RSC Pharmaceutics最新文献

The desmoplastic tumour microenvironment (TME) is a defining feature of pancreatic cancer and serves as a major barrier to drug delivery and efficacy. Vismodegib is a clinically approved drug that targets the Hedgehog pathway via its receptor, Smoothened. This pathway is activated in cancer-associated fibroblasts (CAFs), one of the main cell types in the TME. In this study, vismodegib was loaded into PLGA nanoparticles to improve its solubility and enhance the efficacy of the chemotherapeutic drug gemcitabine. Vismodegib-loaded PLGA nanoparticles (Vis-PLGA NPs) were prepared and optimised based on PLGA polymer, drug to polymer ratio and formulation method. Vis-PLGA NPs formulated by the single emulsion method improved the encapsulation efficiency from 36% to 86% when compared to nanoprecipitation. More importantly, the drug release profile demonstrated a slower burst release, with sustained release for the single emulsion method at 35% vs. 86% for nanoprecipitation after 48 h. In pancreatic stellate cells, Vis-PLGA NP treatment selectively inhibited 2D co-cultured-induced Hh pathway activation via the effector glioma-associated protein 1 (Gli1) when compared to free vismodegib. More importantly, Vis-PLGA NPs enhanced gemcitabine efficacy as a sequential treatment by prolonging spheroid growth inhibition, combined with a higher apoptotic cell population compared to gemcitabine single treatment (10.3% vs. 7.5%). This increase in apoptosis was not observed with free vismodegib pre-treatment compared to gemcitabine alone. These promising results provide a platform for further in vitro characterisation and in vivo studies of Vis-PGLA NPs for pancreatic cancer treatment.

Natural polysaccharides have various applications, and their use is on the rise due to properties including biodegradability, biocompatibility, cytocompatibility and the absence of negative immune responses. Natural polysaccharides have also been reported to be efficient biopolymers that can be used in oral dosage forms. To this end, this study investigated the potential of using the Nigerian baobab polysaccharide as a renewable pharmaceutical excipient and its impact on the release of theophylline as a model drug. The results indicate that the extraction process yielded an amorphous polysaccharide from the baobab oblong fruit. The thermogravimetric analysis showed weight loss to occur in three phases typical of polysaccharide decomposition. Differential scanning calorimetry (DSC) revealed that the polysaccharide was stable until around 175 °C, after which thermal degradation takes place. Tablet formulations containing different concentrations of baobab were evaluated for mechanical properties, flowability, and dissolution characteristics. An increase in baobab content improved the mechanical strength of the tablets. The increase in the baobab concentration simultaneously brings about a decrease in the porosity of the compacts from 11% to 9%, demonstrating its suitability for use in tablet formulations. In vitro dissolution studies in acidic media (pH 1.2) showed that formulations with higher baobab content (30%–57.5%) demonstrated sustained release characteristics, with no burst release observed. At pH 6.8, however, an increase in the polysaccharide content seemed to promote a “burst release”. These distinctive behaviours at different pH values suggest significant potential for exploiting and understanding the functional properties of the polysaccharide to aid formulators in manipulating drug release. These pH-dependent behaviours mean that a formulator can tune release by adjusting the baobab : MCC ratio. Higher baobab content (30–57.5%) enables sustained, burst-free release at pH 1.2, while at pH 6.8, increasing baobab (to B4) enhances the 10 min burst, and the baobab-only formulation (B5) achieves the fastest overall release through rapid erosion.

Drug delivery systems (DDSs), despite extensive research, have yet to achieve optimal therapeutic outcomes. In this study, we synthesized amino acid-coated iron oxide nanoparticles (IONPs) to investigate a nano-bio interface through thermodynamic analysis and assess how surface coating influences DDS efficiency. The synthesized systems were characterized using FTIR, XRD, BET, SEM, and DLS techniques. Isothermal titration calorimetry in combination with spectroscopy was employed for interaction studies and to obtain data on the binding and thermodynamics of interaction. Thermodynamic parameters and therapeutic efficiency were correlated with the functional groups of the coating material of the IONPs. Experimental findings imply that coating IONPs with amino acids improves their interactions with DNA and drug-loading efficiency. Comparison of the efficiency of different amino acid-coated IONPs based on the functional group of the coating material reveals the importance of the –OH group over other functional groups. Additionally, results demonstrated how the efficiency of the DDSs changes in the homologous series of amino acids and highlight how the size and length of the side substituent as well as the type of amino acid impact their interaction with DNA and drug loading efficiency with 5-fluorouracil. Correlating the energetics of the interactions with the structure and physical characteristics of amino acids enabled quantitative structure–activity relationship (QSAR) studies and will facilitate the AI-based design of efficient DDSs.

The use of chemically matched theranostic radiometals in nuclear medicine presents a paradigm shift in personalized medicine with immense potential to treat advanced cancers. The nuclear isomers, mercury-197g (^197gHg, half-life 64.14 h) and mercury-197m (^197mHg, half-life 23.8 h) possess optimal physical decay properties to be applied in theranostic radiopharmaceuticals; however, their use has been limited due to the lack of suitable bifunctional chelators (BFCs) capable of attaching the radionuclides to disease targeting biomolecules. Herein we report the development and evaluation of two novel ^197m/gHg BFCs derived from a 15-membered thiacrown ether macrocycle (NS₄) bearing isothiocyanate (–NCS) or tetrazine (–Tz) bifunctional handles to allow conjugation to biomolecules. Both chelators were synthesized and radiolabeled with ^197m/gHg, assessed for complex stability, and bioconjugation to trastuzumab (TmAb), a monoclonal antibody targeting HER2 receptors. NS₄-Tz efficiently and stably complexes [^197m/gHg]Hg²⁺ and exhibited excellent in vitro stability in both glutathione and human serum. In contrast, NS₄-NCS showed lower radiometal incorporation yields and reduced complex stability, likely attributed to non-specific interactions of the isothiocyanate group with Hg²⁺. NS₄-Tz was successfully conjugated to transcyclooctene-modified TmAb with favourable chelator-to-antibody ratios and subsequently radiolabeled. Due to non-specific Hg²⁺ binding to TmAb observed during direct labeling, a two-step labeling strategy was employed to improve selectivity. The resulting [^197m/gHg]Hg-NS₄-Tz-TmAb construct demonstrated specific binding to HER2-positive SK-BR-3 cells in vitro and, in the first in vivo study of a [^197m/gHg]Hg-labeled immunoconjugate, confirmed tumour-specific uptake in a SKOV-3 xenograft mouse model. Biodistribution and SPECT/CT studies of the BFC complex alone, [^197m/gHg]Hg-NS₄-Tz, revealed high hepatic and splenic accumulation, with some renal uptake possibly due to transchelation or tracer pharmacokinetics. While long-term in vivo stability of the radioimmunoconjugate remains a challenge, NS₄-Tz shows significant promise for applications with faster-clearing vectors such as peptides or small molecules. Future work will focus on improving hydrophilicity and further optimizing chelator design for mercury-based theranostics.

Poorly soluble drugs pose significant challenges in terms of their pharmacokinetics and biopharmaceutical properties, reducing their therapeutic potential. Crystal engineering has emerged as a promising strategy to address this issue. This comprehensive review delves into the transformative potential of crystal engineering in designing eutectic multicomponent systems. Through the strategic exploitation of supramolecular synthons and non-covalent interactions, eutectic formulations demonstrate significantly improved solubilization, enhanced stability profiles, and augmented bioavailability. We explore the details of functional group interactions, molecular structural design, and crystal lattice dynamics to elucidate the underlying mechanisms governing eutectic formations. Our review provides a profound understanding of the interplay between crystal engineering and pharmacokinetics, paving the way for the rational design of eutectic formulations with optimized drug delivery and therapeutic outcomes.

The brain microvasculature represents the blood–brain barrier (BBB) in vivo and it is permeable only to small lipophilic molecules. Polar nutrients, like glucose and amino acids, are transported across the BBB via carrier-mediated transport systems. Large protein-based biotherapeutics are not able to cross the BBB, which has represented a major issue for the development of potential treatments for the central nervous system over the past several decades. The finding that proteins such as insulin and transferrin cross the BBB through receptor-mediated transcytosis (RMT) led to the idea that it may be possible to transport peptidomimetic molecules to the brain by targeting these BBB receptors. It was later demonstrated that monoclonal antibodies (MAb) targeting either insulin and transferrin BBB receptors were able to penetrate the BBB and distribute throughout the brain. A first generation of molecular Trojan horses or shuttle systems were developed, which were able to piggyback therapeutic molecules conjugated directly to these MAbs or bound to them via avidin–biotin chemistry. This technology was also applied to the delivery of genes and antisense oligonucleotides to the brain. A second generation of brain penetrating protein-based biotherapeutics was produced in a form of fusion proteins, comprised of a transport domain and a therapeutic domain. These fusion proteins were validated in various experimental models, including lysosomal storage disorders, stroke, Parkinson's and Alzheimer's disease, respectively. Clinical trials with brain penetrating fusion proteins have been completed or are in progress with valanafusp alpha and lepunafusp alfa for Hurler's syndrome (mucopolysaccharidosis type I, MPS I), with pabinafusp alfa and tividenofusp alpha for Hunter's syndrome (MPS II), and with trontinemab for Alzheimer's disease. Pabinafusp alfa was the first brain penetrating biotherapeutic approved by a regulatory agency for the treatment of Hunter MPSII syndrome. The aim of this article is to review the progress made in the brain delivery of biotherapeutics via RMT across the BBB.

Chlorhexidine (CHX) is a synthetic cationic biguanide commonly used in dentistry to control infections. In the present study, cost-effective biodegradable dental chips of CHX (0.2%) with varying concentrations of high-molecular-weight chitosan (2%, 3%, and 4%) were prepared using the solvent casting method. The identification, purity, and interaction between the active drug and excipients have been confirmed using FTIR spectrometry. The formulated chips exhibited a pH of around 5, with excellent folding endurance of ≥1000, a thickness of 0.34–0.42 mm, and a moisture loss of about 10–14%. Organoleptically, the chips were consistent for at least three months at room temperature. The assay of CHX was performed using a validated HPLC method. The content uniformity of the chips was found to be greater than 90%, indicating a uniform distribution of the active drug. The release of CHX from the chips slowed down from 31 to 72 h with an increase in polymer concentration from 2 to 4%. The release followed the Higuchi model for 2% and 3% chips and the Korsmeyer–Peppas model for 4% chips. All the chips demonstrated stability for only one month under accelerated temperature and humidity conditions (i.e., 40 °C/75% RH). Significant antimicrobial activity has been observed for both placebo and CHX-loaded chips against various standard and clinical isolates, with good activity on cementum. The formulated CHX dental chips offer an economical and effective drug delivery system for treating periodontal infections, due to their potent antimicrobial effect and sustained drug release, which facilitates the desired therapeutic effects.

Therapeutic cancer vaccines elicit an immune response within existing tumours. Our research introduces a strategy to address the low efficacy of peptide-based therapeutic cancer vaccines by employing aluminum-complexed alginate nanoparticles (nAl-Alg) as an adjuvant. Characterisation of nAl-Alg revealed a hydrodynamic diameter of 242.1 ± 126.33 nm. Cytocompatibility studies using the murine macrophage cell line RAW 264.7 demonstrated no change in percentage viability up to 100 μg ml⁻¹ compared to the untreated control. Cell uptake studies conducted in RAW 264.7 macrophages demonstrated an enhanced uptake of nAl-Alg compared to Alhydrogel®, a commercially available adjuvant. In vivo toxicity studies in mouse models also revealed the absence of adverse reactions in haematological analysis after treatment with nAl-Alg. Subsequent in vivo mouse melanoma model studies showed a notable delay in tumour growth in animals treated with nAl-Alg combined with the tumour antigen compared to groups treated with the tumour antigen alone, adjuvant alone, and untreated controls. The median survival time increased from 17 days in untreated animals to 33 days for the nAl-Alg and tumour antigen combination-treated group. Treatment with nAl-Alg and the tumour antigen alone resulted in median survival times of 23 days and 24 days, respectively. These findings highlight the potential therapeutic impact of nAl-Alg in enhancing the immune response against tumours.

Alzheimer's disease (AD) presents significant clinical challenges due to its complex pathology and the limitations of traditional drug delivery routes, which often fail to transport therapeutic agents effectively across the blood–brain barrier (BBB). This review focuses on the potential of intranasal drug delivery to enhance therapeutic efficacy in AD treatment by providing a direct route to the central nervous system (CNS). It examines the mechanisms of intranasal administration, including the olfactory and trigeminal pathways, which facilitate rapid drug absorption and distribution to the brain. Additionally, the advantages of intranasal delivery in improving drug bioavailability, reducing systemic side effects, and enhancing patient compliance are discussed alongside innovative formulation strategies, including lipid nanoparticles and other carrier systems. Despite promising outcomes, challenges such as variability in absorption efficiency and the influence of repeated administration remain critical considerations. Furthermore, this review also surveys the current landscape of research for intranasal drug delivery in AD, integrating imaging technologies, emphasizing ongoing studies and future directions for this promising approach. By synthesizing recent findings, this review aims to provide a comprehensive exploration of the interplay of biologics, intranasal delivery, and brain disorders, offering valuable perspectives into the potential of intranasal gene therapy as a potent drug delivery system for CNS diseases.

Densely charged but neutral sulfobetaine polymeric micelles (PMs) were designed with the aim of efficiently permeating the intestinal mucus and releasing the intact peptide cargo close to the intestinal epithelial surface. Using RAFT chemistry, butyl methacrylate and dimethyl aminoethyl methacrylate copolymers were synthesised and then reacted with propane sultone to form amphiphilic block copolymers comprising hydrophilic zwitterionic sulfobetaine and lipophilic butyl methacrylate (BMA). Small (diameter <50 nm), spherical BMA–sulfobetaine PMs with a near neutral surface charge potential and loaded with a model peptide cargo, the GLP1-agonist peptide exenatide, were then formed by nanoprecipitation. In vitro peptide release studies from the PMs showed that less than 0.9% of the peptide load was released within the first 2 h (i.e. there was no ‘burst’ effect), with the release unaffected by highly acidic conditions. Thereafter, a sustained release was evident with 43% of the peptide load released in 24 h. In vitro screening (cytotoxicity assay) showed that the PMs did not cause loss of epithelial cell viability. Multiple particle tracking showed that the PMs were very highly permeant through the intestinal mucus. An in vivo non-clinical rodent pharmacokinetic study demonstrated the oral delivery of the exenatide-loaded PMs to achieve an extent of peptide bioavailability of 13% relative to subcutaneous (s.c.) exenatide solution injection. A pharmacodynamic study showed the efficacy of the oral exenatide-loaded PMs with significant reductions in blood glucose following a glucose challenge test. In conclusion, a novel family of sulfobetaine PMs have been demonstrated as stable carriers, efficiently permeating the intestinal mucus and with the potential for exploitation in the oral delivery of therapeutic peptides.