo. Remarkably, only T cells treated with FerOX exhibited reduced DOX internalization, potentially minimizing cytotoxic effects on adaptive immunity

Hydrophobin-stabilized dispersions of PVDF nanoparticles in water

In this study, aqueous dispersions of partially crystalline PVDF nanoparticles (NPs) were obtained employing hydrophobin (HFB), an amphiphilic film-forming protein able to film hydrophobic surfaces. Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) analysis of PVDF-HFBII aqueous dispersions confirmed the HPBII ability to film PVDF hydrophobic NPs. Freeze-dried PVDF-HFBII bio-nanocomposites were shown to be effectively re-dispersible in water. An aqueous dispersion of PVDF NPs may have an impact on the applications of this polymer in the perspective of the development of environmentally friendly coating methods

Acid⋅⋅⋅amide supramolecular synthon for tuning amino acid-based hydrogels' properties

: Supramolecular hydrogels formed by the self-assembly of N-Fmoc-l-phenylalanine derivatives are gaining relevance for several applications in the materials and biomedical fields. In the challenging attempt to predict or tune their properties, we selected Fmoc-pentafluorophenylalanine (1) as a model efficient gelator, and studied its self-assembly in the presence of benzamide (2), a non-gelator able to form strong hydrogen bonds with the amino acid carboxylic group. Equimolar mixtures of 1 and 2 in organic solvents afforded a 1 : 1 co-crystal thanks to the formation of an acid⋅⋅⋅amide heterodimeric supramolecular synthon. The same synthon occurred in the transparent gels formed by mixing the two components in 1 : 1 ratio in aqueous media, as revealed by structural, spectroscopic, and thermal characterizations performed on both the co-crystal powder and the lyophilized hydrogel. These findings revealed the possibility of modulating the properties of amino acid-based hydrogels by involving the gelator in the formation of a co-crystal. Such a crystal engineering-based approach is shown also to be useful for the time-delayed release of suitable bioactive molecules, when involved as hydrogel coformers