Molecular Pharmaceutics[JOURNAL]
Sun
200 papers
Investigating the Relationship between In Vitro and In Vivo Performance: The Role of Drug Loading, Release Rate, and Surface Area.
Benson EG, Purohit HS, Zhang GGZ … +5 more , Gao Y, Osterling DJ, Stolarik DF, Jenkins GJ, Taylor LS
Mol Pharm · 2026 Apr · PMID 41855473 · Publisher ↗
Amorphous solid dispersions (ASDs) are a commonly used formulation approach for poorly water-soluble drugs to enhance release rates, generate supersaturated solutions, and improve oral absorption. Hypromellose (HPMC) has...
Amorphous solid dispersions (ASDs) are a commonly used formulation approach for poorly water-soluble drugs to enhance release rates, generate supersaturated solutions, and improve oral absorption. Hypromellose (HPMC) has been used in commercial ASD formulations, but relatively little is known about drug release mechanisms from ASDs based on this polymer. Herein, confocal fluorescence microscopy (CFM) was employed to reveal the morphology of phase separation in tacrolimus/HPMC ASDs in aqueous media. Release and absorption performance of different drug loading (DL) ASDs were monitored in vitro and in vivo CFM revealed that at 10% DL and above, a drug-rich network formed while the polymer diffused into the bulk solution. Surface area-normalized release rate measurements confirmed this observation revealing that HPMC was released 10× faster than tacrolimus at 10% DL, while at 5% DL, the release rates were congruent. Despite reduced drug release rates at 10% DL, sufficiently high surface area and moderate agitation enabled powder formulations to completely release within 40 min and achieve supersaturation under nonsink release conditions. At the commercial DL of 50%, a lower extent of supersaturation was achieved in comparison to the 10% DL. However, the surface area-normalized release rate was 100 times than that estimated for the crystalline form. In vivo absorption data in fasted dogs reflected this difference, with the 50% DL formulation significantly outperforming the crystalline drug with further improvements observed with the 10% DL formulation. This study connects the observations from CFM, surface area-normalized release rates, powder dissolution, and in vivo absorption data to the performance of ASDs at different drug loadings.
Rational Selection of Chelators for Theranostic Radionuclides: Insights from Ab Initio Computational Modeling.
Kim J, Kang K, Shin K … +3 more , Schultz MK, Lee WB, Lee D
Mol Pharm · 2026 Apr · PMID 41855390 · Full text
Targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. While TRT offers potent therapeutic efficacy, its clinical application requires careful control due to the risk of systemic to...
Targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. While TRT offers potent therapeutic efficacy, its clinical application requires careful control due to the risk of systemic toxicity arising from off-target distribution of radionuclides. A key strategy to minimize such toxicity and enhance targeting efficiency lies in selecting an appropriate chelator that forms highly stable complexes with radionuclides and maintains their integrity under physiological conditions. This study aimed to computationally assess the chelation compatibility of four clinically relevant chelators (DOTA, NOTA, NODAGA, and TETA) with various therapeutic and diagnostic radionuclides. Chelator-radionuclide interactions were evaluated using density functional theory (DFT) computational modeling. The thermodynamic stabilities of the chelator-radionuclide complexes were evaluated using interaction energies (), with lower values indicating stronger coordination. Coordination geometries, compatibility between internal cavity volumes of chelators and radii of radionuclides, and charge distributions upon chelation were also assessed to provide a comprehensive evaluation. Computational predictions were validated against existing literature to assess their agreement in coordination geometries and chelator-radionuclide compatibility. DOTA exhibited moderate-to-strong chelation affinity across various radionuclides, generally forming stable 8-coordinate complexes, but with a marked preference for medium-sized ions (e.g., Lu: -4.99 eV vs Ac: -2.45 eV; ). NOTA and NODAGA, which possess smaller cavity volumes (7.29 Å and 4.56 Å, respectively; vs 15.29 Å for DOTA), showed strong size-selective affinity toward smaller metal ions. TETA, structurally flexible, preferentially formed stable 6-coordinate complexes with smaller trivalent ions such as Ga (-4.32 eV; ). Charge neutrality was identified as a critical factor for chelation, as neutral complexes exhibited more homogeneous electrostatic environments and improved stability compared to charged complexes. This computational study identifies three key factors─cavity volume compatibility, structural rigidity/flexibility, and charge neutrality─as critical determinants of chelator-radionuclide stability. By providing predictive insights into chelation behavior, our validated DFT modeling supports the rational selection and optimization of chelators, with direct implications for the development of safer and more effective theranostic radiopharmaceuticals in TRT.
Cytidinyl/Cationic Lipids-siRNA Delivery Silences MYC to Reprogram Macrophages and Circadian Rhythm for Cancer Treatment.
Zhou X, Yu X, Qiu K … +4 more , Hong J, Sun M, Yang L, Yang Z
Mol Pharm · 2026 Apr · PMID 41841193 · Publisher ↗
Nonsmall cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with oncogene overexpression driving tumor progression and immunosuppression. MYC has been deemed "undruggable" for a long period, a...
Nonsmall cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with oncogene overexpression driving tumor progression and immunosuppression. MYC has been deemed "undruggable" for a long period, and the impact of its silencing on the tumor associated macrophage polarization and circadian rhythm remains unexplored. Here, we developed a lipid nanoparticle (siMYC@Dmix) composed of cytidinyl lipid (DNCA), gemini-like cationic lipid (CLD), and DSPE-PEG2000 for efficient siRNA delivery. In vitro, siMYC@Dmix showed robust cellular uptake, lysosomal escape, and ∼77% mRNA silencing in Lewis Lung Carcinoma (LLC) cells. In vivo, siMYC@Dmix treatment significantly inhibited tumor growth in C57BL/6J mice and induced a profound remodeling of the tumor immune microenvironment. This was characterized by a shift in macrophage polarization toward the M1 phenotype, increased infiltration and cytotoxic function of CD8 T cells, enhanced natural killer (NK) cell activity, and maturation of dendritic cells (DCs). Crucially, silencing restored the expression of core circadian clock genes. Our findings unveil a promising RNAi-based strategy that concurrently targets -driven tumorigenesis, corrects circadian dysfunction, and reinstates antitumor immunity, presenting a multifaceted therapeutic approach for NSCLC.
Small Activating RNAs: Delivery and Therapeutic Applications in Disease Treatment.
Pramod Theekshana HM, Ni L, Zhong Y … +4 more , Liu Z, Xiao Y, Yuan Z, Huang H
Mol Pharm · 2026 Apr · PMID 41838952 · Publisher ↗
Over time, RNA oligonucleotides have emerged as critical tools in the field of drug discovery, offering potential therapeutic strategies for various diseases that are considered undruggable by conventional methods. Small...
Over time, RNA oligonucleotides have emerged as critical tools in the field of drug discovery, offering potential therapeutic strategies for various diseases that are considered undruggable by conventional methods. Small activating RNAs (saRNAs) are a distinct subset of artificially designed short RNA duplexes (dsRNAs) that function as regulatory molecules which mediate the upregulation of endogenous gene expression by targeting specific sequences within gene promoters, acting at both the transcriptional and epigenetic levels. This process, termed RNA activation, is a conserved mechanism observed across a broad spectrum of eukaryotes, from small invertebrates like nematodes to humans. Effective in vivo delivery of saRNAs is achieved using various delivery systems, including lipid nanoparticles, aptamers, dendrimers, and lipopolyplexes, enabling the guide strand to direct AGO2 to the nucleus and activate transcription. This represents a promising therapeutic strategy for cancer and other diseases. This paper reviews current literature on saRNA biology, focusing on its characteristics, mechanisms of action, challenges, and role in upregulating transcription, while exploring its therapeutic potential and future applications in disease treatment.
Development of a Sustainable Gel System for Ocular Delivery of -Coumaric Acid for Corneal Wound Healing.
Polopalli S, Saha A, Niri P … +10 more , Kumar M, Das P, Adhikari P, Banerjee A, Kakati A, Rahaman S, Karmakar S, Bhutia YD, Goyary D, Chattopadhyay P
Mol Pharm · 2026 Apr · PMID 41837559 · Publisher ↗
Corneal injuries are a leading cause of vision impairment, yet current therapies provide limited benefit due to poor ocular bioavailability and rapid drug clearance. To address this challenge, we developed a pH-sensitive...
Corneal injuries are a leading cause of vision impairment, yet current therapies provide limited benefit due to poor ocular bioavailability and rapid drug clearance. To address this challenge, we developed a pH-sensitive gel of -coumaric acid (pCA) for sustained ocular delivery and enhanced wound healing. studies on SIRC cells identified 80 μg/mL pCA as a safe and effective concentration for supporting viability and migration. The optimized gel, formulated with Carbopol 940 and HPMC K100 M using central composite design, exhibited rapid gelation at ocular pH, pseudoplastic rheology, suitable zeta potential, and high entrapment efficiency (85.95%). FESEM confirmed pH-triggered sol-gel transition, while release demonstrated sustained delivery for 12 h (92.62% cumulative release). Safety was verified through RBC lysis, CAM, goat corneal histology, and rabbit eye irritation tests, all showing no adverse effects. evaluation in a rat corneal alkali burn model confirmed accelerated wound healing. This system offers a safe, biocompatible, and effective ocular therapy for corneal wounds.
Dissolving Microneedles Loaded with Lipid Nanocarriers for Vaginal Delivery of Clotrimazole: and Evaluation.
Udayakumar P, Škalko-Basnet N, Rondahl V … +5 more , Cotaquispe CFS, Hemmingsen LM, Sotiriou GA, Du J, Teleki A
Mol Pharm · 2026 Apr · PMID 41834717 · Full text
Vaginal yeast infections, such as vulvovaginal candidiasis (VVC), affect nearly three out of four women worldwide. Reoccurrence is frequent and requires repeated treatments with oral, antifungal medications at high doses...
Vaginal yeast infections, such as vulvovaginal candidiasis (VVC), affect nearly three out of four women worldwide. Reoccurrence is frequent and requires repeated treatments with oral, antifungal medications at high doses. Prolonged treatments contribute to development of resistant fungal strains and the risk of systemic adverse effects. Vaginal drug delivery can overcome several of the disadvantages associated with oral drug administration. However, current dosage forms, such as vaginal creams and gels, are rapidly expelled from the vaginal tract and require daily dosing to ensure therapeutic outcome, thus jeopardizing patient compliance. Therefore, we developed rapidly dissolving microneedle arrays with a microneedle height reduction by 50% within 5 min, for local, vaginal delivery of antifungal drugs. Clotrimazole, a poorly water-soluble antifungal agent, was formulated in lipid-based nanocarriers (LNCs) and incorporated in the tips of microneedles. The antifungal activity was then tested against the most common VVC fungal strains, and , using an disk diffusion assay and an explant model from bovine vaginal tissue. LNC loaded microneedles showed consistent significant inhibition of . in comparison to blank microneedles and LNCs alone, with an inhibition diameter of 20-30 mm and a reduction of 3-5-fold fungal colonies . Notably, the LNC-loaded microneedles inhibited fungal growth at a 10-fold lower drug dose than a commercial clotrimazole cream. Finally, a device prototype was developed in the form of an intravaginal ring incorporating multiple microneedle arrays on its surface, delivering a total drug dose of 0.1 mg per ring with 600 μm microneedle height. Local vaginal drug delivery using such microneedle-based devices could enable more effective treatment strategies for VVC.
Role of Dissolution Medium pH in the Release Behavior of Basic Drug-Copovidone Amorphous Solid Dispersions.
Uekusa T, Hate SS, VanDer Kamp KA … +1 more , Taylor LS
Mol Pharm · 2026 Apr · PMID 41834422 · Publisher ↗
Amorphous solid dispersions (ASDs) are one of the most effective formulation strategies for improving the release rate and bioavailability of poorly water-soluble drugs. However, the release rates of polyvinylpyrrolidone...
Amorphous solid dispersions (ASDs) are one of the most effective formulation strategies for improving the release rate and bioavailability of poorly water-soluble drugs. However, the release rates of polyvinylpyrrolidone vinyl acetate (PVPVA) based ASDs typically decrease dramatically once a certain drug loading (DL) is exceeded. The purpose of this study was to evaluate the impact of dissolution medium pH on the release behavior of basic drug-PVPVA ASDs for ASDs with different DLs. Loratadine (LRD) and ritonavir (RTV) were used as model basic drugs. The surface area normalized release rates of drug and polymer from the ASD were measured in over a range of solution pH conditions from 1.6 to 7.5. The evolving phase morphology of the hydrated ASD compact surface was observed using confocal fluorescence microscopy. To provide insight into the gel layer pH, a pH indicator was added to the ASD and the gel layer color was observed following immersion in media of different pH values. Surface area normalized release rate measurements revealed that ASDs with low DLs, where release was controlled by the polymer, showed rapid and pH-independent release. However, ASDs with higher DLs exhibited pH-dependent release. From the confocal fluorescence microscopy imaging, formation of a drug-rich barrier layer at the gel layer-solution interface was observed for higher DL ASDs. Visual imaging of the gel layer suggested formation of a pH-gradient for LRD-PVPVA ASDs but not for RTV-PVPVA ASDs. In conclusion, for weakly basic drugs with highly pH-dependent solubility, the medium pH is expected to impact the release rate of higher DL ASDs where release is controlled by the drug-rich layer formed following hydration. In contrast, for low DL ASDs where the polymer controls the release, pH is anticipated to have less impact on release. This study contributes additional understanding of the release mechanisms of PVPVA-based ASDs.
Synthesis and and Properties of Tc-Labeled Fibroblast Activation Protein Inhibitors.
Tang S, Yang Z, Nie J … +6 more , Wu T, Li H, Liu Y, Liu N, Chen Y, Zhou Z
Mol Pharm · 2026 Apr · PMID 41834401 · Publisher ↗
Fibroblast activation protein (FAP) is expressed in more than 90% of tumor-associated fibroblasts in epithelial cancers, providing an excellent target for nuclear medicine diagnostics and therapy. Given the high cost of...
Fibroblast activation protein (FAP) is expressed in more than 90% of tumor-associated fibroblasts in epithelial cancers, providing an excellent target for nuclear medicine diagnostics and therapy. Given the high cost of PET-CT, developing SPECT probes targeting FAP is necessary. A novel FAP inhibitor derived from UAMC1110 was synthesized and conjugated to DOTA via PEG chains. This resulted in a series of inhibitors with good targeting specificity, tumor uptake, and pharmacokinetics. In this study, UAMC1110 derivatives were used as FAP-targeting pharmacophores; PEG chains of varying lengths were employed for pharmacokinetic modification, and HYNIC was used as a bifunctional chelator. The derivatives were labeled with Tc using different coligand combinations to explore how PEG chain length and coligand composition affect the and properties of Tc-labeled FAPI. Four UAMC1110 derivatives (P4, P6, P8, P12) with different PEG chain lengths were synthesized, and a series of hydrophilic Tc complexes were prepared. Stability and specificity studies demonstrated that these complexes exhibited good and stability and FAP-targeting specificity. In micro-SPECT imaging, these tracers showed rapid tumor accumulation, with Tc-TE-P12 and Tc-TT-P12 showing promising tumor uptake, low nontarget organ uptake, and high T/NT ratios, indicating potential as SPECT probes.
A Novel Immune-Modulating Nanodrug Enhances Liver-Targeted mRNA Delivery.
Luo D, Guo D, Luo M … +3 more , Li Y, Luo J, Lu H
Mol Pharm · 2026 Apr · PMID 41826253 · Full text
Liver-specific delivery of mRNAs encoding key regulatory genes via lipid nanoparticles (LNPs) is promising to restore liver homeostasis and resume liver functions in inflammatory liver diseases. However, inflammation dow...
Liver-specific delivery of mRNAs encoding key regulatory genes via lipid nanoparticles (LNPs) is promising to restore liver homeostasis and resume liver functions in inflammatory liver diseases. However, inflammation downregulates the global mRNA expression in general as a self-defensive mechanism, e.g., to block viral protein expression, which also reduces the efficiency of therapeutic mRNA delivered to hepatocytes. In addition, ionizable LNPs are immunogenic, which exacerbates inflammation. In this project, we applied a novel immune-modulating telodendrimer (TD) nanodrug (ND) to inhibit inflammation and improve specific mRNA delivery. We tested TD ND in both mouse and human immune cells, liver cell lines, and primary human hepatocytes (PHH) to inhibit endotoxin-induced inflammation. TD ND was able to inhibit both endogenous and LPS-induced inflammation in liver cells, which improved cell proliferation in culture and also significantly enhanced the efficiency of mRNA/LNP delivery both in human monocytes and PHH. Finally, we demonstrated that TD ND is superior to steroid drugs in inhibiting endotoxin-induced inflammation and sustaining liver function in mice, thereby rebooting the efficacy of liver-targeted LNP mRNA delivery and expression. These findings highlight the potential of TD ND as an effective adjuvant therapy to enhance mRNA delivery for inflammatory disease treatments.
Development and Preliminary Evaluations of a Novel F-Labeled Tracer for Detection of BRAF Mutant Status in Animal Models of Melanoma.
Guo Y, Wang Z, He Y … +5 more , Zhuang W, Qian J, Li Z, Shen C, Han J
Mol Pharm · 2026 Apr · PMID 41826245 · Publisher ↗
The BRAF mutation is a well-established oncogenic driver, and several oral inhibitors have achieved clinical success. However, radiolabeled tracers for the non-invasive imaging of this mutation remain limited. -(2-Chloro...
The BRAF mutation is a well-established oncogenic driver, and several oral inhibitors have achieved clinical success. However, radiolabeled tracers for the non-invasive imaging of this mutation remain limited. -(2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluorophenyl)propane-1-sulfonamide () is a novel oral inhibitor targeting BRAF with high inhibitory potency. Here, we report the synthesis of its precursor and the radiosynthesis of its F-labeled version, [F]LP-1 ([F]). The tracer exhibited nanomolar cellular binding affinity for BRAF-positive A375 melanoma cells (IC = 31.6 nM) and demonstrated selective uptake in tumor models with distinct BRAF mutation status. Blocking studies with the BRAF-selective inhibitor vemurafenib further confirmed its specific binding. Our findings highlight the potential of [F]LP-1 as a lead structure for the development of PET molecular tracers capable of detecting BRAF mutation status in vivo and support the development of next-generation radiotracers based on the scaffold.
Drug-Polymer Interactions and Molecular Miscibility in Amorphous Solid Dispersions: The Duality of Hydrogen Bond-Donor Groups.
Cools L, Derveaux E, Reniers F … +3 more , Dehaen W, Adriaensens P, Van den Mooter G
Mol Pharm · 2026 Apr · PMID 41818776 · Publisher ↗
Hydrogen bonds (H-bonds) can have a critical impact on the stability and drug release characteristics of amorphous solid dispersions (ASDs). Based on the structure of the ASD components, it remains however difficult to p...
Hydrogen bonds (H-bonds) can have a critical impact on the stability and drug release characteristics of amorphous solid dispersions (ASDs). Based on the structure of the ASD components, it remains however difficult to predict the strength and influence of these H-bond interactions on the phase behavior of the ASDs. Therefore, this study assessed the miscibility and H-bond interactions of diflunisal (DIF) and four structural analogues in ASDs with Eudragit S100 (ES100) as a model polymer that contains H-bond-donor as well as H-bond-acceptor groups. The highest possible drug loading in the ASDs was smaller for native DIF and the DIF methyl ester derivative (25 wt %) as compared to the methoxy DIF and dimethyl DIF derivatives (35 wt %). Solid-state NMR relaxometry was employed to evaluate the molecular miscibility of the ASD components. In addition, C-CPMAS ssNMR spectroscopy was performed on spray-dried ASDs to evaluate the H-bond interactions between the API and polymer. It was observed that the ES100 carboxyl group interacted as an H-bond donor with the C═O carbonyl group of the DIF derivatives, leading to homogeneous mixing for all ASDs. However, it was also shown that competition between intermolecular H-bonds and intramolecular H-bonds, present as stable six-membered rings, is possible. The competition limited the availability of the API acceptor C═O group and explains the lower maximum drug loadings for native DIF and the DIF methyl ester. A comparison was also made between these ES100-based ASDs and PVPVA-based ASDs studied in a previous study. It became clear that for ASDs with a polymer that only carries H-bond-acceptor groups (like PVPVA), the availability of API H-bond-donor groups is crucial for the formation of H-bonds between the drug and the polymer. Contrastingly, for ASDs formed with a polymer that carries both H-bond-donor and -acceptor groups (like ES100), it seems to be the availability of API H-bond-acceptor groups that is crucial for intermolecular H-bond formation and drug-polymer miscibility.
An Estrogen Receptor α-Targeted NIR-II Probe for Breast Tumor Imaging and Image-Guided Surgery.
Xu D, Wang L, Tang Z … +4 more , Xu M, Huang M, Jiang T, Tang C
Mol Pharm · 2026 Apr · PMID 41818444 · Publisher ↗
Breast cancer (BC) is a serious health threat to women worldwide and is on the steady rise in morbidity and mortality, of which estrogen receptor α (ERα)-positive cases account for nearly 70%. ERα is highly expressed in...
Breast cancer (BC) is a serious health threat to women worldwide and is on the steady rise in morbidity and mortality, of which estrogen receptor α (ERα)-positive cases account for nearly 70%. ERα is highly expressed in ERα-positive (ERα+) BC, and it is involved in tumorigenesis and metastasis, making it a compelling target for BC theranostics. Herein, we developed and evaluated an ERα-targeted fluorescent probe (IRDye800-4OHT) by conjugating ERα targeting ligand 4-hydroxytamoxifen with near-infrared fluorescence dye IRDye800CW for ERα+ BC detection via imaging ERα. The probe demonstrated a second near-infrared (NIR-II) imaging capability (λ = 950 nm), high binding affinity (RBA = 2.3) toward ERα, and excellent biocompatibility. cellular uptake further confirmed that IRDye800-4OHT could specifically target the ERα. Moreover, NIR-II imaging clearly revealed that IRDye800-4OHT enabled real-time imaging of ERα, specifically illuminated tumor tissue, and successfully guided breast tumor resection. Therefore, we postulate that IRDye800-4OHT can serve as a valuable tool for the precise diagnosis and surgical excision of ERα-positive tumors.
Endoplasmic Reticulum Mediates Prolonged Tumor Retention of FAPI Radioconjugates and Enhanced Radiotherapeutic Efficacy.
Wang G, Zhang F, Liu D … +7 more , Liu X, Hu X, Cai J, Xu Y, Wang P, Song J, Chen J
Mol Pharm · 2026 Apr · PMID 41813582 · Publisher ↗
Radiolabeled fibroblast activation protein inhibitors (FAPIs) face a critical challenge in radionuclide therapy due to their short tumor retention. While existing strategies to prolong retention are often limited in clin...
Radiolabeled fibroblast activation protein inhibitors (FAPIs) face a critical challenge in radionuclide therapy due to their short tumor retention. While existing strategies to prolong retention are often limited in clinical translation, we hypothesized that targeting the endoplasmic reticulum (ER) could provide a solution. We therefore designed a novel agent for sequential targeting, first to fibroblast activation protein (FAP) and then to the ER, aiming to enhance both tumor retention and radiotherapy efficacy. The sequential targeting agent, FAPI-PEG-K-PTSA, was synthesized by conjugating a PTSA ER-targeting moiety to the FAPI-46 core via a PEG-K linker. The compound was radiolabeled with Lu and synthesized with high radiochemical yield (>95%). Cellular assays demonstrated specific binding to FAP and successful ER localization. This sequential-targeting capability resulted in superior performance, demonstrating a 3-5-fold higher tumor uptake and a retention time exceeding 72 h compared to FAPI-46. Consequently, Lu-FAPI-PEG-K-PTSA achieved remarkable tumor suppression. The developed compound pioneers a three-level active targeting mechanism. It utilizes FAP for primary tumor enrichment, followed by ER-mediated internalization and specific organelle localization. This strategy effectively circumvents rapid efflux, dramatically prolongs intratumoral retention, and significantly enhances radiotherapeutic outcomes. Our findings provide crucial insights into organelle-targeted radionuclide therapy (TRT) and highlight its strong translational potential.
NMR Crystallography at 1 GHz: Insight into a Rich World of Binary Forms of Meloxicam.
Nowak P, Jeziorna A, Oszajca M … +3 more , Paluch P, Senthurpandi D, Dudek MK
Mol Pharm · 2026 Apr · PMID 41812025 · Full text
NMR crystallography, which is based on both diffraction- and solid-state NMR-based observables, can deliver a precise description of the crystal structure of powdered samples of pharmaceuticals. On the other hand, it is...
NMR crystallography, which is based on both diffraction- and solid-state NMR-based observables, can deliver a precise description of the crystal structure of powdered samples of pharmaceuticals. On the other hand, it is by no means a straightforward technique, not least because of the overcrowding of solid-state NMR spectra and difficulties in reliably assigning all resonances, even when advanced 2D techniques are applied. In this work, we showcase the advantages of using very high magnetic field spectrometers in NMR crystallography to solve the structural puzzles posed by four new binary forms of meloxicam (MLX), an anti-inflammatory drug. In particular, we revealed a hidden disorder in the scXRD-determined crystal structure of one of the polymorphic forms of MLX with pyrazole (POL). In this instance, we discovered, through the use of N solid-state NMR data, that there is an exchange between two possible tautomeric forms, and by calculating the weighted average of N shielding constants, we determined the occupancy of the disordered sites to be 70:30. For the next two binaries, with pyrazine (MLX:PNA) and imidazole in a 1:2 ratio (MLX:IMI 1:2), we solved their crystal structures from powder XRD data and determined the protonation state mainly through the use of quadrupolar product () of N, derived from H-N T-HMQC experiments recorded at two different magnetic field strengths. The signal assignment was done with a set of H-H DQ-SQ Back-to-Back, H-C and H-N HETCOR experiments. For MLX:PNA, we found a very unusual tautomer of MLX inside this crystal, the one which has not been found in any other MLX forms discovered so far. For MLX:IMI 1:2, we established it to be an ionic cocrystal. Finally, for the second MLX binary with imidazole in 1:1 ratio (MLX:IMI 1:1), we used solid-state NMR data to first unambiguously prove that this is a salt and that it comprises one of the two possible tautomers of the MLX anion. This enabled reliable crystal structure prediction calculations for this form, leading to its final crystal structure through Rietveld refinement against the experimental powder XRD pattern.
Synthesis and Evaluation of Cu-Labeled Small-Size Antibody Fragments for Immuno-PET Imaging of Thyroid-Stimulating Hormone Receptor in Thyroid Cancer.
Fu W, Parent EE, Knight JA … +3 more , Liu B, Copland JA, Cai H
Mol Pharm · 2026 Apr · PMID 41811708 · Publisher ↗
The thyroid-stimulating hormone receptor (TSHR) is a promising molecular target for thyroid cancer imaging and therapy. Our previous work has demonstrated that PET imaging with the radiolabeled anti-TSHR human monoclonal...
The thyroid-stimulating hormone receptor (TSHR) is a promising molecular target for thyroid cancer imaging and therapy. Our previous work has demonstrated that PET imaging with the radiolabeled anti-TSHR human monoclonal antibody K1-70 enables assessment of TSHR expression in thyroid cancer. However, full-length antibody-based radiopharmaceuticals exhibit delayed systemic clearance and increased off-target radiation burden, resulting in suboptimal pharmacokinetics for immuno-PET imaging. Herein, we report the synthesis and evaluation of Cu-labeled anti-TSHR K1-70 antibody fragment antigen-binding (Fab) and single-chain variable fragment (scFv), for immuno-PET imaging of TSHR in thyroid cancer mouse models. These smaller formats enabled rapid tumor targeting and favorable pharmacokinetics with high tumor-to-background contrast. Two radiotracers, named Cu-NOTA-TSHR-Fab and Cu-NOTA-TSHR-scFv, were prepared by conjugating TSHR-Fab or TSHR-scFv to -SCN-Bn-NOTA, followed by radiolabeling with Cu, achieving high radiochemical purity (>99%). The specificity and binding affinity of each radiotracer were determined by cellular uptake and binding assays using TSHR-positive THJ529T cells and corresponding wild-type controls. Both radiotracers exhibited specific, nanomolar binding affinity to TSHR-positive cells. Immuno-PET imaging, ex vivo biodistribution, and blocking studies of each radiotracer were performed in NSG mice bearing subcutaneous TSHR-positive THJ529T tumor xenografts at various time points (1, 4, 18, and 24 h postinjection). In comparative in vivo evaluations, Cu-NOTA-TSHR-Fab showed rapid and superior TSHR-specific tumor accumulation compared with Cu-NOTA-TSHR-scFv, evident as early as 1 h postinjection. Both radiotracers demonstrated rapid pharmacokinetics and low background signal, but with high renal uptake. This head-to-head comparison of small-size antibody fragment-based radiotracers for TSHR-targeted immuno-PET imaging identifies Cu-NOTA-TSHR-Fab as a promising immuno-PET radiotracer for in vivo detection of TSHR expression in thyroid cancer and for guiding TSHR-targeted therapy.
Paeoniflorin-Copper-Coordinated Nanoparticles Targeting Dual Organelles Induce Lung Cancer Apoptosis.
Lin J, Huang P, Wang Y … +10 more , Wu J, Jian Y, Zhu L, Wen H, Gao W, Miao Y, Wang H, Yu X, Liu C, Zhou Y
Mol Pharm · 2026 Apr · PMID 41810719 · Publisher ↗
The intrinsic resistance of tumor cells to apoptosis frequently results in chemoresistance and therapeutic failure in clinical settings. The main active ingredients of traditional Chinese medicine, in combination with ch...
The intrinsic resistance of tumor cells to apoptosis frequently results in chemoresistance and therapeutic failure in clinical settings. The main active ingredients of traditional Chinese medicine, in combination with chemotherapy drugs, have become one of the effective treatment methods to overcome this kind of drug resistance by targeting double subcellular organelles to promote apoptosis. In this study, we developed a Cu-coordinated paeoniflorin (PF)/doxorubicin (DOX) biocomplex, referred to as PCD, with the aim of overcoming cellular apoptosis resistance for combinational lung cancer therapy. PCD demonstrates remarkable water solubility and superior in vivo biocompatibility. Owing to the coordination effect, the self-assembled PCD exhibits a nanoscale particle size, a narrow and homogeneous grain distribution, as well as exceptional dispersion stability. Furthermore, PCD has the potential to disassemble under conditions of high glutathione levels and low pH, thereby facilitating effective drug release. PF-mediated endoplasmic reticulum stress (ERS) can downregulate the expression of FDX1 and DLAT proteins. Ca overload induced by ERS disrupts mitochondrial matrix ion balance, accelerates water efflux, and ultimately leads to mitochondrial volume reduction and a decrease in mitochondrial membrane potential. Ultimately, this process synergizes with DOX-induced reactive oxygen species production to enhance apoptosis in lung cancer cells. PCD exhibits significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity via enhanced induction of lung cancer apoptosis. This study may provide a promising avenue for advancing self-delivery nanomedicine to overcome apoptosis resistance in lung cancer therapy.
Photoinduced Trp and Tyr Side Chain Cleavage in IgG4-Fc: Impact on Physicochemical Stability and Receptor Binding and Effect of - vs -Glycosylation.
Kang H, Larson NR, Wei Y … +3 more , Middaugh RC, Tolbert T, Schöneich C
Mol Pharm · 2026 Apr · PMID 41804791 · Publisher ↗
In previous studies, we discovered that the exposure of IgG4-Fc and IgG1 to UV light resulted in the side chain cleavage of specific Tyr and Trp residues, converting these amino acids into a series of products, including...
In previous studies, we discovered that the exposure of IgG4-Fc and IgG1 to UV light resulted in the side chain cleavage of specific Tyr and Trp residues, converting these amino acids into a series of products, including Gly [Haywood, J. 2013, 10(3), 1146-1150; Kang, H. 2019, 16, 258-272]. In order to evaluate the physicochemical consequences of such photochemical transformations, we prepared a series of IgG4-Fc mutants, in which Trp and Tyr residues were replaced by Gly, i.e., Y300G, Y373G, Y436G, and W381G, for biophysical studies. As the expression yields of W381G IgG4-Fc were low, we also prepared W381A to achieve higher yields required for some of the studies. Among these mutants, Y373G displayed significantly lower melting temperatures compared to wild-type IgG4-Fc, as analyzed by differential scanning calorimetry and fluorescence spectroscopy, indicating a decrease in thermal stability of both the C and C domains. In contrast, W381A showed no thermal transitions, indicating a significant loss of overall thermal stability. As for binding affinity to FcγRIIIA, Y300G and Y436G displayed ca. 10-fold reduction compared to wild-type IgG4-Fc. Interestingly, W381A and W381G IgG4-Fc did not only contain -linked glycans but also high levels of -mannose (>60%) at Ser. Therefore, we prepared additional mutants, S375A and S375A/W381A IgG4-Fc, to evaluate the effect of - vs -glycosylation on thermal stability and the susceptibility of Tyr and Trp residues to undergo photodegradation. The removal of -glycans specifically destabilized the C domain of IgG4-Fc. The removal of -glycans did not affect the overall thermal stability of S375A IgG4-Fc, and S371A/W381A shows no thermal transitions, suggesting that the W381A mutation alone is sufficient to perturb the protein structure irrespective of -glycosylation. As for photostability, we observed a 2.6-13.5 fold reduction of yields of Tyr side chain fragmentation products for W381A IgG4-Fc, potentially due to a lower probability for electron transfer between Tyr and oxidized Trp, and photodegradation of alternative Trp residues in W381A IgG4-Fc.
Acoustic Monitoring of Lubrication and Compaction Effects on Tablet Performance Using Broadband Acoustic Resonance Dissolution Spectroscopy.
Peddapatla RVG, Ahmed MR, Sousa-Gallagher MJ … +5 more , Kumar R, McSweeney S, Krüse J, Fitzpatrick D, Crean AM
Mol Pharm · 2026 Apr · PMID 41797342 · Publisher ↗
Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is a novel analytical technology based on the change in the acoustic phenomena observed when a material is added into a solvent. Addition of a solid material...
Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) is a novel analytical technology based on the change in the acoustic phenomena observed when a material is added into a solvent. Addition of a solid material results in the introduction of air (gas) into the solvent, which changes the compressibility of the liquid system and reduces the velocity of the sound (resonance) contained therein. In this study, the behavior of tablets in water was monitored using the BARDS technique. Tablets investigated contained 10% metoclopramide HCl (model water-soluble drug) and a microcrystalline cellulose filler and were formulated with and without a lubricant (0.5% magnesium stearate) at a range of tensile strength and porosity properties. The BARDS frequency-time profile for lubricated tablets showed an extended profile, indicating a slower wetting and prolonged displacement of gas compared to those of tablets without a lubricant. BARDS frequency-time profiles were transformed into gas volume-time profiles from which the areas under the total gas volume and volume curve (AUVC) were calculated. Lubricated tablets displayed a greater AUVC compared with unlubricated tablets. A decrease in the AUVC was observed for tablets up to the yield pressure of the formulation. For unlubricated tablets compacted at lower pressures, the gas elimination phase displayed first-order rate elimination kinetics. However, for lubricated tablets and unlubricated tablets compacted at higher pressures, two phases of gas elimination were observed: an initial fast elimination phase followed by a slower terminal elimination phase. This preliminary analysis of BARDS profiles collected demonstrates the capability of BARDS to capture differences between tablet formulations manufactured under different conditions.
Molecular and Antiangiogenic Effects of Paclitaxel-Loaded Nanoparticles: Influence of the Nanocarrier Type.
Passos JS, de Melo GB, Salata GC … +3 more , Machado-Neto JA, Panitch A, Lopes LB
Mol Pharm · 2026 Apr · PMID 41790974 · Full text
Nanostructured lipid carriers (NLCs) and lipid-polymeric hybrid nanoparticles (H-NPs) were developed for the local administration of paclitaxel (PTX) and breast cancer therapy. Here, we investigated how nanoparticle type...
Nanostructured lipid carriers (NLCs) and lipid-polymeric hybrid nanoparticles (H-NPs) were developed for the local administration of paclitaxel (PTX) and breast cancer therapy. Here, we investigated how nanoparticle type and composition influence the molecular effects and in vivo antiangiogenic activity of PTX. Elevated BAX expression and PARP-1 cleavage in MCF-7 and MDA-MB-231 breast cancer cells treated with nanoencapsulated PTX indicate that apoptosis is the primary mechanism of cell death, regardless of the nanocarrier type. However, distinct molecular effects were observed for other markers. Both unloaded nanocarriers increased α-tubulin acetylation in MCF-7 cells, indicating an intrinsic ability of the carriers to modulate cytoskeletal organization. Upon PTX loading, these effects became carrier-dependent: NLC-PTX induced higher α-tubulin acetylation than H-NP-PTX compared to the PTX solution. Moreover, in MCF-7 cells, NLC-PTX, but not H-NP-PTX, markedly enhanced drug-induced DNA damage, increasing γH2AX expression by 13.4-fold compared to PTX as a solution. These findings suggest that the nanocarriers not only act as delivery systems but may also confer additional biological effects that may contribute to PTX cytotoxicity. In the chicken chorioallantoic membrane model, nanoencapsulation reduced PTX-induced irritation from moderately irritant (irritation score 6) to nonirritant while preserving its antiangiogenic activity, achieving a 6.1-7.8-fold inhibition of vessel growth at subcytotoxic doses. Collectively, these results highlight nanoencapsulation as a promising strategy to potentiate PTX activity while improving safety for local breast cancer therapy. The distinct molecular responses of lipid and hybrid systems demonstrate that nanocarrier composition and structure modulate biological outcomes, underscoring the importance of rational nanocarrier design to overcome current therapeutic challenges.
Gastrointestinal pH Gradient-Induced Phase Transition of Crizotinib: The Significance of pH-Dependent Ionization (Protonation) on Liquid-Liquid Phase Separation of a Weakly Basic Drug.
Chen Z, Chen S, Lv H … +9 more , Chao R, Jiang Y, Li S, Li A, Liu B, Hu Y, Yang Y, Cui L, Lu M
Mol Pharm · 2026 Apr · PMID 41782551 · Publisher ↗
Although weakly basic drugs with specific properties (e.g., dose number >1-10, p 5-9) are known to form supersaturated solutions and exhibit complex phase behavior in the gastrointestinal tract, key aspects of this proce...
Although weakly basic drugs with specific properties (e.g., dose number >1-10, p 5-9) are known to form supersaturated solutions and exhibit complex phase behavior in the gastrointestinal tract, key aspects of this process (namely, the physical stability of nanodroplets and the charge site) remain poorly characterized. This work employs the dual-p anticancer drug crizotinib (CZT; p 5.6, 9.4) as a model drug to establish a systematic methodological framework for investigating the complex behaviors of weakly basic drugs induced by pH shift. The results revealed that upon pH shift from 1.0 to above 5.4, a 1 mg/mL CZT solution underwent liquid-liquid phase separation with nanodroplets forming immediately. H nuclear magnetic resonance (NMR), C solid-state NMR, and synchrotron single-crystal X-ray diffraction (SCXRD) data together confirmed that this phase transition is attributed to the deprotonation from a dicationic species (with both piperidinium and pyridinium protonated) to a monocationic species (with only the piperidinium protonated) in both the drug-rich and drug-lean phases. Ultraviolet-visible spectroscopy, dynamic light scattering, confocal laser scanning microscopy, and polarized optical microscopy together revealed that the resulting additive-free CZT droplets are unstable at pH 6.5 with a low zeta potential of 5.1 mV, and sedimented into a bulk gel within minutes. This sedimentation significantly reduces the surface area of the colloidal particles (drug reservoir) and, consequently, slows the dissolution of CZT from the drug-rich phase─but interestingly, it has little effect on transmembrane flux through a cellulose membrane, suggesting that for CZT, transport across the membrane, not interphase diffusion, is the rate-limiting step. By establishing the methodology, which integrates NMR spectroscopy and X-ray crystallography to precisely locate the charge site of drug in both drug-rich phase (droplets or gel-like precipitate) and drug-lean phase (bulk solution), this work bridges the critical gap between macroscopic phase behavior and molecular-level understanding. These insights provide a mechanistic foundation for the rational design of oral formulations for weakly basic drugs.
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