Molecular Pharmaceutics最新文献

To enhance the therapeutic efficacy of breast cancer, multimodal therapy with the aid of a pH-responsive controlled release platform is proposed in this work. Indocyanine green (ICG) is loaded in honeycomb MnO₂ (hMnO₂) synthesized by a template method, which is coencapsulated with 5-fluorouracil (5-FU) in the hydrogels cross-linked between carboxymethyl chitosan (CMCS) and oxidized hyaluronic acid (OHA). The imine linkage (-HC═N-) between CMCS and OHA is hydrolyzed under weakly acidic conditions, leading to the release of 5-FU for chemotherapy and ICG/hMnO₂. The hMnO₂ can convert the optical energy of near-infrared (NIR) light into heat for photothermal therapy (PTT). Additionally, the hMnO₂ can be reduced to Mn²⁺ at low pH and high glutathione (GSH) level, and the produced Mn²⁺ can further react with H₂O₂ to generate hydroxyl radicals (·OH) through a Fenton-like reaction for chemodynamic therapy (CDT). ICG can be simultaneously released during the reduction of hMnO₂, which can catalyze the conversion of oxygen to singlet oxygen (¹O₂) upon exposure to NIR light for photodynamic therapy (PDT). Due to the synergistic effects of chemotherapy, PTT, CDT, and PDT, the developed ICG/hMnO₂/5-FU/CMCS/OHA hydrogels can significantly inhibit the growth of the 4T1 mouse breast cancer cell line.

Porphyrin-based nanovesicles have emerged as promising platforms for pharmaceutical applications due to their inherent biocompatibility and unique photosensitive properties. Their vesicular architecture facilitates both photodynamic and photothermal therapies while enabling targeted drug delivery through photoactivation. Incorporation of porphyrins into nanovesicle bilayers enhances therapeutic efficacy, stability, and cellular uptake. Moreover, porphyrins' ability to chelate metal ions extends their use to diagnostic imaging and theranostics. Specifically, cobalt-chelated porphyrin vesicles have demonstrated potential for the targeted delivery of macromolecules, including peptides and vaccines. This review highlights recent advances in the design, modification, and biomedical application of porphyrin-based nanovesicles, with a focus on their chemical versatility and multifunctionality.

Antibody-based zirconium-89 (⁸⁹Zr)-containing immunological positron emission tomography (immuno-PET) agents have applications in high-precision cancer imaging. These agents require a bifunctional chelator to bind the positron-emitting ⁸⁹Zr isotope and facilitate the covalent attachment to a cancer-targeting monoclonal antibody (mAb). The hexadentate hydroxamic acid chelator desferrioxamine B (DFO) is commonly used in the development of ⁸⁹Zr-immunoPET agents. While DFO is efficiently radiolabeled with ⁸⁹Zr, vacancies in the unsaturated ⁸⁹Zr-DFO coordination sphere can reduce the ⁸⁹Zr-DFO complex stability and increase the risk of ⁸⁹Zr dissociating and accumulating in nontarget tissues, particularly bone. This potential shortcoming of ⁸⁹Zr-DFO can be addressed by using an octadentate chelator to fully saturate the ⁸⁹Zr coordination sphere. The octadentate chain-extended DFO analogue DFO* was the first exemplar of this class and showed ⁸⁹Zr-DFO* was more stable than ⁸⁹Zr-DFO. The current work designed, synthesized, and evaluated the properties of a new octadentate DFO analogue, named D8W, where "W" designates "water-soluble". This property has been built into D8W by including water-solubilizing ether oxygen atoms in the hydroxamic acid extension unit appended to DFO and a PEG₄ unit. Comparison of the two most water-soluble chelators from the set of DFO, DFO* and D8W, showed that compared to [⁸⁹Zr]Zr-DFO-mAb (mAb = Girentuximab), [⁸⁹Zr]Zr-D8W-mAb had improved ⁸⁹Zr radiolabeling kinetics and in vitro stability. Key to its utility, bone deposition of ⁸⁹Zr was lower for [⁸⁹Zr]Zr-D8W-mAb than [⁸⁹Zr]Zr-DFO-mAb, as assessed by PET imaging in a CAIX-expressing HT-29 tumor-bearing Balb/C nude mouse model. The performance of D8W coupled with its water solubility supports its merit in its use in ⁸⁹Zr-immunoPET agents.

Multiple myeloma (MM), the second most common hematologic malignancy, often presents with a gradual onset and minimal symptoms in its early stages, leading to frequent misdiagnosis and delays in treatment. In recent years, radionuclide-based molecular imaging has emerged as a pivotal tool in the noninvasive evaluation and clinical management of MM, particularly in assessing the expression of CD38─a transmembrane glycoprotein that is robustly expressed on approximately 80-100% of malignant plasma cells. Notably, clinical studies have revealed a negative correlation between CD38 expression levels and treatment outcomes, underscoring the importance of accurate and dynamic measurement of CD38 for diagnostic precision and individualized treatment stratification. Radiolabeled molecular imaging targeting CD38 enables repeated, in vivo assessments of its expression status, allowing clinicians to monitor molecular heterogeneity and temporal changes throughout disease progression or therapeutic intervention. To this end, a variety of CD38-targeted imaging agents have been developed, including monoclonal antibodies, antibody fragments, nanobodies and peptide. Many of these probes are currently undergoing preclinical evaluation or have entered early phase clinical trials. This review summarizes recent advances in the development and application of CD38-targeted molecular imaging probes in MM, highlighting their potential to improve disease characterization, therapeutic monitoring, and personalized management strategies.

High neurotensin receptor 1 (NTSR1) expression is strongly associated with progression and poor prognosis across multiple malignancies. We designed an NTSR1-targeted peptide-based PET probe conjugated with the albumin-binding moiety ibuprofen, designated [⁶⁸Ga]Ga-DOTA-NT-20.3-Ibu, which was synthesized with high radiochemical yield and purity, exhibited sufficient in vitro stability, and demonstrated favorable serum albumin-binding capacity. Cell binding/uptake assays, animal-based PET imaging, and biodistribution studies confirmed the radiotracer's high affinity and specificity for NTSR1. In human participants, [⁶⁸Ga]Ga-DOTA-NT-20.3-Ibu was safe and primarily excreted via the urinary system. Bone marrow uptake was detectable with SUVmean of 4.11 ± 1.59 and 4.99 ± 1.82 at 60 and 120 min postinjection, respectively. Mild uptake was observed in the blood pool, liver, spleen, pancreas, stomach, and bowel, while other tissues showed minimal uptake. Importantly, lung tumor uptake of [⁶⁸Ga]Ga-DOTA-NT-20.3-Ibu correlated with NTSR1 expression levels. Collectively, [⁶⁸Ga]Ga-DOTA-NT-20.3-Ibu PET enables accurate, noninvasive assessment of tumor NTSR1 expression, facilitating NTSR1-targeted cancer treatment and prognosis monitoring.

A vitamin K3 (VK3)-loaded metal-organic framework (Cu/ZIF-8/VK3) was synthesized by a one-pot method. After the coencapsulation of Cu/ZIF-8/VK3 and 5-fluorouracil (5-FU) in the hyaluronate acid (HA)/carboxymethyl chitosan (CMCS) hydrogels formed via an amidation reaction, a drug-controlled release system (Cu/ZIF-8/VK3/5-FU/HA/CMCS) was obtained. In the weakly acidic media, the amide bonds in the HA/CMCS hydrogels are prone to be hydrolyzed, resulting in the release of 5-FU and Cu/ZIF-8/VK3; and the Cu/ZIF-8/VK3 is further degraded in the acidic environment, leading to the release of VK3 and Cu²⁺. The released Cu²⁺ can be reduced by glutathione (GSH) to Cu⁺, which can react with intracellular H₂O₂ to produce cytotoxic hydroxyl radicals (·OH) for chemodynamic therapy (CDT). On the other hand, H₂O₂ can be replenished through the redox cycling of VK3 in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), generating stable ·OH for enhanced CDT. Cytotoxicity assay demonstrates that the developed drug-controlled release system has excellent biocompatibility, which can effectively inhibit the growth of mouse breast tumor cells 4T1 due to the synergistic chemotherapy and enhanced CDT.

A c*-guided high-temperature rheological approach and solid-state NMR (ssNMR) ¹H T_1ρ and ¹H T₁ relaxation time measurements were used to estimate the miscibility of celecoxib (CEL)/polyvinylpyrrolidone (PVP) amorphous solid dispersions (ASDs) prepared by melt quench and spray drying. The ssNMR spin diffusion method is capable of investigating the miscibility of ASDs processed by the two methods, as it measures as-is ASD powders, while the c*-guided high-temperature rheological approach cannot, since it erases the processing history. Our results indicate a general agreement of the estimated miscibility of ASDs prepared by the two processing methods. The crystallization tendency is significantly different when the polymer concentration c is below and above c*. When c < c*, the onset of crystallization in dilute CEL/PVP ASDs is approximately identical to that of neat amorphous CEL. However, when c > c*, the first evidence of CEL crystallization is significantly delayed, indicating a reduced crystallization propensity. These results confirm that the efficient and material-sparing rheological approach can be used to estimate the miscibility (limit) and predict stability against crystallization for both melt-extruded and spray-dried ASDs. Our findings are useful in the rational and efficient design of robust ASDs with a desirable stability against crystallization during long-term storage.

Studies have frequently shown that successful drug release from amorphous solid dispersions (ASDs) is highly dependent on polymer dissolution. Underpinning drug release from ASDs is a series of complex steps involving solvent penetration into the glassy core, gel formation and swelling, and colloid formation and release. The objective of this study was to predict ritonavir (RTV) and polymer release from ASDs of RTV and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) from discs with varying geometries based solely on solvent penetration. Using vacuum compression molding, ASD discs containing RTV/PVPVA were fabricated with drug load ranging from 0 to 50%. Three disc geometries were 8 mm thin disc, 20 mm thin discs, and 8 mm thick discs, where 8 and 20 mm denoted disc diameter. Hence, ASDs varied in drug load and geometry. ASDs were subjected to microscope-enabled disc dissolution system (MeDDiS) testing (i.e., simultaneous imaging and dissolution from disc side) as well as USP II dissolution testing, which allowed release from additional surfaces. Five disc models were derived based on solvent penetration and varied in releasing surface areas [i.e., disc side model, disc top and bottom (T&B) model, disc top model, sunken disc model, and total disc model]. Solvent penetration rate was visually observed to be rate-limiting and was quantitatively measured from MeDDiS imaging, where the solvent penetration rate was approximately the same across drug loads from 0 to 25% and across disc geometries. Predicted drug and polymer release was obtained from each of the five disc dissolution models for each of the three disc geometries, including base-case models that reflected visual observations of disc dissolution (i.e., disc side model for MeDDiS and either sunken disc model or total disc model for USP II). There was excellent agreement between predicted and observed ASD drug (and polymer) release. In particular, the observed drug and polymer release from MeDDiS closely matched the disc side model, reflecting the base-case of only release from the disc side. Meanwhile, release from USP II testing closely matched the base-cases of the sunken disc model (for 8 mm thin and 8 mm thick discs) and the total disc model (for 20 mm discs). However, predicted profiles were slightly faster than the observed profiles, indicating solvent penetration was rate-dominating, although not the only barrier to drug and polymer release. Results here indicate successful model predictions of drug release from a well-studied ASD drug/polymer pair, which has promise to aid the understanding of less well-studied ASDs.

Solubilization of poorly water-soluble drugs in human intestinal fluids influences oral absorption and is linked to food effects. Current empirical equations for calculating intestinal solubilization via lipophilicity are built on limited data and do not adequately account for drug ionization. We aim to expand the data set and build a model to clarify the link between lipophilicity and solubilization for charged compounds. We determined the aqueous solubility, octanol-water partition coefficient, and solubilization in fed-state simulated intestinal fluids (FeSSIF) of 26 hydrophobic drugs. Combined with literature data, a good correlation (R² = 0.74, n = 198) between intestinal solubilization and LogP/D was observed. However, data segregation showed that the solubilization of neutral compounds correlated very well with LogP (R² = 0.89, n = 114), whereas the correlation with LogD was lost for the charged compounds (R² = 0.40, n = 84). To better understand this behavior, the pH of FeSSIF was varied to study the solubilization of the same compounds in the neutral and charged states. While a very good correlation between solubilization and LogD was observed in the neutral state of the compounds (R² = 0.92, n = 8), the correlation was again lost (R² = 0.02, n = 4) in their charged state. Electrostatic interactions were suggested to play a key role in the unexpectedly low solubilization of anionic drugs and in the phase separation observed for cationic drugs. The presented insights further advance the understanding of the solubilization of hydrophobic drugs in biorelevant media and provide a foundation for broader and improved modeling approaches.

Mechanical stress of protein solutions in contact with a compressible interface can cause protein aggregation. This is a known problem for air-liquid and silicone-liquid interfaces, which occur during processing and handling of biopharmaceuticals. A systematic study comparing and unraveling the mechanism of particle formation at different compressible interfaces is lacking. To this end, we combined novel molecular dynamics simulations and established experimental setups that isolate and precisely define compression-decompression stress to elucidate and compare the mechanism of protein particle formation at the silicone-liquid interface, reflecting tubing used in pumping, and air-liquid interface. Simulations revealed that protein molecules bind rather loosely to the air-liquid interface and show high mobility. During interfacial compression, protein molecules therefore move from the air-liquid interface toward the bulk, reducing protein aggregation. At the silicone-liquid interface, strongly bound protein molecules are forced together upon compression of the adsorbed protein film, promoting particle formation already at little compression. Aggregates detach easily from the air-liquid interface, and compression further facilitates detachment. This enhanced detachment from the air-liquid interface renders similar particle counts in the bulk for both interface types at high interfacial compression, although simulations indicate less aggregate formation directly at the air-liquid interface. Clusters at the silicone-liquid interface break up during relaxation, whereas clusters at the air-liquid interface persist. This, in combination with more easy detachment leads to the formation of smaller particles at the air-liquid interface compared to the silicone-liquid interface. The simulations indicate that at high compression speed, the highly mobile protein molecules at the air-liquid interface do not have sufficient time to interact during compression and form fewer particles. Additionally, strong repulsive protein self-interaction resulting from high charge at low pH values reduced particle formation at the air-liquid interface more strongly due to the high molecular mobility at this interface as compared to the silicone-liquid interface. Our findings provide insights into the mechanisms of protein aggregation at different compressible interfaces, which is essential for developing strategies to mitigate particle formation in biopharmaceutical manufacturing and handling.