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Resistant pathogens are increasingly posing a heightened risk to healthcare systems, leading to a growing concern due to the lack of effective antimicrobial treatments. This has prompted the adoption of antimicrobial photodynamic therapy (aPDT), which eradicates microorganisms by generating reactive oxygen species (ROS) through the utilization of a photosensitizer, photons, and molecular oxygen. However, a challenge arises from the inherent characteristics of photosensitizers, including photobleaching, aggregation, and self-quenching. Consequently, a strategy has been devised to adsorb or bind photosensitizers to diverse carriers to facilitate their delivery. Notably, metal-organic frameworks (MOFs) have emerged as a promising means of transporting photosensitizers, even though achieving uniform particle sizes through room-temperature synthesis remains a complex task. In this work, we have tackled the issue of heterogeneous particle size distribution in MOFs, achieving a particle size of 150 ± 50 nm. Subsequently, we harnessed Zeolite Imidazolate Framework 8 (ZIF-8), an excellent subclass of biocompatible MOF, to effectively load two distinct categories of photosensitizers, namely, Rose Bengal (RB) and porphyrin, using a simple, straightforward, and single-step process. Our findings indicate that the prepared RB@ZIF-8 complex generates a more substantial amount of reactive singlet oxygen species when subjected to photoirradiation (using green light-emitting diode (LED)) at low concentrations, in comparison with porphyrin@ZIF-8, as demonstrated in in vitro experiments. Additionally, we investigated the pH-responsive behavior of the complex to ascertain its implications under biological conditions. Correspondingly, the RB@ZIF-8 complex exhibited a more favorable IC₅₀ value against Escherichia coli compared to bare photosensitizers, ZIF-8 alone, and other photosensitizer-loaded ZIF-8 complexes. This underscores the potential of BioMOF as a promising strategy for combatting multidrug-resistant bacteria across a spectrum of infection scenarios, complemented by its responsiveness to stimuli.

Tyrosine kinase inhibitors have been employed for the treatment of lung cancer, owing to their role in regulating irregulated pathways or mutated genes. Bosutinib, a nonreceptor tyrosine kinase, has been recently investigated for lung cancer treatment. Bosutinib can also be used with paclitaxel as a combinatorial approach to receive a synergistic effect for the effective management of lung cancer. Furthermore, the nanocrystals of each can also be prepared and in combination can produce a more pronounced impact than the drug combination. Herein, the prepared Soluplus/lipid-stabilized nanocrystals of paclitaxel and bosutinib were rod to cubic in shape of about 150-250 nm. The nanocrystals were stable, provided controlled drug release, and exhibited a higher aerosolization performance. The nanocrystal combination demonstrated higher anticancer activity than the drug combination synergy against A549 cancer cells. The nanocrystals increased the level of cellular internalization in cancer cells, thereby inducing higher ROS generation and apoptosis of cancer cells. Furthermore, the lipid/Soluplus-stabilized nanocrystals exhibited higher translocation potential compared with only Soluplus-stabilized nanocrystals. The nanocrystals administered intratracheally showed a lower drug distribution to other organs, with prolonged drug retention in the lungs, suggesting the higher efficacy of developed nanocrystals in targeting the lungs. In conclusion, lipid-modified nanocrystals can be a novel approach for the effective management of lung cancer.

Malignant tumors pose a considerable threat to human life and health. Traditional treatments, such as radiotherapy and chemotherapy, often lack specificity, leading to collateral damage to normal tissues. Tumor microenvironment (TME) is characterized by hypoxia, acidity, redox imbalances, and elevated ATP levels factors that collectively promote tumor growth and metastasis. This review provides a comprehensive overview of the nanoparticles developed in recent years for TME-responsive strategies or TME-modulating methods for tumor therapy. The TME-responsive strategies focus on designing and synthesizing nanoparticles that can interact with the tumor microenvironment to achieve precisely controlled drug release. These nanoparticles activate drug release under specific conditions within the tumor environment, thereby enhancing the efficacy of the drugs while reducing toxicity to normal cells. Moreover, simply eliminating tumor cells does not fundamentally solve the problem. Only by comprehensively regulating the TME to make it unsuitable for tumor cell survival and proliferation can we achieve more thorough therapeutic effects and reduce the risk of tumor recurrence. TME regulation strategies aim to suppress the growth and metastasis of tumor cells by modulating various components within the TME. These strategies not only improve treatment outcomes but also have the potential to lay the foundation for future personalized cancer therapies.

Fungal mycelial materials can mimic numerous nonrenewable materials; they are even capable of outperforming certain materials at their own applications. Fungi's versatility makes mock leather, bricks, wood, foam, meats, and many other products possible. That said, there is currently a critical need to develop efficient mycelial materials design techniques. In mycelial materials, and the wider field of biomaterials, design is primarily limited to costly forward techniques. New mycelial materials could be developed faster and cheaper with robust inverse design techniques, which are not currently used within the field. However, computational inverse design techniques will not be tractable unless clear and concrete design parameters are defined for fungi, derived from genotype and bulk phenotype characteristics. Through mycelial materials case studies and a comprehensive review of metamaterials design techniques, we identify three critical needs that must be addressed to implement computational inverse design in mycelial materials. These critical needs are the following: 1) heuristic search/optimization algorithms, 2) efficient mathematical modeling, and 3) dimensionality reduction techniques. Metamaterials researchers already use many of these computational techniques that can be adapted for mycelial materials inverse design. Then, we suggest mycelium-specific parameters as well as how to measure and use them. Ultimately, based on a review of metamaterials research and the current state of mycelial materials design, we synthesize a generalizable inverse design paradigm that can be applied to mycelial materials or related design fields.

Glaucoma is a vision-threatening disease that is currently treated with intraocular-pressure-reducing eyedrops that are instilled once or multiple times daily. Unfortunately, the treatment is associated with low patient adherence and suboptimal treatment outcomes. We developed carbonic anhydrase II inhibitors (CAI-II) for a prolonged reduction of intraocular pressure (IOP). The long action is based on the melanin binding of the drugs that prolongs ocular drug retention and response. Overall, 63 new CAI-II compounds were synthesized and tested for melanin binding in vitro. Carbonic anhydrase affinity and IOP reduction of selected compounds were tested in rabbits. Prolonged reduction of IOP in pigmented rabbits was associated with increasing melanin binding of the compound. Installation of a single eye drop of a high melanin binder carbonic anhydrase inhibitor (CAI) resulted in ≈2 weeks' decrease of IOP, whereas the effect lasted less than 8 h in albino rabbits. Duration of the IOP response correlated with melanin binding of the compounds. Ocular pharmacokinetics of a high melanin binder compound was studied after eye drop instillation to the rat eyes. The CAI showed prolonged drug retention in the pigmented iris-ciliary body but was rapidly eliminated from the albino rat eyes. The melanin-bound drug depot maintained effective free concentrations of CAI in the ciliary body for several days after application of a single eye drop. In conclusion, melanin binding is a useful tool in the discovery of long-acting ocular drugs.

As an enzyme that plays an important role in DNA repair, poly(ADP-ribose) polymerase-1 (PARP-1) has become a popular target for cancer therapy. Nuclear medicine molecular imaging technology, supplemented by radiolabeled PARP-1 inhibitors, can accurately determine the expression level of PARP-1 at lesion sites to help patients choose an appropriate treatment plan. In this work, niraparib was modified with a hydrazinonicotinamide (HYNIC) group to generate the ligand NPBHYNIC, which has an in vitro affinity (IC₅₀) of 450.90 nM for PARP-1. The ligand NPBHYNIC was labeled with technetium-99m and six different coligands to yield [^99mTc]Tc-(X/tricine)-NPBHYNIC (X = TPPTS, TPPMS, PSA, PDA, NIC and ISONIC). These complexes were hydrophilic and exhibited good stability in vitro, and low levels of these complexes were taken up by nontarget organs and tissues in Kunming mice. Among these complexes, [^99mTc]Tc-(TPPTS/tricine)-NPBHYNIC and [^99mTc]Tc-(NIC/tricine)-NPBHYNIC were selected for biodistribution in HeLa tumor-bearing BALB/c nude mice at 2 h post injection. The results revealed that the tumor uptake of [^99mTc]Tc-(TPPTS/tricine)-NPBHYNIC (1.02 ± 0.07% ID/g) was greater than that of [^99mTc]Tc-(NIC/tricine)-NPBHYNIC (0.36 ± 0.05% ID/g). Additionally, in biodistribution, single-photon emission computed tomography/computed tomography (SPECT/CT) and radioautography experiments, the tumor uptake of [^99mTc]Tc-(TPPTS/tricine)-NPBHYNIC was significantly reduced in the blocked group, indicating PARP-1 specificity. Therefore, it has potential for use as a niraparib-based tumor imaging agent that targets PARP-1.

Lumefantrine (LMF) is a low-solubility antimalarial drug that cures acute, uncomplicated malaria. It exerts its pharmacological effects against erythrocytic stages of Plasmodium spp. and prevents malaria pathogens from producing nucleic acid and protein, thereby eliminating the parasites. Modifying the structure of a drug through the formation of a pharmaceutical cocrystal or salt presents an avenue through which its physicochemical properties can be optimized. In this work, we report the design/synthesis and solid-state characterization of four new salts and cocrystal-salt forms of LMF; an LMF-ADP salt, monoclinic space group P2₁/n; an LMF-FUM cocrystal-salt, monoclinic space group P2₁/c; an LMF-TAR solvate salt, monoclinic space group P2₁/n; and an LMF-SUC salt, triclinic, space group P1̅ (ADP, dianion of adipic acid; FUM, monoanion of fumaric acid; TAR, dianion of tartaric acid; SUC, dianion of succinic acid). These salts can be obtained by solution as well as by mechanochemical cocrystallization methods. The multicomponent systems gain their stability from hydrogen and partial ionic bonding interactions (N-H···O, O-H···O, N⁺-H···O^-, and O-H⁺···O^-) originating from both the dibutyl ammonium (N⁺-H) site and the alcohol hydroxyl (-OH) site of LMF toward the carboxylate (-C(O^-)═O) functional groups of the coformer anions. SCXRD indicates for LMF-ADP, LMF-TAR, and LMF-SUC complete transfer of all carboxylic acid protons (H⁺) toward the LMF nitrogen, while for LMF-FUM, one of the protons is transferred (leaving a hydrofumarate monoanion). Using salicylic and acetylsalicylic acids as coformers yielded coamorphous solids. Solid-state characterization using powder X-ray diffraction (XRD) and thermal techniques (DSC and TGA) support and confirm the structures obtained from single-crystal XRD. LMF-ADP and LMF-FUM present superior stability under standard conditions (40 ± 2 °C, 75 ± 5% RH, and 3 months) compared to the amorphous samples and the other two salts. LMF-SUC showed poor thermal stability by DSC/TGA, and powder XRD patterns for LMF-TAR showed substantial change after the 3-month stability test. Finally, the calculated equilibrium solubilities for the cocrystal salts indicate an increase of more than twofold compared to LMF's solubility.

Amorphous solid dispersions (ASDs) are a prevalent method for increasing the bioavailability and apparent solubility of poorly soluble drugs. Consequently, extensive research, encompassing both experimental and computational approaches, has been dedicated to developing methods for assessing the key factors influencing their stability, notably drug-polymer interactions. A common computational approach to rank the compatibility of a drug with a set of solvents or polymers is to compare thermodynamic observables, such as solvation free energies at infinite dilution. However, the impact of the molecular weight of the polymer excipient on these interactions remains underexplored. This study delves into this impact through atomistic simulations of Indomethacin in PVP(-VA) and HPMC, and through simulations using a coarse-grained model, emphasizing its critical importance. First, we demonstrate that the molecular weight of the polymer plays a pivotal role in determining the solvation free energy of the drug, at times exerting a more significant influence than the specific chemical identity of the polymer. Additionally, our simulations suggest that higher molecular weight polymers lead to lower solvation free energies and, thus, suggest better compatibility with the drug. Yet, the lower free energy of solvation of the drug in longer polymers does not translate into a higher solubility. This work highlights the subtle role polymer molecular weight plays when measuring thermodynamic observables in amorphous solid dispersions, a role which must be considered when optimizing pharmaceutical formulations.

With increasing prevalence globally, obesity presents unique challenges to the clinical management of other diseases. In the case of acute respiratory distress syndrome (ARDS), glucocorticoid therapy (e.g., dexamethasone (DEX)) represents one of the few pharmacological treatment options, but it comes with severe adverse effects, especially when long-term usage (>1 week) is required. One important reason for the adverse effects of DEX is its nonspecific accumulation in healthy tissues upon systemic administration. Therefore, we hypothesize that refining its pharmacokinetics (PK) and in vivo biodistribution may improve its therapeutic index (higher efficacy, lower toxicity) and thus make it safer for obese populations. To achieve this goal, DEX was conjugated with polyethylene glycol (PEG) with three different molecular weights (M_w, 2K, 5K, and 10K) via a reactive oxygen species (ROS)-cleavable linker. Their anti-inflammatory efficacy and long-term adverse effects were evaluated in a murine obesity-ARDS model. Strikingly, DEX-PEG-2K (conjugates with 2K PEG M_w) provided the optimal therapeutic index compared to free DEX and to the other two conjugates with longer PEGs (M_w of 5K and 10K): While retaining the comparable therapeutic efficacy to DEX, DEX-PEG-2K significantly reduced the accumulation of free DEX in the liver and spleen, which led to a 51% reduction of fatty area in liver and a 32% reduction of blood triglycerides concentration. DEX-induced apoptosis of the thymus was also rescued by DEX-PEG-2K under normal conditions. The PK and biodistribution were also investigated to elicit the underlying mechanism. In summary, we provided here a chemical modification strategy to improve the therapeutic index of dexamethasone and possibly other glucocorticoid drugs for ARDS treatment with an obesity background.

Given that the amphiphilicity of polysorbates represents a key factor in the protection of proteins from particle formation, the loss of this property through degradative processes is a significant concern. Therefore, the present study sought to identify the factors that contribute to the oxidative cleavage of the polysorbate (PS) molecule and to ascertain the preferred sites of degradation. In order to gain insight into the radical susceptibility of the individual polysorbate segments and their accessibility to water, conceptual density functional theory calculations and molecular dynamics simulations were performed. The behavior of monoesters and diesters was examined in both monomer form and within the context of micelles. The theoretical results were corroborated by experimental findings, wherein polysorbate 20 was subjected to 50 ppb Fe²⁺ and 100,000 lx·h of visible light, and subsequently stored at 25 °C/60% r.h. or 40 °C/75% r.h. for a period of 3 months. Molecular dynamics simulations demonstrated that unesterified polyoxyethylene(POE) chains within a polysorbate 20 molecule exhibited the greatest water accessibility, indicating their heightened susceptibility to oxidation. Nevertheless, the oxidative cleavage of esterified polyoxyethylene chains of a polysorbate 20 molecule is highly detrimental to the protective effect on protein particle formation. This occurs presumably at the oxyethylene (OE) units in the vicinity of the sorbitan ring, leaving a nonamphiphilic molecule in the worst case. Consequently, the critical degradation sites were identified, resulting in the formation of degradation products that indicate a loss of amphiphilicity in PS.