Molecular Pharmaceutics最新文献

{"title":"Macropinocytosis and Fast Endophilin-Mediated Endocytosis Mediate Absorption of Garlic Chive-Derived Vesicle-like Nanoparticles in Human Intestinal Epithelial Cells.","authors":"Phuong Linh Nguyen, Baolong Liu, Shuying Zhang, Jingjie Hao, Jiujiu Yu","doi":"10.1021/acs.molpharmaceut.5c00190","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00190","url":null,"abstract":"<p><p>Dietary extracellular vesicles (EVs) or vesicle-like nanoparticles (VLNs) have been shown to exert beneficial functions in a wide range of diseases such as cancer, colitis, and metabolic diseases. They have also been used as natural carriers for medications. Despite the promising translational potential of dietary EVs or VLNs, the molecular mechanisms of their absorption in the gastrointestinal tract are not well understood. In this study, we investigated the absorption mechanisms of garlic chive-derived VLNs (GC-VLNs) using C57BL/6J mice and a human intestinal epithelial cell line, Caco-2 cells. We found that orally administered GC-VLNs crossed the epithelial layer of the small intestine and entered the underlying lamina propria. GC-VLNs were taken up and transported across the fully differentiated Caco-2 epithelial monolayer. Proteins and lipids, but not RNAs, in GC-VLNs mediated their uptake by Caco-2 cells. Chemical inhibitor treatments demonstrated that macropinocytosis and fast endophilin-mediated endocytosis (FEME) played key roles in the internalization of GC-VLNs. On the other hand, clathrin-coated pit-mediated endocytosis and clathrin-independent carrier/glycosylphosphatidylinositol-anchored protein-enriched early endocytic compartment endocytosis did not contribute to GC-VLN uptake. Activation of macropinocytosis and FEME using their specific activators promoted the internalization of GC-VLNs. In addition, genetic manipulation of key molecules in macropinocytosis and FEME confirmed the important engagement of these two specific endocytic pathways in GC-VLN absorption by human intestinal epithelial cells. Our study has provided proof-of-principle evidence to advance our understanding of the absorption mechanism of GC-VLNs, which would be the key to further manipulation and engineering of these nanoparticles to improve their delivery efficiency as therapeutic modalities or drug carriers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"¹⁷⁷Lu-Anti-CD25 Antibody for Interleukin-2 Receptor-α-Targeted Radioimmunotherapy of SUDHL1 Lymphomas in Mice.","authors":"Choong Mo Kang, Jung Lim Kim, Hye Jin Jung, Kyung-Ho Jung, Mina Kim, Giro Kim, Hyunjong Lee, Kyung-Han Lee","doi":"10.1021/acs.molpharmaceut.4c01410","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01410","url":null,"abstract":"<p><p>Antibodies (Abs) conjugated with particle-emitting radioisotopes are used for cancer therapy, and the CD25 receptor (IL-2Rα) is a promising target for lymphomas. We functionalized an anti-CD25 Ab with TCO-PEG₃-maleimide, specifically on sulfhydryl moieties, at 1.89 molecules per Ab. Radiosynthesis was achieved by efficiently prelabeling DOTA-PEG₄-tetrazine with ¹⁷⁷Lu at a high temperature and then linking it to the TCO-conjugated Abs via facile click chemistry under mild conditions. The [¹⁷⁷Lu]Lu-DOTA-PEG₄-Tz-TCO-PEG₃-anti-CD25 Ab (¹⁷⁷Lu-CD25 Ab) had a radiochemical purity of >99%, a specific activity of 707.9 ± 271.5 MBq/mg, an immunoreactive fraction of 77.6%, and high radiolabel stability in serum for up to 7 days. CD25-positive SUDHL1 human T lymphoma cells showed ¹⁷⁷Lu-CD25 Ab uptake that was completely blocked by pretreatment with unlabeled Ab. The ¹⁷⁷Lu-CD25 Ab dose-dependently suppressed SUDHL1 cell survival <i>in vitro</i>. In mice, ¹⁷⁷Lu-CD25 Ab uptake at 5 days was high in the SUDHL1 tumors (7.1 ± 1.6%ID/g), modest in the liver, kidneys, and spleen, and low in the blood, lungs, and bones. CD25-specific targeting was confirmed by 66.7% suppression of tumor uptake by pretreatment with unlabeled CD25 Ab. Treatment with 18.5 MBq of ¹⁷⁷Lu-CD25 Ab shrank the xenograft tumors, and they remained undetectable until study termination on day 61. In contrast, the tumors in all control and CD25 Ab-treated mice grew to exceed the end point criterion of 2,000 mm³. The standardized tumor growth rate and 19-day tumor volume were completely suppressed in the ¹⁷⁷Lu-CD25 Ab group (109.9 ± 73.5 and 132.6 ± 111.5 mm³), compared with the control (1053.9 ± 151.1 and 1804.5 ± 283.1 mm³) and CD25 Ab groups (1049.7 ± 212.2 and 1443.8 ± 839.4 mm³; all <i>p</i> < 0.001). A Kaplan-Meier survival analysis showed that ¹⁷⁷Lu-CD25 Ab-treated mice survived significantly longer than mice in the control and CD25 Ab groups. Tumors in a separate set of mice that were treated with ¹⁷⁷Lu-CD25 Ab displayed increased PARP1 cleavage fragments, a signature of apoptosis. Toxicity studies showed that white blood cell, red blood cell, and platelet counts in the ¹⁷⁷Lu-CD25 Ab group decreased from days 3-14, reaching a nadir on days 17-21 and returning to the normal range by days 24-31. Liver and renal function tests on day 28 did not differ from those of untreated mice. Thus, the ¹⁷⁷Lu-CD25 Ab prepared as described here could be useful for radioimmunotherapy of CD25-positive lymphomas.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure, Self-Association, and Aggregation Properties of a Long-Acting Amylin Receptor Agonist.","authors":"Christian Poulsen, Mathias Norrman, Jens Kaalby Thomsen, Per-Olof Wahlund","doi":"10.1021/acs.molpharmaceut.5c00161","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00161","url":null,"abstract":"<p><p>Pharmacokinetic (PK) properties of therapeutic peptides can be extended through covalent conjugation to albumin-binding fatty acids. The present study examines the effects of fatty acid conjugation and vehicle composition on structure, self-association pattern, and aggregation propensity of an amylin analogue. Small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and circular dichroism (CD) were applied to elucidate structural features and self-association patterns, whereas the propensity toward formation of amyloid fibrils under extreme stressful conditions was assessed based on thioflavin T fluorescence. Fatty acid conjugation of the unstructured amylin analogue induced a transition from a flexible and disordered state to a helix-enriched globular core-shell self-associate consistent with a size average of five monomers (pentamer). These structural changes did not increase the propensity toward formation of amyloid fibrils, suggesting that the self-associated species are not on the pathway to amyloid fibril formation. Increasing concentration of the fatty acid-conjugated amylin analogue 1) induced self-association to an average size corresponding to a pentamer around 30 μM, 2) increased repulsion between self-associated species, and 3) increased α-helix content which leveled off around 0.25 mM. Only at significantly higher peptide concentrations (2.2 mM), amyloid fibril formation was observed following 24 h continuous exposure to extreme mechanical stress conditions. The extent of electrostatic repulsion between the self-associated species was reduced by increasing NaCl concentration (up to 50 mM) or by raising pH (from pH 3 to pH 5). However, under conditions with the least electrostatic repulsion, 4 h of continuous exposure to extreme mechanical stress was needed to induce formation of amyloid fibrils of this inherently stable molecule.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"In Vivo Evaluation of Reduction-Responsive Alendronate-Hyaluronan-Curcumin Polymer-Drug Conjugates for Targeted Therapy of Bone Metastatic Breast Cancer\".","authors":"Kaili Wang, Chunjing Guo, Xue Dong, Yueming Yu, Bingjie Wang, Wanhui Liu, Daquan Chen","doi":"10.1021/acs.molpharmaceut.5c00583","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00583","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical ImmunoPET Imaging of Thyroid-Stimulating Hormone Receptor Expression in Thyroid Cancer using [⁶⁴Cu]Cu-NOTA-TSHR-Ab.","authors":"Wenhui Fu, Ephraim E Parent, Justyna J Gleba, Joshua A Knight, Otto Muzik, John A Copland, Hancheng Cai","doi":"10.1021/acs.molpharmaceut.5c00325","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00325","url":null,"abstract":"<p><p>Advanced thyroid cancers are aggressive and often refractory to the current standard of care. The thyroid-stimulating hormone receptor (TSHR) is highly expressed in thyroid cancers and rarely expressed outside the thyroid, making it a viable target for developing radiotheranostics for imaging and therapy of advanced thyroid cancer. This study reports the radiosynthesis and preclinical evaluation of a ⁶⁴Cu-labeled human antibody for positron emission tomography (PET) imaging of TSHR expression in advanced thyroid cancer mouse models. Human anti-TSHR recombinant antibody K1-70 (TSHR-Ab) was labeled with copper-64, yielding [⁶⁴Cu]Cu-NOTA-TSHR-Ab with a radiochemical yield of 46.89 ± 3.74%, radiochemical purity of 98.77 ± 0.89%, and specific activity >212 GBq/μmol (<i>n</i> = 5). <i>In vitro</i> studies on TSHR-positive (THJ529T<i>^TSHR+</i>) and wild-type (THJ529T<i>^WT</i>) cells demonstrated the radiotracer's high specificity and nanomolar binding affinity for THJ529T<i>^TSHR+</i> cells, with a dissociation constant (<i>K</i>_d) of 4.74 nM and an inhibition constant (<i>K</i>_i) of 0.92 nM. ImmunoPET imaging in mice bearing dual-flank tumors (THJ529T<i>^WT</i> and THJ529T<i>^TSHR+</i>) at multiple time points (1, 2, 4, 18, 24, and 48 h) postinjection (p.i.) revealed rapid tumor targeting and high uptake in TSHR-positive thyroid tumors (SUV_max: 3.63 ± 0.42, 3.82 ± 0.44, and 4.09 ± 0.56 at 18, 24, and 48 h p.i., respectively). Co-injection studies with varying doses of unlabeled TSHR-Ab (0, 25, 50, 100 μg) demonstrated that the coinjection significantly reduced background signals, especially in the spleen, liver, and bone, with a dose of 25 μg effectively reducing off-target signals without affecting tumor uptake. Biodistribution and immunohistochemistry analyses supported these immunoPET imaging results. Furthermore, a comparison study with traditional [¹⁸F]FDG PET imaging showed that [⁶⁴Cu]Cu-NOTA-TSHR outperformed [¹⁸F]FDG in tumor detection. In conclusion, [⁶⁴Cu]Cu-NOTA-TSHR-Ab is a promising radiotracer for PET imaging of TSHR-positive advanced thyroid cancers, with the potential to guide and monitor TSHR-targeted therapies. Further clinical evaluation of [⁶⁴Cu]Cu-NOTA-TSHR-Ab could provide valuable insights for patient stratification and optimization of anti-TSHR treatments.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Novel Engineered Antibody Format for PSMA-Targeted Radionuclide Therapy.","authors":"Nicholas L Fletcher, Zachary H Houston, Peter G Chandler, Eddie Yan, Rob Holgate, Michael Wheatcroft, Kristofer J Thurecht","doi":"10.1021/acs.molpharmaceut.4c01193","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01193","url":null,"abstract":"<p><p>Prostate cancer remains a prevalent and lethal malignancy across the globe. Despite ongoing advances in therapeutic approaches, these remain ineffective, and new treatments are drastically needed. Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is a well-developed approach for prostate cancer treatment; however, current small molecule and antibody carriers for molecular radiotherapy each have drawbacks in their biodistribution and consequent side effects as highlighted in current clinical trials. To address this, we developed an approach to bioengineer the well clinically validated antibody carrier HuJ591 to yield an engineered, full-length antibody construct that achieves the beneficial fast pharmacokinetic profile of small molecule carriers alongside the enhanced tumor targeting and reduced renal toxicity of antibody carriers. We report here a rational design process to produce a novel humanized PSMA-targeting antibody designed for the delivery of radiation with abrogated FcRn recycling that aims to reduce blood circulation time and minimize systemic exposure. We demonstrate that these IgG-based constructs retain the favorable properties of HuJ591, such as inherent protein stability, expression in systems compatible with industrial manufacture, and comparable, highly specific PSMA-binding characteristics. We then radiolabeled constructs with the diagnostic radionuclide ⁶⁴Cu as a surrogate for therapeutic radionuclide payloads and undertook a proof-of-concept preclinical imaging study to probe the resulting <i>in vivo</i> behaviors. This demonstrated the success of this design strategy to yield the intended <i>in vivo</i> and radiopharmaceutical characteristics, with the resulting construct being rapidly cleared from circulation over 3 days. Together, this study demonstrates the rational design of a novel targeting antibody platform for PSMA-expressing tumors with reduced systemic exposure. Such a platform is extremely promising for future radiotherapeutic delivery approaches, whereby effective tumor treatment can be achieved while mitigating potential hematologic toxicity observed with standard antibody delivery approaches.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile Salts Trigger Deformability in Liposomal Vesicles through Edge-Activating Action.","authors":"Deepak Kumar, Sanjay Tiwari","doi":"10.1021/acs.molpharmaceut.5c00129","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00129","url":null,"abstract":"<p><p>This study investigates how bile-salt-based edge activators (EAs) (sodium cholate, NaC; sodium deoxycholate, NaDC; and sodium taurocholate, NaTC) can influence the mechanical properties and deformability of liposomal vesicles. We have elucidated their effect on liposomes composed of l-α-phosphatidylcholine (SPC). Liposomes were formulated using thin-film hydration and characterized using scattering, spectroscopic, and atomic force microscopic (AFM) techniques. Our data show that bile salts can alter the hydrodynamic diameter (<i>D</i>_h), morphology, and mechanical characteristics of vesicles. Their effect on the deformability and Young's modulus of vesicles followed the order NaDC ≥ NaC > NaTC. Breakthrough events were noticed in the vesicles at specific depth levels during force-deformation and force-indentation experiments. Based on the lack of hysteresis in the approach-retract curve, we inferred that the vesicles attained elasticity at lower concentrations of NaDC. Hydrophobic interactions between phospholipids and bile salts were verified from Fourier-transformed infrared spectrophotometer (FTIR) experiments. Increase in bile salt concentration was accompanied by a red shift of the acyl chain (asymmetric stretching CH₂ and symmetric stretching CH₃) and phosphate groups. This shift suggests enhanced hydrogen bonding between liposomes and bile salts. The affinity of bile salts for the SPC molecule correlated with their relative hydrophobicity. We conclude that NaDC can indeed improve the mechanical properties of liposomes and their ability to penetrate biological barriers.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Delivery of Metabolically Resilient Glutathione: <i>In Vivo</i> Pharmacokinetic, Permeation, and Efficacy Studies.","authors":"Kiran D Bhilare, Prakashkumar Dobariya, Antonio Lee, Wei Xie, Jiashu Xie, Joyce Meints, Robert Vince, Michael K Lee, Swati S More","doi":"10.1021/acs.molpharmaceut.5c00382","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00382","url":null,"abstract":"<p><p>Nose-to-brain delivery is an attractive drug delivery strategy for the treatment of Alzheimer's disease (AD) as it offers direct penetration of drugs into the brain by surpassing the blood-brain barrier, while reducing the potential systemic side effects. We developed a glutathione analogue, ψ-GSH, that resists catabolism and reduces AD-related behavioral and pathological abnormalities <i>in vivo</i>. Although ψ-GSH is effective via intraperitoneal administration, limited oral availability hinders the clinical translation of ψ-GSH. In this study, we sought to evaluate if intranasal ψ-GSH administration can provide neuroprotection in an acute mouse model of AD-related pathology. The pharmacokinetic analysis confirmed brain delivery of the compound to levels 4-fold higher than those achieved by an efficacious systemic dose of ψ-GSH. Unaffected stability in simulated nasal fluid and mucosa further displayed the feasibility of this delivery method. Repeated intranasal administration of ψ-GSH prevented cognitive impairment induced by the intracerebroventricular injection of Aβ_1-42 without significant adverse effects. Biochemical and immunohistochemical analyses displayed the beneficial effect of the treatment on oxidative stress and inflammatory markers by engaging GSH-dependent mechanisms, mirroring the pharmacological effects of intraperitoneal ψ-GSH. Additionally, <i>in vitro</i> directional transport studies using a human nasal epithelial cell line showed directional brain transport of ψ-GSH, without compromising the integrity of tight junction proteins. Collectively, our results demonstrate intranasal delivery as a safe and effective alternative for brain delivery of ψ-GSH at pharmacologically relevant concentrations for the treatment of neurological conditions. The study supports future formulation studies for intranasal ψ-GSH administration and its efficacy evaluation in transgenic AD mouse models for preclinical advancement.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH/GSH Dual-Responsive Janus-Type Au@H-MP@DOX MR Molecular Imaging Nanomotor for Combined Photothermal/Chemotherapeutic Treatment of Pancreatic Cancer.","authors":"Hao Zhang, Dan Xie, Meng Chen, Qiangqiang Yin, Guangyue Shi, Jialong He, Xiaoyang Yu, Qian Lu, Zhengji Wang, Jing Dong, Liguo Hao","doi":"10.1021/acs.molpharmaceut.5c00542","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00542","url":null,"abstract":"<p><p>Chemotherapy is a widely used cancer treatment modality, while the complex tumor microenvironment (TME) significantly impedes drug delivery and deep tissue penetration. An MR molecular imaging drug-loaded nanomotor has been developed to achieve deep tumor tissue penetration and imaging-guided drug delivery, enabling combined photothermal and chemotherapeutic treatment of pancreatic cancer. A Janus-type nanomotor (Au@H-MP NMs) was fabricated via magnetron sputtering for application in photothermal therapy. Doxorubicin (DOX) was loaded onto one hemisphere of the nanomotor, achieving combined photothermal and chemotherapeutic treatment. Additionally, the nanomotor exhibits dual responsiveness to pH and glutathione (GSH), facilitating the controlled release of DOX within deep tumor tissues. Studies confirmed the nanomotors excellent biosafety, strong photothermal conversion capability, and effective induction of apoptosis. Tumor tissue penetration was validated through in vitro migration and infiltration assays, while in vivo experiments demonstrated significant tumor suppression and enhanced drug accumulation. Moreover, MR imaging technology enables real-time monitoring of nanomotor dynamics. These findings suggest that the synthesized Janus-type MR molecular imaging nanomotor offers a promising strategy for multimodal treatment of pancreatic cancer with significant clinical potential.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cleavable PEGylation Enhances the Antitumor Efficacy of Small-Sized Antibody-Drug Conjugates.","authors":"Jiani Han, Keyuan Xu, Liu Yang, Yu Ding, Xi Wang, Dongming Yin, Jian Wang, Hongru Zhang, Zhangyong Hong","doi":"10.1021/acs.molpharmaceut.5c00090","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.5c00090","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics. However, traditional ADCs are often limited by poor tumor penetration due to their large molecular size. While the use of small-sized antibody fragments or analogues can improve tumor permeability, this approach typically results in an extremely shortened blood circulation half-life, which diminishes the therapeutic benefits and brings other metabolic challenges. In addition, the expression of target antigens on normal tissues often leads to unnecessary on-target/off-tumor toxicity. To address these issues, we developed a novel tumor site-specific cleavable PEGylation strategy for small-sized ADC design. The small ADC molecule Z_HER2-MMAE was site-specifically PEGylated at its N-terminus with a 20 kDa polyethylene glycol (PEG) chain and a uPA (LSGRSDNH) cleavage sequence was inserted between them (PEG_20k-U-Z_HER2-MMAE). Our results showed that PEG_20k-U-Z_HER2-MMAE achieves a similar half-life extension (6.4 and 6.0 h) compared to the conventional PEG_20k-Z_HER2-MMAE, both representing about a 26-fold improvement compared to Z_HER2-MMAE. Importantly, PEG_20k-U-Z_HER2-MMAE exhibited significantly higher drug accumulation at the tumor site, leading to the complete eradication of NCI-N87 and SK-OV-3 tumors at a dose of 5.5 mg/kg. Additionally, it demonstrated a maximum tolerated dose (MTD) exceeding 35 mg/kg, while the noncleavable PEG_20k-Z_HER2-MMAE could only slow tumor growth. In addition, compared to Z_HER2-MMAE, the in vitro cytotoxic activity of PEG_20k-Z_HER2-MMAE or PEG_20k-U-Z_HER2-MMAE was reduced by about 50 times, with the latter expected to reduce the on-target/off-tumor side effects due to the specific activation by uPA at tumor sites. These data fully demonstrate the effectiveness and high safety of our tumor-specific cleavable PEGylation strategy, supporting the potential in the development of next-generation ADCs for cancer therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}