RSC Pharmaceutics最新文献

Correction for ‘Pharmaceutical salts of azole anti-fungal drugs: physicochemical behaviour and activity studies’ by Hafsa Qadri et al., RSC Pharm., 2024, https://doi.org/10.1039/d4pm00003j.

Therapeutic proteins have drawn increasing attention in the development of advanced drugs and biomedical devices, yet there are outstanding challenges for the delivery of multiple-protein therapies with customized release profiles. Hydrogel-based drug delivery systems (DDS) have been widely investigated, primarily via highly specific chemical modification routes, for programmable topical, injectable, and depot-based protein delivery. In this paper, we propose a microgel/hydrogel composite (MHC) DDS for tunable and programmable multi-protein delivery, which leverages different physical states of proteins (freely dissolved or coacervated) and completely avoids bespoke chemical modifications on the hydrogels. We load model proteins in distinct physical states into dextran-based hydrogel microparticles (microgels) fabricated using microfluidics, after which simple discrete combinations of these microgel ‘unit ingredients’ are packaged into poly(ethylene glycol) hydrogel matrices to formulate the MHC DDS. With discrete combinations of unit ingredients, we demonstrate how these MHC DDSs can achieve both tunable release for a single low-molecular-weight model protein (and ideally, highly similar proteins) and a counterintuitive rate-reversed release of two model proteins that are vastly different in size. Moreover, we show that these MHCs follow Korsmeyer-Peppas kinetic behavior as a function of the discrete combinations packaged, thus highlighting the quantitative tunability of release behaviors. We envision the use of these MHC DDSs as topically applied wound dressings or implantable protein-releasing depots that allow scheduled and programmable multi-protein delivery in biomedical and clinical applications.

The development of innovative nanoplatforms for cancer immunotherapy has garnered considerable attention in biomedical research. Layered double hydroxide (LDH) is a two-dimensional inorganic nanomaterial consisting of positively charged brucite-like cationic layers and negatively charged anions intercalated in the interlayer space. LDH-based nanoplatforms have been emerging as promising candidates for enhancing the efficacy of cancer immunotherapy. This review highlights the latest advancements in the application of LDH in cancer immunotherapy. The unique physicochemical properties of LDH, such as a high surface area, tunable porosity, and facile surface modification, entail it to be a versatile platform to deliver antigens, drugs, and other therapeutic agents. In addition, LDH's inherent biocompatibility and biodegradability contribute to its suitability for in vivo applications. Moreover, the nanoplatform formed by the integration of self-adjuvant LDH with tumor antigen and immunomodulatory components has shown promising results in enhancing antigen presentation, promoting immune cell activation and regulating the immune suppressive tumor microenvironment. In this review, we discuss the application of LDH as a carrier-supported immune modulator in immunotherapy and the application of LDH as an adjuvant to construct tumor vaccines. Finally, future research challenges of LDH in immunotherapy are briefly discussed. Conclusively, the versatility and adaptability of LDH-based nanoplatforms make them promising candidates for the next generation of cancer immunotherapeutics.

Donepezil (DPZ) is a reversible, noncompetitive inhibitor of acetylcholinesterase commonly prescribed against Alzheimer's disease (AD). Its dose-dependent side effects limit its therapeutic benefits. The current study endeavors to design an in situ gel for intranasal delivery of a DPZ nanostructured lipid carrier (DPZ-NLC) to boost pharmacokinetic and pharmacodynamic outcomes. The Box–Behnken design was employed to optimize the NLCs that were produced utilizing a melt emulsification high-pressure homogenization process. Afterward, NLCs were embedded in an in situ gel based on Lutrol F127 and analyzed further. The effects of formulation pharmacodynamics were evaluated in a Wistar rat model with trimethyl tin (TMT) induced neurodegeneration. The batch of the optimized DPZ in situ gel had a spherical shape, with a mean particle size of 112.5 ± 2.44 nm. It showed a high drug entrapment of 98.7 ± 4.01% and an in vitro drug release of 89.51 ± 2.94%. With a C_max value of 193.41 ± 26.4 ng mL⁻¹ and a T_max value of 2 hours, the drug's significant therapeutic concentration in the CNS following intranasal (IN) administration was demonstrated by in vivo single-dose pharmacokinetic investigation. The Drug Targeting Efficiency (DTE) of 213.123% and the Drug Targeting Potential (DTP) of 66.27% were greater for the constructed DPZ in situ gel, indicating superior brain targeting efficiency through NLCs. The outcomes showed that as compared to the neurodegeneration control group, the DPZ in situ gel treatment group dramatically reduced the escape latency and path length. The DPZ in situ gel demonstrated superior anti-AD potency to DPZ-sol, as revealed by biochemical and histological investigations. Its potential for managing AD is suggested by the favorable outcomes of the developed and enhanced intranasal DPZ in situ gel.

Carbapenems are crucial antibiotics in the battle against bacterial infections, targeting both Gram-positive and Gram-negative bacteria with exceptional potency. These antibiotics are part of a group of vital ‘last resort’ antibiotics, reserved for severe infections caused by multi-drug resistant bacteria. However, their misuse poses a significant threat and the overuse of carbapenems accelerates the development of antibiotic resistance, thereby jeopardizing the efficacy of these lifesaving drugs. Another contributing factor complicating this issue is the emergence of biofilms. These complex microbial communities are encased in a polymeric matrix and contribute to the onset of serious infections which are challenging to treat. This review explores the biofilm potency of different clinically approved carbapenems, delving into the latest strategies and delivery systems employed to augment their anti-biofilm activity. The goal is to provide valuable insights into the development of more potent carbapenems specifically tailored for combating biofilms.

Nucleic acid (NA) based therapeutics have witnessed tremendous progress and breakthroughs in treating pathological conditions, including viral infections, neurological disorders, genetic diseases, and metabolic disorders. NAs such as plasmid DNA (pDNA), short interfering RNA (siRNA), microRNA (miRNA), and antisense oligonucleotides (ASOs) can be modified to revolutionize personalized medicine. Despite the great potential of NA-based therapeutics, their clinical transformation is significantly hampered by instability, degradation, and inefficient delivery to the targeted site in the in vivo system. Lipid-based delivery systems hold great potential to overcome these shortcomings to enhance the delivery and bioavailability, improve stability, and increase the therapeutic effect of the NAs by delivering them to the active site. This review emphasized various nucleic acid-based therapeutics and their enhanced and improved delivery using different nanocarriers. Ultimately, the importance of lipid-based nanocarriers for delivering NAs is discussed and provides perspective in this field.

Cell penetrating peptides (CPPs) have emerged as promising materials for the fabrication of synthetic nanovectors endowed with potential for improving the future landscape of gene therapy. A group of well-studied CPPs includes the transportan family, comprised of chimeric molecules combining segments derived from the antimicrobial wasp-venom mastoporan and the neuropeptide galanin. The success of these CPPs is supported by their effective use as the base for commercial peptide-based transfection reagents. Herein, we present a comprehensive study of the structure of peptiplexes formed between DNA fragments and transportan 10, a prototype example of amphipathic CPP. We conducted a thorough analysis of the self-aggregation of TP10, its secondary structure, and revealed details of its interaction with DNA. We employed atomic force microscopy-based nanospectroscopy to obtain single-particle data that revealed details of the conformations assumed by the peptide and DNA in the inner structure of nanoassemblies with different morphologies. Our structural results showed that TP10 exhibits self-aggregation capabilities and a strong propensity to assume α-helical conformations upon association with DNA strands. This behavior contrasts with that of prototype CPPs such as TAT-HIV and penetratin, potentially explaining why peptiplexes based on transportans demonstrate increased uptake compared to their cationic counterparts. Also, single-particle spectroscopy indicated that the secondary structure in peptiplexes is strongly dependent on the size and shape, reinforcing that controlled self-assembly is crucial for optimizing CPP-based nanotherapeutics. The peptiplexes were also evaluated for cell uptake efficiency and kinetics, revealing a logistic time–response increase in permeability, suggestive of cooperativeness. We anticipate that the findings presented here might contribute to refining structure–activity relationships of peptiplexes based on amphipathic CPPs, assisting the optimization of products based on this relevant class of CPPs with potential applications in therapeutic delivery systems.

In the pursuit of a new generation of protein pharmaceuticals, the efficient delivery of these therapeutics into cells stands out as a crucial challenge. In this study, we have developed a novel approach utilizing protein capsules modified with VHH antibodies as cytosolic carriers for protein pharmaceuticals. For the protein capsule component, we opted for the OLE-ZIP protein capsules, which can be prepared from the amphiphilic two-helix bundled protein OLE-ZIP using the water-in-oil (w/o) emulsion method. The spacious interior of the OLE-ZIP capsules allows for the stable encapsulation of over 200 molecules of protein pharmaceuticals, such as RNase A and Cre recombinase, in one capsule. By presenting the VHH antibody with an affinity for cell-type-specific receptors such as the epidermal growth factor receptor (EGFR) on the capsule surface, we achieved cell-type selective endocytic uptake in A431 cell lines (high expression level of EGFR) over NHDF and MCF-7 cells (normal expression level of EGFR). This selective uptake was followed by the subsequent release of the encapsulated protein pharmaceuticals into the cytosol of the target cells. Unlike our previous version of the OLE-ZIP protein capsules modified with IgG antibodies, cytosolic delivery of pharmaceutical proteins was little impacted by the presence of other IgGs, which are abundant in the bloodstream. This improved characteristic suggests potential advantages for practical applications, including intravenous administration.

The present work deals with designing a biocompatible controlled drug delivery system (DDS) based on 12-tungstophosphoric acid (TPA)-functionalized SBA-15 for anti-osteoporotic drug alendronate sodium (ALD) and its characterization using different physicochemical techniques such as TGA, FT-IR spectroscopy, XRD, N₂ adsorption measurements, HRTEM, and SEM. The designed DDS, ALD/TPA/SBA-15, was assessed for its drug delivery potential by carrying out in vitro drug release in simulated body fluid (pH 7.4, 37 °C) under stirring conditions as well as for the dissolution study. Release kinetics and mechanisms using zero order, first order, and Higuchi model were also carried out. Further, the release profile of the designed DDS was compared with the available marketed formulation (Osteofos), and ALD/TPA/SBA-15 shows a more controlled release. To explore the direct anti-tumour potency of ALD on osteosarcoma cells, an MTT assay was carried out at different concentrations, and the results show concentration-dependent inhibition of osteosarcoma cell proliferation.

Drug combinations have been shown to be highly effective in many cancer therapies but the ratios of the individual drugs must be adjusted carefully and formulated appropriately to ensure synergistic action. Here we assessed combinations of doxorubicin and gemcitabine for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). 2D and 3D spheroid in vitro models of GBM were generated from patient-derived glioblastoma cells resected from brain tumour cores and invasive margins. Drug combinations were screened for synergy using the Chou–Talalay method and mechanisms of action investigated using measures of caspase 3/7-mediated apoptosis and γH2AX-mediated DNA damage. Single drug and drug combinations were formulated in a supramolecular hydrogel based on a peptide-functionalised hyaluronic acid backbone dynamically linked by cucurbit[8]uril-mediated host–guest interactions as an implantable drug-delivery vehicle. Drug efficacy data from in vitro assays demonstrated synergistic activity with doxorubicin and gemcitabine combinations in a molar ratio-dependent manner. These compounds were included in the drug screen as exemplars of DNA intercalators and nucleoside analogue respectively. Consistent with this, enhanced apoptosis and DNA damage were also observed in a synergistic manner. Overall, these drug-loaded hydrogels demonstrated potency and maintenance of synergy with drug-combination hydrogels, in an easy-to-administer in situ gelling formulation suitable for post-resection delivery to prevent GBM recurrence.