Pub Date : 2024-10-22DOI: 10.1021/acs.molpharmaceut.4c00941
Barbara Jachimska, Magdalena Goncerz, Paweł Wolski, Callum Meldrum, Łukasz Lustyk, Tomasz Panczyk
The work presents correlations between the physicochemical properties of the carrier and the active substance and optimization of the conditions for creating an active system based on PAMAM dendrimers and doxorubicin. The study monitored the influence of the ionized form of the doxorubicin molecule on the efficiency of complex formation. The deprotonated form of doxorubicin occurs under basic conditions in the pH range of 9.0-10.0. In the presence of doxorubicin, changes in the zeta potential of the complex concerning the initial system are observed. These changes result from electrostatic interactions between the drug molecules and external functional groups. Based on changes in the absorbance intensity of UV-vis spectra, the binding of the drug in the polymer structure is observed depending on the pH of the environment and the molar ratio. Optimal conditions for forming complexes occur under alkaline conditions. UV-vis, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy confirmed the stability of the formed dendrimer-DOX complex. Molecular dynamics simulations were conducted to gain a deeper insight into the molecular mechanism of DOX adsorption on and within the G4.0 PAMAM dendrimers. It was observed that the protonation state of both the dendrimer and DOX significantly influences the adsorption stability. The system exhibited high stability at high pH values (∼9-10), with DOX molecules strongly adsorbed on the dendrimer surface and partially within its bulk. However, under lower pH conditions, a reduction in adsorption strength was observed, leading to the detachment of DOX clusters from the dendrimer structure.
{"title":"Theoretical and Experimental Analyses of the Interfacial Mechanism of Dendrimer-Doxorubicin Complexes Formation.","authors":"Barbara Jachimska, Magdalena Goncerz, Paweł Wolski, Callum Meldrum, Łukasz Lustyk, Tomasz Panczyk","doi":"10.1021/acs.molpharmaceut.4c00941","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00941","url":null,"abstract":"<p><p>The work presents correlations between the physicochemical properties of the carrier and the active substance and optimization of the conditions for creating an active system based on PAMAM dendrimers and doxorubicin. The study monitored the influence of the ionized form of the doxorubicin molecule on the efficiency of complex formation. The deprotonated form of doxorubicin occurs under basic conditions in the pH range of 9.0-10.0. In the presence of doxorubicin, changes in the zeta potential of the complex concerning the initial system are observed. These changes result from electrostatic interactions between the drug molecules and external functional groups. Based on changes in the absorbance intensity of UV-vis spectra, the binding of the drug in the polymer structure is observed depending on the pH of the environment and the molar ratio. Optimal conditions for forming complexes occur under alkaline conditions. UV-vis, Fourier transform infrared spectroscopy, and circular dichroism spectroscopy confirmed the stability of the formed dendrimer-DOX complex. Molecular dynamics simulations were conducted to gain a deeper insight into the molecular mechanism of DOX adsorption on and within the G4.0 PAMAM dendrimers. It was observed that the protonation state of both the dendrimer and DOX significantly influences the adsorption stability. The system exhibited high stability at high pH values (∼9-10), with DOX molecules strongly adsorbed on the dendrimer surface and partially within its bulk. However, under lower pH conditions, a reduction in adsorption strength was observed, leading to the detachment of DOX clusters from the dendrimer structure.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453467","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}
Despite the potent immunoadjuvant properties of mevalonate pathway inhibitors, their application is constrained by poor solubility and instability. In this study, we developed a cationic nanoparticle-stabilized Pickering emulsion loaded with lovastatin (Lov-PPE), using polyethylenimine (PEI)-modified PLGA nanoparticles and squalene as carriers. The system was prepared and tested by evaluating the physicochemical properties and adjuvant efficacy of the Lov-PPE. Lov-PPE/O demonstrated good particle size distribution and zeta potential, with an adsorption efficiency of up to 73.07%. The immunization results showed that Lov-PPE/O significantly promoted the production of OVA-specific IgG antibodies, activated CD4+ and CD8+ T cells, and induced a strong mixed Th1/2 immune response. Additionally, safety assessments indicated that Lov-PPE/O has good in vivo safety. This study demonstrates that the PEI-modified lovastatin PLGA nanoparticle Pickering emulsion (Lov-PPE) is an effective vaccine adjuvant capable of significantly enhancing humoral and cellular immune responses while possessing good safety, offering a new strategy for vaccine formulation development.
{"title":"Enhancing Vaccine Efficacy with Polyethylenimine-Modified Lovastatin-Loaded Nanoparticle Pickering Emulsion Adjuvant.","authors":"Wei Miao, Zuchen Song, Lina Jiao, Ruihong Yu, Deyun Wang, Lan Jin, Xincheng Ge, Yantong Zhou, Zheng Wang, Linjun Han, Jing He, Haifeng Sun, Xiaoxuan Sun, Aqin Zhang, Li Zhang, Zhenguang Liu","doi":"10.1021/acs.molpharmaceut.4c00828","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00828","url":null,"abstract":"<p><p>Despite the potent immunoadjuvant properties of mevalonate pathway inhibitors, their application is constrained by poor solubility and instability. In this study, we developed a cationic nanoparticle-stabilized Pickering emulsion loaded with lovastatin (Lov-PPE), using polyethylenimine (PEI)-modified PLGA nanoparticles and squalene as carriers. The system was prepared and tested by evaluating the physicochemical properties and adjuvant efficacy of the Lov-PPE. Lov-PPE/O demonstrated good particle size distribution and zeta potential, with an adsorption efficiency of up to 73.07%. The immunization results showed that Lov-PPE/O significantly promoted the production of OVA-specific IgG antibodies, activated CD4<sup>+</sup> and CD8<sup>+</sup> T cells, and induced a strong mixed Th1/2 immune response. Additionally, safety assessments indicated that Lov-PPE/O has good <i>in vivo</i> safety. This study demonstrates that the PEI-modified lovastatin PLGA nanoparticle Pickering emulsion (Lov-PPE) is an effective vaccine adjuvant capable of significantly enhancing humoral and cellular immune responses while possessing good safety, offering a new strategy for vaccine formulation development.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453458","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}
Pub Date : 2024-10-21DOI: 10.1021/acs.molpharmaceut.4c00332
Akash Pandya, Cheng Zhang, Teresa S Barata, Steve Brocchini, Mark J Howard, Mire Zloh, Paul A Dalby
<p><p>The design of stable formulations remains a major challenge for protein therapeutics, particularly the need to minimize aggregation. Experimental formulation screens are typically based on thermal transition midpoints (<i>T</i><sub>m</sub>), and forced degradation studies at elevated temperatures. Both approaches give limited predictions of long-term storage stability, particularly at low temperatures. Better understanding of the mechanisms of action for formulation of excipients and buffers could lead to improved strategies for formulation design. Here, we identified a complex impact of glycine concentration on the experimentally determined stability of an antibody Fab fragment and then used molecular dynamics simulations to reveal mechanisms that underpin these complex behaviors. <i>T</i><sub>m</sub> values increased monotonically with glycine concentration, but associated Δ<i>S</i><sub>vh</sub> measurements revealed more complex changes in the native ensemble dynamics, which reached a maximum at 30 mg/mL. The aggregation kinetics at 65 °C were similar at 0 and 20 mg/mL glycine, but then significantly slower at 50 mg/mL. These complex behaviors indicated changes in the dominant stabilizing mechanisms as the glycine concentration was increased. MD revealed a complex balance of glycine self-interaction, and differentially preferred interactions of glycine with the Fab as it displaced hydration-shell water, and surface-bound water and citrate buffer molecules. As a result, glycine binding to the Fab surface had different effects at different concentrations, and led from preferential interactions at low concentrations to preferential exclusion at higher concentrations. During preferential interaction, glycine displaced water from the Fab hydration shell, and a small number of water and citrate molecules from the Fab surface, which reduced the protein dynamics as measured by root-mean-square fluctuation (RMSF) on the short time scales of MD. By contrast, the native ensemble dynamics increased according to Δ<i>S</i><sub>vh</sub>, suggesting increased conformational changes on longer time scales. The aggregation kinetics did not change at low glycine concentrations, and so the opposing dynamics effects either canceled out or were not directly relevant to aggregation. During preferential exclusion at higher glycine concentrations, glycine could only bind to the Fab surface through the displacement of citrate buffer molecules already favorably bound on the Fab surface. Displacement of citrate increased the flexibility (RMSF) of the Fab, as glycine formed fewer bridging hydrogen bonds to the Fab surface. Overall, the slowing of aggregation kinetics coincided with reduced flexibility in the Fab ensemble at the very highest glycine concentrations, as determined by both RMSF and Δ<i>S</i><sub>vh</sub>, and occurred at a point where glycine binding displaced neither water nor citrate. These final interactions with the Fab surface were driven by mass ac
设计稳定的制剂仍然是蛋白质疗法面临的一大挑战,尤其是需要尽量减少聚集。实验制剂筛选通常基于热转变中点(Tm)和高温强制降解研究。这两种方法对长期储存稳定性的预测都很有限,尤其是在低温条件下。更好地了解辅料和缓冲剂配方的作用机制,可以改进配方设计策略。在这里,我们确定了甘氨酸浓度对实验测定的抗体 Fab 片段稳定性的复杂影响,然后利用分子动力学模拟揭示了这些复杂行为的作用机制。Tm 值随着甘氨酸浓度的增加而单调增加,但相关的 ΔSvh 测量显示了本机集合动力学中更复杂的变化,在 30 mg/mL 时达到最大值。在 65 °C,甘氨酸浓度为 0 和 20 毫克/毫升时,聚集动力学相似,但浓度为 50 毫克/毫升时,聚集动力学明显减慢。这些复杂的行为表明,随着甘氨酸浓度的增加,主要的稳定机制发生了变化。MD 显示了甘氨酸自身相互作用的复杂平衡,以及甘氨酸在取代水合壳水、表面结合水和柠檬酸缓冲液分子时与 Fab 的不同优先相互作用。因此,甘氨酸与 Fab 表面的结合在不同浓度下有不同的效果,从低浓度下的优先相互作用到高浓度下的优先排斥。在优先相互作用过程中,甘氨酸取代了 Fab 水合壳中的水,也取代了 Fab 表面的少量水和柠檬酸盐分子,从而降低了短时间尺度 MD 的均方根波动(RMSF)所测量的蛋白质动力学。与此相反,根据ΔSvh,本机集合动力学增加了,这表明在较长的时间尺度上构象变化增加了。在甘氨酸浓度较低时,聚合动力学没有变化,因此相反的动力学效应要么相互抵消,要么与聚合没有直接关系。在甘氨酸浓度较高时的优先排除过程中,甘氨酸只能通过置换已与 Fab 表面有利结合的柠檬酸盐缓冲液分子而与 Fab 表面结合。由于甘氨酸与 Fab 表面形成的桥接氢键较少,柠檬酸盐的置换增加了 Fab 的柔韧性(RMSF)。总体而言,根据 RMSF 和 ΔSvh 的测定,在甘氨酸浓度最高时,聚集动力学的减慢与 Fab 组合灵活性的降低相吻合,并且发生在甘氨酸结合既不取代水也不取代柠檬酸盐的时刻。这些与 Fab 表面的最终相互作用是由质量作用驱动的,也是最不利的,从而导致了优先排斥机制下的大分子拥挤效应,稳定了 Fab 的动力学。
{"title":"Molecular Dynamics Simulations Reveal How Competing Protein-Surface Interactions for Glycine, Citrate, and Water Modulate Stability in Antibody Fragment Formulations.","authors":"Akash Pandya, Cheng Zhang, Teresa S Barata, Steve Brocchini, Mark J Howard, Mire Zloh, Paul A Dalby","doi":"10.1021/acs.molpharmaceut.4c00332","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00332","url":null,"abstract":"<p><p>The design of stable formulations remains a major challenge for protein therapeutics, particularly the need to minimize aggregation. Experimental formulation screens are typically based on thermal transition midpoints (<i>T</i><sub>m</sub>), and forced degradation studies at elevated temperatures. Both approaches give limited predictions of long-term storage stability, particularly at low temperatures. Better understanding of the mechanisms of action for formulation of excipients and buffers could lead to improved strategies for formulation design. Here, we identified a complex impact of glycine concentration on the experimentally determined stability of an antibody Fab fragment and then used molecular dynamics simulations to reveal mechanisms that underpin these complex behaviors. <i>T</i><sub>m</sub> values increased monotonically with glycine concentration, but associated Δ<i>S</i><sub>vh</sub> measurements revealed more complex changes in the native ensemble dynamics, which reached a maximum at 30 mg/mL. The aggregation kinetics at 65 °C were similar at 0 and 20 mg/mL glycine, but then significantly slower at 50 mg/mL. These complex behaviors indicated changes in the dominant stabilizing mechanisms as the glycine concentration was increased. MD revealed a complex balance of glycine self-interaction, and differentially preferred interactions of glycine with the Fab as it displaced hydration-shell water, and surface-bound water and citrate buffer molecules. As a result, glycine binding to the Fab surface had different effects at different concentrations, and led from preferential interactions at low concentrations to preferential exclusion at higher concentrations. During preferential interaction, glycine displaced water from the Fab hydration shell, and a small number of water and citrate molecules from the Fab surface, which reduced the protein dynamics as measured by root-mean-square fluctuation (RMSF) on the short time scales of MD. By contrast, the native ensemble dynamics increased according to Δ<i>S</i><sub>vh</sub>, suggesting increased conformational changes on longer time scales. The aggregation kinetics did not change at low glycine concentrations, and so the opposing dynamics effects either canceled out or were not directly relevant to aggregation. During preferential exclusion at higher glycine concentrations, glycine could only bind to the Fab surface through the displacement of citrate buffer molecules already favorably bound on the Fab surface. Displacement of citrate increased the flexibility (RMSF) of the Fab, as glycine formed fewer bridging hydrogen bonds to the Fab surface. Overall, the slowing of aggregation kinetics coincided with reduced flexibility in the Fab ensemble at the very highest glycine concentrations, as determined by both RMSF and Δ<i>S</i><sub>vh</sub>, and occurred at a point where glycine binding displaced neither water nor citrate. These final interactions with the Fab surface were driven by mass ac","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453464","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}
Pub Date : 2024-10-19DOI: 10.1021/acs.molpharmaceut.4c00830
Flavio Costa, Giorgia Giorgini, Cristina Minnelli, Giovanna Mobbili, Carlo Guardiani, Alberto Giacomello, Roberta Galeazzi
Berberine (BBR) is a natural molecule with noteworthy pharmacological properties, including the prevention of antibiotic resistance in Gram-negative bacteria. However, its oral bioavailability is poor, thus resulting in an impaired absorption and efficacy in humans. In combination with other drugs, liposomes have been shown to enhance the availability of the drug, representing a smart delivery system to target tissues and reduce negative side effects. To date, there is a lack of studies on BBR and liposomes that enable the rationalization and molecular-based design of such formulations for future use in humans. In this work, the encapsulation of BBR into liposomes is proposed to overcome current limitations using a combination of experimental and computational assays to rationalize the membrane composition of liposomes that maximizes BBR encapsulation. First, the encapsulation efficiency was measured for several membrane compositions, revealing that it is enhanced by cholesteryl hemisuccinate and, to a lesser extent, by cholesterol. The physical basis of the BBR encapsulation efficiency and permeability was clarified using molecular dynamics simulation: using the lipid composition, one can tune the capability of membranes to attract, i.e., to adsorb, the molecules onto their surface. Overall, these findings suggest a rational strategy to maximize the encapsulation efficiency of liposomes by using negatively charged lipids, thus representing the basis for designing delivery systems for BBR, useful to treat, e.g., antibiotic resistance.
{"title":"Membrane Composition Allows the Optimization of Berberine Encapsulation in Liposomes.","authors":"Flavio Costa, Giorgia Giorgini, Cristina Minnelli, Giovanna Mobbili, Carlo Guardiani, Alberto Giacomello, Roberta Galeazzi","doi":"10.1021/acs.molpharmaceut.4c00830","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00830","url":null,"abstract":"<p><p>Berberine (BBR) is a natural molecule with noteworthy pharmacological properties, including the prevention of antibiotic resistance in Gram-negative bacteria. However, its oral bioavailability is poor, thus resulting in an impaired absorption and efficacy in humans. In combination with other drugs, liposomes have been shown to enhance the availability of the drug, representing a smart delivery system to target tissues and reduce negative side effects. To date, there is a lack of studies on BBR and liposomes that enable the rationalization and molecular-based design of such formulations for future use in humans. In this work, the encapsulation of BBR into liposomes is proposed to overcome current limitations using a combination of experimental and computational assays to rationalize the membrane composition of liposomes that maximizes BBR encapsulation. First, the encapsulation efficiency was measured for several membrane compositions, revealing that it is enhanced by cholesteryl hemisuccinate and, to a lesser extent, by cholesterol. The physical basis of the BBR encapsulation efficiency and permeability was clarified using molecular dynamics simulation: using the lipid composition, one can tune the capability of membranes to attract, i.e., to adsorb, the molecules onto their surface. Overall, these findings suggest a rational strategy to maximize the encapsulation efficiency of liposomes by using negatively charged lipids, thus representing the basis for designing delivery systems for BBR, useful to treat, e.g., antibiotic resistance.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453462","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}
Pub Date : 2024-10-18DOI: 10.1021/acs.molpharmaceut.4c00188
Ran Sun, Yaoqi Wang, Qi Sun, Yan Su, Jie Zhang, Danni Liu, Ran Huo, Yang Tian, Myagmarsuren Baldan, Shuang Zhang, Chunying Cui
Gold nanorods (Au NRs) are a valuable photothermal nanomaterial for tumor therapy. However, when treated with Au NRs for photothermal therapy, the expression of heat shock proteins in tumors will increase, which will induce heat resistance in tumor cells and reduce the photothermal therapeutic effect of Au NRs. By RNA interference, the expression of heat shock proteins would be effectively inhibited to improve the efficasy of tumor photothermal therapy. However, deep and noninvasive tissue penetration remains a great obstacle to applying siRNA successfully. Thus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced photothermal tumor therapy by RNA interference. In the AGC/HSP-70 siRNA complex, the Au-S bond modified the matrix metalloproteinase-2 (MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods. Moreover, the natural basic polysaccharide (chitosan) was reacted with the peptide by an amide bond for delivering heat shock protein 70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker could cause more Au NRs to accumulate in tumors to exert a photothermal effect and promote the penetration of HSP-70 siRNA and chitosan complexes into deep tumor tissues. In vitro experiments indicated that the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70 siRNA could promote the cellular uptake and perinuclear distribution of HSP-70 siRNA in tumor cells, which may be due to the smaller size and positive electricity of the complexes. All of these results ensured the efficient gene silencing effect of HSP-70 siRNA to enhance the photothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated by the gene silencing and cellular apoptotic experiments. In vivo experiments further proved that the AGC/HSP-70 siRNA nanoplatform efficiently improved the photothermal effect of Au NRs. In summary, this work proved that AGC/HSP-70 siRNA is a promising drug delivery strategy for enhancing the photothermal therapy of tumors by regulating the photothermal sensitivity of deep tumor cells as well as retaining more Au NRs in tumor tissues, and also provides a novel strategy for tumor photothermal therapy.
{"title":"MMP-2 Responsive Gold Nanorods Loaded with HSP-70 siRNA for Enhanced Photothermal Tumor Therapy.","authors":"Ran Sun, Yaoqi Wang, Qi Sun, Yan Su, Jie Zhang, Danni Liu, Ran Huo, Yang Tian, Myagmarsuren Baldan, Shuang Zhang, Chunying Cui","doi":"10.1021/acs.molpharmaceut.4c00188","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00188","url":null,"abstract":"<p><p>Gold nanorods (Au NRs) are a valuable photothermal nanomaterial for tumor therapy. However, when treated with Au NRs for photothermal therapy, the expression of heat shock proteins in tumors will increase, which will induce heat resistance in tumor cells and reduce the photothermal therapeutic effect of Au NRs. By RNA interference, the expression of heat shock proteins would be effectively inhibited to improve the efficasy of tumor photothermal therapy. However, deep and noninvasive tissue penetration remains a great obstacle to applying siRNA successfully. Thus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced photothermal tumor therapy by RNA interference. In the AGC/HSP-70 siRNA complex, the Au-S bond modified the matrix metalloproteinase-2 (MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods. Moreover, the natural basic polysaccharide (chitosan) was reacted with the peptide by an amide bond for delivering heat shock protein 70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker could cause more Au NRs to accumulate in tumors to exert a photothermal effect and promote the penetration of HSP-70 siRNA and chitosan complexes into deep tumor tissues. <i>In vitro</i> experiments indicated that the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70 siRNA could promote the cellular uptake and perinuclear distribution of HSP-70 siRNA in tumor cells, which may be due to the smaller size and positive electricity of the complexes. All of these results ensured the efficient gene silencing effect of HSP-70 siRNA to enhance the photothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated by the gene silencing and cellular apoptotic experiments. <i>In vivo</i> experiments further proved that the AGC/HSP-70 siRNA nanoplatform efficiently improved the photothermal effect of Au NRs. In summary, this work proved that AGC/HSP-70 siRNA is a promising drug delivery strategy for enhancing the photothermal therapy of tumors by regulating the photothermal sensitivity of deep tumor cells as well as retaining more Au NRs in tumor tissues, and also provides a novel strategy for tumor photothermal therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453463","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}
Pub Date : 2024-10-16DOI: 10.1021/acs.molpharmaceut.4c00769
Xia Song, Yuting Wen, Aaron Wei Liang Li, Jingling Zhu, Cho Yeow Koh, R Manjunatha Kini, Mark Yan Yee Chan, Jun Li
Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.
{"title":"PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects.","authors":"Xia Song, Yuting Wen, Aaron Wei Liang Li, Jingling Zhu, Cho Yeow Koh, R Manjunatha Kini, Mark Yan Yee Chan, Jun Li","doi":"10.1021/acs.molpharmaceut.4c00769","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00769","url":null,"abstract":"<p><p>Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453465","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}
Pub Date : 2024-10-15DOI: 10.1021/acs.molpharmaceut.4c00869
Alessia Giglio, Marco Bellotti, Bice Conti, Nur E-Hasnat, Ferdinando Auricchio, Ida Genta, Alessandro Caimi, Enrica Chiesa
Oral immunization offers a minimally invasive administration, inducing local and systemic immune responses and facilitating mass immunization without needle-related risks. However, the gastrointestinal environment poses challenges, compromising vaccine effectiveness through enzymatic degradation and poor absorption by Peyer's patches. Advances in nanoparticle and microparticle (NP/MP) technology protect vaccines from degradation and enhance targeted release. The aim of this study was to develop pH-controlled polymeric carriers for the oral delivery of protein vaccines in order to target the antigen-presenting cells and M cells in the region of Peyer's patches. Here, myoglobin was chosen as a model protein vaccine. This study focuses on Eudragit L100, a pH-responsive polymer stable in acidic conditions and dissolving at higher pH, to develop carriers for controlled myoglobin release in the intestinal tract. A microfluidic-based manufacturing process for Eudragit L100 NPs and MPs is optimized using a comprehensive experimental and computational approach to obtain NPs and MPs through the same setup. Integrating in silico and experimental methods highlights the potential of numerical simulations to streamline final product development. This approach improves the efficiency and cost-effectiveness of NP/MP production, demonstrating how the combination of design of experiment and numerical simulations can optimize production parameters and refine manufacturing processes for advanced drug delivery systems.
{"title":"Experimental and Numerical Integrated Strategy for the Optimization of Microfluidic Parameters for Eudragit L100 Nanoparticles and Microparticles.","authors":"Alessia Giglio, Marco Bellotti, Bice Conti, Nur E-Hasnat, Ferdinando Auricchio, Ida Genta, Alessandro Caimi, Enrica Chiesa","doi":"10.1021/acs.molpharmaceut.4c00869","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00869","url":null,"abstract":"<p><p>Oral immunization offers a minimally invasive administration, inducing local and systemic immune responses and facilitating mass immunization without needle-related risks. However, the gastrointestinal environment poses challenges, compromising vaccine effectiveness through enzymatic degradation and poor absorption by Peyer's patches. Advances in nanoparticle and microparticle (NP/MP) technology protect vaccines from degradation and enhance targeted release. The aim of this study was to develop pH-controlled polymeric carriers for the oral delivery of protein vaccines in order to target the antigen-presenting cells and M cells in the region of Peyer's patches. Here, myoglobin was chosen as a model protein vaccine. This study focuses on Eudragit L100, a pH-responsive polymer stable in acidic conditions and dissolving at higher pH, to develop carriers for controlled myoglobin release in the intestinal tract. A microfluidic-based manufacturing process for Eudragit L100 NPs and MPs is optimized using a comprehensive experimental and computational approach to obtain NPs and MPs through the same setup. Integrating in silico and experimental methods highlights the potential of numerical simulations to streamline final product development. This approach improves the efficiency and cost-effectiveness of NP/MP production, demonstrating how the combination of design of experiment and numerical simulations can optimize production parameters and refine manufacturing processes for advanced drug delivery systems.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453459","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}
Pub Date : 2024-10-15DOI: 10.1021/acs.molpharmaceut.4c00823
Nasim Sarrami, Melinda Wuest, Igor Moura de Paiva, Samantha Leier, Afsaneh Lavasanifar, Frank Wuest
<p><p><i>Objective</i>: About 65-90% of nonsmall cell lung cancer (NSCLC) express the epithelial growth factor receptor (EGFR) as a transmembrane protein that is activated by binding of specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Identifying EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including the full-length human IgG<sub>2</sub> monoclonal antibody panitumumab. The main goal of the present study was to investigate <sup>64</sup>Cu-labeled panitumumab with immuno-PET in subcutaneous and metastatic EGFR-positive NSCLC xenografts. <i>Methods:</i> Bifunctional chelating agent 2-<i>S</i>-(4-isothiocyanatobenzyl)-1,4,7-triazacyclo-nonane-1,4,7-triacetic acid (NOTA-NCS) was attached to panitumumab. The number of chelators per panitumumab was determined using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The incorporation efficiency of <sup>64</sup>Cu into NOTA-panitumumab was measured by using radio-TLC. EGFR-expressing epithelial-like H1299-luc+ NSCLC cells were used for <i>in vitro</i> and <i>in vivo</i> experiments. Cell uptake of [<sup>64</sup>Cu]Cu-NOTA-panitumumab was measured in the presence and absence of panitumumab. Subcutaneous and metastatic H1299-luc tumor models were grown in male NSG mice. The presence of tumors at lung and metastatic sites was analyzed by [<sup>18</sup>F]FLT PET. Immuno-PET with [<sup>64</sup>Cu]Cu-NOTA-panitumumab was performed as static PET imaging at 2, 24, and 48 h postinjection in both tumor models. Proof-of-target was confirmed by blocking experiments with panitumumab. Detailed <i>ex vivo</i> biodistribution experiments were performed in both animal tumor models to confirm biodistribution profiles obtained by immuno-PET imaging. <i>Results:</i> MALDI analysis confirmed the attachment of ∼1.5 NOTA per antibody. Radiolabeling efficiency with [<sup>64</sup>Cu]CuCl<sub>2</sub> was 93.8 ± 5.7% and a molar activity of 0.65 MBq/μg. Cellular uptake studies with [<sup>64</sup>Cu]Cu-NOTA-panitumumab in H1299 cells demonstrated increasing uptake over time, reaching 29.1 ± 2.9% radioactivity(Bq)/mg protein (<i>n</i> = 3) and plateauing at 45 min. Addition of 25 μg of panitumumab reduced radioligand uptake to 1.22 ± 0.06% radioactivity/mg protein (<i>n</i> = 3). PET imaging revealed high uptake of [<sup>64</sup>Cu]Cu-NOTA-panitumumab in subcutaneous tumors: Standardized uptake values (SUV)<sub>mean</sub> reached 4.70 ± 0.42 and 5.37 ± 0.40 (<i>n</i> = 5) after 24 and 48 h postinjection, respectively. Administration of 1 mg panitumumab reduced tumor uptake significantly to 1.94 ± 0.22 and 1.66 ± 0.08 (<i>n</i> = 4; <i>p</i> < 0.001). In the metastatic model, the following SUV<sub>mean</sub> were analyzed from liver and lung lesions: 5.55 ± 0.34 and 6.28 ± 0.46 (both n = 23 lesions from 6 mice) after 24 and 48 h postinjection, which was also significantly reduced to 2.53 ± 0.39 and 2.31 ± 0.15 (both <i>
{"title":"Immuno-PET Imaging of EGFR with <sup>64</sup>Cu-NOTA Panitumumab in Subcutaneous and Metastatic Nonsmall Cell Lung Cancer Xenografts.","authors":"Nasim Sarrami, Melinda Wuest, Igor Moura de Paiva, Samantha Leier, Afsaneh Lavasanifar, Frank Wuest","doi":"10.1021/acs.molpharmaceut.4c00823","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00823","url":null,"abstract":"<p><p><i>Objective</i>: About 65-90% of nonsmall cell lung cancer (NSCLC) express the epithelial growth factor receptor (EGFR) as a transmembrane protein that is activated by binding of specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Identifying EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including the full-length human IgG<sub>2</sub> monoclonal antibody panitumumab. The main goal of the present study was to investigate <sup>64</sup>Cu-labeled panitumumab with immuno-PET in subcutaneous and metastatic EGFR-positive NSCLC xenografts. <i>Methods:</i> Bifunctional chelating agent 2-<i>S</i>-(4-isothiocyanatobenzyl)-1,4,7-triazacyclo-nonane-1,4,7-triacetic acid (NOTA-NCS) was attached to panitumumab. The number of chelators per panitumumab was determined using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The incorporation efficiency of <sup>64</sup>Cu into NOTA-panitumumab was measured by using radio-TLC. EGFR-expressing epithelial-like H1299-luc+ NSCLC cells were used for <i>in vitro</i> and <i>in vivo</i> experiments. Cell uptake of [<sup>64</sup>Cu]Cu-NOTA-panitumumab was measured in the presence and absence of panitumumab. Subcutaneous and metastatic H1299-luc tumor models were grown in male NSG mice. The presence of tumors at lung and metastatic sites was analyzed by [<sup>18</sup>F]FLT PET. Immuno-PET with [<sup>64</sup>Cu]Cu-NOTA-panitumumab was performed as static PET imaging at 2, 24, and 48 h postinjection in both tumor models. Proof-of-target was confirmed by blocking experiments with panitumumab. Detailed <i>ex vivo</i> biodistribution experiments were performed in both animal tumor models to confirm biodistribution profiles obtained by immuno-PET imaging. <i>Results:</i> MALDI analysis confirmed the attachment of ∼1.5 NOTA per antibody. Radiolabeling efficiency with [<sup>64</sup>Cu]CuCl<sub>2</sub> was 93.8 ± 5.7% and a molar activity of 0.65 MBq/μg. Cellular uptake studies with [<sup>64</sup>Cu]Cu-NOTA-panitumumab in H1299 cells demonstrated increasing uptake over time, reaching 29.1 ± 2.9% radioactivity(Bq)/mg protein (<i>n</i> = 3) and plateauing at 45 min. Addition of 25 μg of panitumumab reduced radioligand uptake to 1.22 ± 0.06% radioactivity/mg protein (<i>n</i> = 3). PET imaging revealed high uptake of [<sup>64</sup>Cu]Cu-NOTA-panitumumab in subcutaneous tumors: Standardized uptake values (SUV)<sub>mean</sub> reached 4.70 ± 0.42 and 5.37 ± 0.40 (<i>n</i> = 5) after 24 and 48 h postinjection, respectively. Administration of 1 mg panitumumab reduced tumor uptake significantly to 1.94 ± 0.22 and 1.66 ± 0.08 (<i>n</i> = 4; <i>p</i> < 0.001). In the metastatic model, the following SUV<sub>mean</sub> were analyzed from liver and lung lesions: 5.55 ± 0.34 and 6.28 ± 0.46 (both n = 23 lesions from 6 mice) after 24 and 48 h postinjection, which was also significantly reduced to 2.53 ± 0.39 and 2.31 ± 0.15 (both <i>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453461","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}
Pub Date : 2024-10-14DOI: 10.1021/acs.molpharmaceut.4c00608
Pranati P Mondkar, Hannah S Seo, Timothy P Lodge, Samira M Azarin
The blood-brain barrier (BBB) is a highly restrictive barrier at the interface between the brain and the vascular system. Even under BBB dysfunction, it is extremely difficult to deliver therapies across the barrier, limiting the options for treatment of neurological injuries and disorders. To circumvent these challenges, there is interest in developing therapies that directly engage with the damaged BBB to restore its function. Previous studies revealed that poloxamer 188 (P188), a water-soluble triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), partially mitigated BBB dysfunction in vivo. In the context of stabilization of the damaged BBB, the mechanism of action of PEO-PPO block copolymers is unknown, and there has been minimal exploration of polymers beyond P188. In this study, a human-based in vitro BBB model under oxidative stress was used to investigate polymer-BBB interactions since oxidative stress is closely linked with BBB dysfunction in many neurological injuries and disorders. PEO-PPO block copolymers of varied numbers of chemically distinct blocks, PEO block length, and functionality of the end group of the PPO block were assessed for their efficacy in improving key physiological readouts associated with BBB dysfunction. While treatment with P188 did not mitigate damage in the in vitro BBB model, treatment with three diblock copolymers improved barrier integrity under oxidative stress to a similar extent. Of the considered variations in the block copolymer design, the reduction in the number of chemically distinct blocks had the strongest influence on therapeutic function. The demonstrated efficacy of three alternative PEO-PPO diblock copolymers in this work reveals the potential of these polymers as a class of therapeutics that directly treat the damaged BBB, expanding the options for treatment of neurological injuries and disorders.
{"title":"Diblock Copolymers of Poly(ethylene oxide)-<i>b</i>-poly(propylene oxide) Stabilize a Blood-Brain Barrier Model under Oxidative Stress.","authors":"Pranati P Mondkar, Hannah S Seo, Timothy P Lodge, Samira M Azarin","doi":"10.1021/acs.molpharmaceut.4c00608","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00608","url":null,"abstract":"<p><p>The blood-brain barrier (BBB) is a highly restrictive barrier at the interface between the brain and the vascular system. Even under BBB dysfunction, it is extremely difficult to deliver therapies across the barrier, limiting the options for treatment of neurological injuries and disorders. To circumvent these challenges, there is interest in developing therapies that directly engage with the damaged BBB to restore its function. Previous studies revealed that poloxamer 188 (P188), a water-soluble triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), partially mitigated BBB dysfunction in vivo. In the context of stabilization of the damaged BBB, the mechanism of action of PEO-PPO block copolymers is unknown, and there has been minimal exploration of polymers beyond P188. In this study, a human-based in vitro BBB model under oxidative stress was used to investigate polymer-BBB interactions since oxidative stress is closely linked with BBB dysfunction in many neurological injuries and disorders. PEO-PPO block copolymers of varied numbers of chemically distinct blocks, PEO block length, and functionality of the end group of the PPO block were assessed for their efficacy in improving key physiological readouts associated with BBB dysfunction. While treatment with P188 did not mitigate damage in the in vitro BBB model, treatment with three diblock copolymers improved barrier integrity under oxidative stress to a similar extent. Of the considered variations in the block copolymer design, the reduction in the number of chemically distinct blocks had the strongest influence on therapeutic function. The demonstrated efficacy of three alternative PEO-PPO diblock copolymers in this work reveals the potential of these polymers as a class of therapeutics that directly treat the damaged BBB, expanding the options for treatment of neurological injuries and disorders.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453456","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}
Pub Date : 2024-10-13DOI: 10.1021/acs.molpharmaceut.4c00271
Yanjiao Liu, Xingang Yao, Cheng Wen, Dan Li, Jiawen Zhang, Baomin Xi, Brian S Cummings, Guodong Zhu
Upregulated secretory phospholipase A2 (sPLA2) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA2-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA2-preferred lipids. Here, a membrane-destabilizing mechanism based on enzymatic extraction and the transition of facial amphiphiles (FAs) within lipid membranes was introduced. Enzymatic degradation of FA-modified lipids, a process involving substrate extraction of lipids from membranes and cleavage of sn-2 ester bonds by sPLA2, rotation, and interface settling of detached FAs, caused tremendous efflux of payloads from liposomes, termed the SECRIS effect. In the presence of sPLA2, oxaliplatin (L-OHP) loaded liposomes containing FA-modified lipids showed enhanced drug release, comparable in vitro cytotoxicity, and excellent in vivo antitumor efficacy and reduced adverse syndromes in Colo205-bearing mice compared to conventional sPLA2-labile formulations. The discovery of the SECRIS effect creates a new pathway to engineer liposome platforms for the treatment of sPLA2-positive tumors.
{"title":"Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A<sub>2</sub>.","authors":"Yanjiao Liu, Xingang Yao, Cheng Wen, Dan Li, Jiawen Zhang, Baomin Xi, Brian S Cummings, Guodong Zhu","doi":"10.1021/acs.molpharmaceut.4c00271","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00271","url":null,"abstract":"<p><p>Upregulated secretory phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA<sub>2</sub>-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA<sub>2</sub>-preferred lipids. Here, a membrane-destabilizing mechanism based on enzymatic extraction and the transition of facial amphiphiles (FAs) within lipid membranes was introduced. Enzymatic degradation of FA-modified lipids, a process involving substrate extraction of lipids from membranes and cleavage of <i>sn-2</i> ester bonds by sPLA<sub>2</sub>, rotation, and interface settling of detached FAs, caused tremendous efflux of payloads from liposomes, termed the SECRIS effect. In the presence of sPLA<sub>2</sub>, oxaliplatin (L-OHP) loaded liposomes containing FA-modified lipids showed enhanced drug release, comparable in vitro cytotoxicity, and excellent in vivo antitumor efficacy and reduced adverse syndromes in Colo205-bearing mice compared to conventional sPLA<sub>2</sub>-labile formulations. The discovery of the SECRIS effect creates a new pathway to engineer liposome platforms for the treatment of sPLA<sub>2</sub>-positive tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453460","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}