Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-309
Joelle P. Straehla, Natalie Boehnke, M. Kocak, Melissa M Ronan, H. Safford, M. Rees, J. Roth, A. Koehler, P. Hammond
Background: Nanoparticles (NPs) hold enormous promise for the targeted delivery of therapeutics for cancer, but clinical translation is lacking largely due to limited tumor accumulation. Tumor heterogeneity and NP complexity make it challenging to deconvolute individual factors that contribute to NP-cell interactions. To address this, we developed a competition assay leveraging 500 stably DNA-barcoded adherent cancer cell lines annotated with multi-omic data from the Broad Institute (PRISM cells) to investigate cell association patterns across a library of NPs. We hypothesize that simultaneous screening of hundreds of cancer cell lines will identify factors underlying differential NP-cancer cell interactions. Methods: We synthesized a library of 40 fluorescently-labeled NPs comprising clinical and experimental formulations. Clinical formulations included liposomal doxorubicin and irinotecan analogs and liposomal or poly(lactide-co-glycolide, PLGA) NPs with and without polyethylene glycol (PEG); these are either FDA-approved or in clinical trials. Experimental formulations included liposomal and PLGA cores electrostatically coated with a range of native and synthetic polymers as well as polystyrene NPs of varying sizes and surface chemistries. Fluorescent antibodies -in free form or NP-conjugated—were included as validation compounds. PRISM cells were pooled and incubated with NPs prior to fluorescence-activated cell sorting (FACS) to bin cells based on strength of NP association. After cell lysis, DNA barcodes were amplified and sequenced. Using appropriate controls to adjust for baseline barcode abundance, we generated an association score for each NP-cell line pair. Next, we performed multi-omic univariate analyses and applied a random forest algorithm to identify factors predictive of NP-cancer cell association. Results: After pooled screening of PRISM cells, we consistently identified cancer cell lines based on strength of NP-association across technical and biologic replicates. Using antibodies and antibody-conjugated NPs targeting epidermal growth factor receptor (EGFR), we identified EGFR gene and protein expression as highly significant hits, validating our ability to robustly identify relevant biomarkers. Additional hits were evaluated based on strength and direction of association to identify predictive biomarkers by formulation. We also employed k-means clustering to investigate hits across NP formulations, identifying highly interconnected protein association networks that elucidate likely mechanisms of NP-cancer cell association. Conclusions: We report a new pooled screening platform to investigate factors influencing NP-cancer cell interactions. We validated the screen by identifying known biomarkers, and also identified new predictive biomarkers that may pave the way for more effective nanotherapeutics. Citation Format: Joelle P. Straehla, Natalie Boehnke, Mustafa Kocak, Melissa Ronan, Hannah Safford, Matthew G. Rees, Jennifer A. R
背景:纳米颗粒(NPs)在靶向递送癌症治疗药物方面具有巨大的前景，但由于肿瘤积累有限，缺乏临床转化。肿瘤的异质性和NP的复杂性使得解卷积影响NP-细胞相互作用的个体因素具有挑战性。为了解决这个问题，我们开发了一种竞争分析，利用500个稳定的dna条形码贴壁癌细胞系，用Broad研究所的多组学数据(PRISM细胞)注释，研究NPs库中的细胞关联模式。我们假设同时筛选数百种癌细胞系将确定不同np -癌细胞相互作用的因素。方法:我们合成了40个荧光标记的NPs文库，包括临床和实验配方。临床制剂包括脂质体阿霉素和伊立替康类似物，脂质体或聚乳酸-羟基乙酸酯(PLGA) NPs，含或不含聚乙二醇(PEG);这些药物要么是fda批准的，要么是在临床试验中。实验配方包括脂质体和PLGA芯静电涂覆一系列天然和合成聚合物，以及不同尺寸和表面化学性质的聚苯乙烯NPs。荧光抗体-自由形式或np -偶联-包括作为验证化合物。在荧光激活细胞分选(FACS)之前，将PRISM细胞与NP一起孵育，根据NP关联的强度对bin细胞进行筛选。细胞裂解后，扩增DNA条形码并测序。使用适当的控制来调整基线条形码丰度，我们为每个np细胞系对生成关联评分。接下来，我们进行了多组学单变量分析，并应用随机森林算法来识别预测np -癌细胞关联的因素。结果:在PRISM细胞的汇总筛选后，我们基于技术和生物重复的np关联强度一致地鉴定出癌细胞系。利用针对表皮生长因子受体(EGFR)的抗体和抗体偶联的NPs，我们鉴定出EGFR基因和蛋白表达是高度显著的命中点，验证了我们强有力地鉴定相关生物标志物的能力。根据关联的强度和方向评估其他命中值，以通过配方确定预测性生物标志物。我们还采用k-means聚类来研究NP配方中的hit，确定了高度互连的蛋白质关联网络，阐明了NP-癌细胞关联的可能机制。结论:我们报告了一个新的汇集筛选平台来研究影响np -癌细胞相互作用的因素。我们通过鉴定已知的生物标记物来验证筛选结果，并鉴定出新的预测性生物标记物，这些生物标记物可能为更有效的纳米治疗铺平道路。引用格式:Joelle P. Straehla, Natalie Boehnke, Mustafa kocaak, Melissa Ronan, Hannah Safford, Matthew G. Rees, Jennifer A. Roth, Angela N. Koehler, Paula T. Hammond纳米颗粒递送的多组学、集合癌细胞筛选的发展[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第309期。
{"title":"Abstract 309: Development of a multi-omic, pooled cancer cell screen for nanoparticle delivery","authors":"Joelle P. Straehla, Natalie Boehnke, M. Kocak, Melissa M Ronan, H. Safford, M. Rees, J. Roth, A. Koehler, P. Hammond","doi":"10.1158/1538-7445.AM2021-309","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-309","url":null,"abstract":"Background: Nanoparticles (NPs) hold enormous promise for the targeted delivery of therapeutics for cancer, but clinical translation is lacking largely due to limited tumor accumulation. Tumor heterogeneity and NP complexity make it challenging to deconvolute individual factors that contribute to NP-cell interactions. To address this, we developed a competition assay leveraging 500 stably DNA-barcoded adherent cancer cell lines annotated with multi-omic data from the Broad Institute (PRISM cells) to investigate cell association patterns across a library of NPs. We hypothesize that simultaneous screening of hundreds of cancer cell lines will identify factors underlying differential NP-cancer cell interactions. Methods: We synthesized a library of 40 fluorescently-labeled NPs comprising clinical and experimental formulations. Clinical formulations included liposomal doxorubicin and irinotecan analogs and liposomal or poly(lactide-co-glycolide, PLGA) NPs with and without polyethylene glycol (PEG); these are either FDA-approved or in clinical trials. Experimental formulations included liposomal and PLGA cores electrostatically coated with a range of native and synthetic polymers as well as polystyrene NPs of varying sizes and surface chemistries. Fluorescent antibodies -in free form or NP-conjugated—were included as validation compounds. PRISM cells were pooled and incubated with NPs prior to fluorescence-activated cell sorting (FACS) to bin cells based on strength of NP association. After cell lysis, DNA barcodes were amplified and sequenced. Using appropriate controls to adjust for baseline barcode abundance, we generated an association score for each NP-cell line pair. Next, we performed multi-omic univariate analyses and applied a random forest algorithm to identify factors predictive of NP-cancer cell association. Results: After pooled screening of PRISM cells, we consistently identified cancer cell lines based on strength of NP-association across technical and biologic replicates. Using antibodies and antibody-conjugated NPs targeting epidermal growth factor receptor (EGFR), we identified EGFR gene and protein expression as highly significant hits, validating our ability to robustly identify relevant biomarkers. Additional hits were evaluated based on strength and direction of association to identify predictive biomarkers by formulation. We also employed k-means clustering to investigate hits across NP formulations, identifying highly interconnected protein association networks that elucidate likely mechanisms of NP-cancer cell association. Conclusions: We report a new pooled screening platform to investigate factors influencing NP-cancer cell interactions. We validated the screen by identifying known biomarkers, and also identified new predictive biomarkers that may pave the way for more effective nanotherapeutics. Citation Format: Joelle P. Straehla, Natalie Boehnke, Mustafa Kocak, Melissa Ronan, Hannah Safford, Matthew G. Rees, Jennifer A. R","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87538730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-317
T. Jarboe, N. Desouza, Sarnath Singh, A. Moscatello, J. Geliebter, R. Tiwari, Xiu-Min Li
{"title":"Abstract 317: Berberine-mediated reprogramming of the inflammatory environment in anaplastic thyroid cancer","authors":"T. Jarboe, N. Desouza, Sarnath Singh, A. Moscatello, J. Geliebter, R. Tiwari, Xiu-Min Li","doi":"10.1158/1538-7445.AM2021-317","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-317","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76162981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-307
M. Valic, Mark Zheng, L. Ding, Michelle Lai, Chris J. Zhang, T. Ye, Jenny Ma, M. Halim, P. Schimmer, Wenlei Jiang, Juan Chen, G. Zheng
Background: Accumulation of systemically administered nanoparticles (NPs) in lymph nodes has been exploited clinically for diagnostic imaging (e.g., USPIOs for lymph node metastasis) and therapeutic applications (e.g., vaccine delivery). However, the combination of diagnostic and therapeutic functionalities into a single theranostic NP has obliged undesirable trade-offs between either the imaging or drug delivery of the NP and their specific accumulation in lymph nodes. To overcome these trade-offs, we conducted a screen of various lipid-based theranostic NPs focusing on differing NP design and their resulting pharmacokinetic behaviours in healthy and diseased lymph node models. Methods: Lipid-based theranostic NPs with varying physicochemical characteristics (e.g., formulation, size and morphology, surface targeting, etc.) were prepared with positron emitting Cu-64 and administered systemically at equivalent NP doses in healthy and diseased rodent models (i.e., mice and rats). NP types were assessed for time-dependent accumulation in major lymph node basins via non-invasive whole-body PET/MR imaging at two or more timepoints per animal. 72-hours post-injection the animals were sacrificed, and lymph nodes and major organs were excised for gamma counting and pathological evaluation. Pharmacokinetic behaviour of NPs in healthy versus diseased lymph nodes were calculated in individual animals and in naively pooled datasets using non-compartmental analysis. Results: Preliminary analysis identified a leading NP candidate with specific lymph node targeting in healthy and diseased rodents: a discoidal, 35-nm peptide-targeted HDL-mimetic. In comparison with a spherical, 100-nm PEGylated NP, the discoidal NP obtained greater absolute (%ID) and relative (%ID/g) amounts of injected dose in anatomically matched lymph nodes than the spherical NP, regardless of lymph node pathology. At greatest measured concentration in healthy lymph nodes, typically 24-hpi, the differences between the discoidal and spherical NPs were on average 3-fold greater (2.893 vs. 0.864, %ID/g). Differences in other pharmacokinetic parameters such as AUC (%ID/g*h) and MRT (h) were equally pronounced. Conclusions: Our preliminary analysis uncovered a discoidal, peptide-targeted HDL-mimetic with remarkable accumulation in lymph nodes of healthy and diseased models. Future investigations will focus on the biochemical and cellular mechanisms underlying their unique lymphatic pharmacokinetics. These preliminary results provide key insights for design of theranostic NPs for non-invasive imaging and staging lymph node pathologies, and for applications in delivery of therapeutics to lymph nodes following systemic administration. Citation Format: Michael S. Valic, Mark Zheng, Lili Ding, Michelle Lai, Chris J. Zhang, Tina Ye, Jenny Ma, Michael Halim, Pamela Schimmer, Wenlei Jiang, Juan Chen, Gang Zheng. Lymph node accumulation of theranostic lipid-based nanoparticles in healthy and diseased model
背景:在临床上，系统给药纳米颗粒(NPs)在淋巴结中的积累已被用于诊断成像(例如，用于淋巴结转移的USPIOs)和治疗应用(例如，疫苗递送)。然而，将诊断和治疗功能结合到单一治疗性NP中，在NP的成像或药物传递及其在淋巴结中的特异性积累之间存在着不希望的权衡。为了克服这些权衡，我们对各种基于脂质的治疗性NP进行了筛选，重点关注不同NP设计及其在健康和病变淋巴结模型中的药代动力学行为。方法:用正电子发射的Cu-64制备具有不同理化特性(如配方、大小和形态、表面靶向等)的脂质治疗性NP，并以相同NP剂量全身给药于健康和患病啮齿动物模型(即小鼠和大鼠)。在每只动物的两个或多个时间点，通过非侵入性全身PET/MR成像，评估NP类型在主要淋巴结盆地的时间依赖性积累。注射后72h处死动物，切除淋巴结及主要脏器进行伽马计数和病理评估。NPs在健康和病变淋巴结中的药代动力学行为在单个动物和使用非区室分析的原始汇总数据集中进行计算。结果:初步分析确定了一种主要的NP候选物，在健康和患病啮齿动物中具有特异性淋巴结靶向:一种盘状的，35纳米的肽靶向高密度脂蛋白模拟物。与球形、100 nm聚乙二醇化NP相比，盘状NP在解剖匹配的淋巴结中获得的绝对(%ID)和相对(%ID/g)注射剂量量大于球形NP，无论淋巴结病理如何。在健康淋巴结(通常为24 hpi)的最大测量浓度下，盘状和球形NPs之间的差异平均大3倍(2.893比0.864，%ID/g)。其他药代动力学参数如AUC (%ID/g*h)和MRT (h)的差异同样明显。结论:我们的初步分析揭示了一种盘状的、肽靶向的高密度脂蛋白模拟物，在健康和患病模型的淋巴结中有显著的积累。未来的研究将集中在其独特的淋巴药代动力学背后的生化和细胞机制。这些初步结果为设计用于无创成像和淋巴结病理分期的治疗性NPs，以及在全身给药后向淋巴结输送治疗药物的应用提供了关键见解。引用格式:Michael S. Valic, Mark Zheng, Lili Ding, Michelle Lai, Chris J. Zhang, Tina Ye, Jenny Ma, Michael Halim, Pamela Schimmer，蒋文蕾，陈娟，郑刚健康和患病模型中治疗性脂基纳米颗粒的淋巴结积聚:纳米颗粒形态和靶向性比较的初步结果[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):第307期。
{"title":"Abstract 307: Lymph node accumulation of theranostic lipid-based nanoparticles in healthy and diseased models: Preliminary results comparing nanoparticle morphology and targeting","authors":"M. Valic, Mark Zheng, L. Ding, Michelle Lai, Chris J. Zhang, T. Ye, Jenny Ma, M. Halim, P. Schimmer, Wenlei Jiang, Juan Chen, G. Zheng","doi":"10.1158/1538-7445.AM2021-307","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-307","url":null,"abstract":"Background: Accumulation of systemically administered nanoparticles (NPs) in lymph nodes has been exploited clinically for diagnostic imaging (e.g., USPIOs for lymph node metastasis) and therapeutic applications (e.g., vaccine delivery). However, the combination of diagnostic and therapeutic functionalities into a single theranostic NP has obliged undesirable trade-offs between either the imaging or drug delivery of the NP and their specific accumulation in lymph nodes. To overcome these trade-offs, we conducted a screen of various lipid-based theranostic NPs focusing on differing NP design and their resulting pharmacokinetic behaviours in healthy and diseased lymph node models. Methods: Lipid-based theranostic NPs with varying physicochemical characteristics (e.g., formulation, size and morphology, surface targeting, etc.) were prepared with positron emitting Cu-64 and administered systemically at equivalent NP doses in healthy and diseased rodent models (i.e., mice and rats). NP types were assessed for time-dependent accumulation in major lymph node basins via non-invasive whole-body PET/MR imaging at two or more timepoints per animal. 72-hours post-injection the animals were sacrificed, and lymph nodes and major organs were excised for gamma counting and pathological evaluation. Pharmacokinetic behaviour of NPs in healthy versus diseased lymph nodes were calculated in individual animals and in naively pooled datasets using non-compartmental analysis. Results: Preliminary analysis identified a leading NP candidate with specific lymph node targeting in healthy and diseased rodents: a discoidal, 35-nm peptide-targeted HDL-mimetic. In comparison with a spherical, 100-nm PEGylated NP, the discoidal NP obtained greater absolute (%ID) and relative (%ID/g) amounts of injected dose in anatomically matched lymph nodes than the spherical NP, regardless of lymph node pathology. At greatest measured concentration in healthy lymph nodes, typically 24-hpi, the differences between the discoidal and spherical NPs were on average 3-fold greater (2.893 vs. 0.864, %ID/g). Differences in other pharmacokinetic parameters such as AUC (%ID/g*h) and MRT (h) were equally pronounced. Conclusions: Our preliminary analysis uncovered a discoidal, peptide-targeted HDL-mimetic with remarkable accumulation in lymph nodes of healthy and diseased models. Future investigations will focus on the biochemical and cellular mechanisms underlying their unique lymphatic pharmacokinetics. These preliminary results provide key insights for design of theranostic NPs for non-invasive imaging and staging lymph node pathologies, and for applications in delivery of therapeutics to lymph nodes following systemic administration. Citation Format: Michael S. Valic, Mark Zheng, Lili Ding, Michelle Lai, Chris J. Zhang, Tina Ye, Jenny Ma, Michael Halim, Pamela Schimmer, Wenlei Jiang, Juan Chen, Gang Zheng. Lymph node accumulation of theranostic lipid-based nanoparticles in healthy and diseased model","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86994537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-292
G. Gutierrez, T. Phares, V. Kotraiah, P. Buontempo, James Pannucci, L. Keltner
{"title":"Abstract 292: A dual CTLA4 and PD1 microbially derived inhibitor shows efficacy in anti-PD1 mAb unresponsive tumor models through a unique allosteric mechanism of action","authors":"G. Gutierrez, T. Phares, V. Kotraiah, P. Buontempo, James Pannucci, L. Keltner","doi":"10.1158/1538-7445.AM2021-292","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-292","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"515 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77086902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-303
Mingfang Wu, Xinming Xia, Danna Sun, Chen Zhong
Drug-loaded nanocarrier is a promising treatment for targeted therapy in hepatocellular carcinoma (HCC) due to their sustained release and outstanding tumor-targeting properties. Nevertheless, a limitation of current nanocarriers is the contradiction between multiple functions and favorable biocompatibility, owing to most of functional substances are non-biological. In this study, we introduced a targeting arginine-glycine-aspartic acid (RGD)-peptide on the surface of polydopamine (PDA)-ploy (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) to develop a novel nanoparticle, which were employed as a drug delivery system loaded with paclitaxel (PTX) for HCC therapy. Paclitaxel-loaded PHBV nanoparticles (PHBV-PTX-NPs) were prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine. The RGD and PDA coated nanoparticles were combined through the Michael addition. The chemical structures and properties of these nanoparticles were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray photoelectron spectroscopy. As expected, these RGD-PDA-PHBV-PTX-NPs achieved excellent targeting efficiency, which was revealed by the cellular uptake and cytotoxicity assay in HCC cells. Compared with that of free PTX, the RGD-PDA-PHBV-PTX-NPs showed more superior antitumor efficacy in the xenograft mouse model. Notably, in addition to efficient anticancer activities, RGD-PDA-PHBV-PTX-NPs exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. These studies suggest the potential beneficial use of RGD-PDA-PHBV-PTX-NPs in future HCC-targeted therapy with drug-loaded nanocarriers. Citation Format: Mingfang Wu, Xinming Xia, Danna Sun, Chen Zhong. Surface modification of paclitaxel-loaded nanoparticles based on polydopamine with pH sensitive property for targeted therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 303.
{"title":"Abstract 303: Surface modification of paclitaxel-loaded nanoparticles based on polydopamine with pH sensitive property for targeted therapy in hepatocellular carcinoma","authors":"Mingfang Wu, Xinming Xia, Danna Sun, Chen Zhong","doi":"10.1158/1538-7445.AM2021-303","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-303","url":null,"abstract":"Drug-loaded nanocarrier is a promising treatment for targeted therapy in hepatocellular carcinoma (HCC) due to their sustained release and outstanding tumor-targeting properties. Nevertheless, a limitation of current nanocarriers is the contradiction between multiple functions and favorable biocompatibility, owing to most of functional substances are non-biological. In this study, we introduced a targeting arginine-glycine-aspartic acid (RGD)-peptide on the surface of polydopamine (PDA)-ploy (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) to develop a novel nanoparticle, which were employed as a drug delivery system loaded with paclitaxel (PTX) for HCC therapy. Paclitaxel-loaded PHBV nanoparticles (PHBV-PTX-NPs) were prepared by emulsion solvent evaporation. As a gatekeeper, the pH-sensitive coating was formed by self-polymerization of dopamine. The RGD and PDA coated nanoparticles were combined through the Michael addition. The chemical structures and properties of these nanoparticles were characterized by dynamic light scattering-autosizer, transmission electron microscope, fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetry and X-ray photoelectron spectroscopy. As expected, these RGD-PDA-PHBV-PTX-NPs achieved excellent targeting efficiency, which was revealed by the cellular uptake and cytotoxicity assay in HCC cells. Compared with that of free PTX, the RGD-PDA-PHBV-PTX-NPs showed more superior antitumor efficacy in the xenograft mouse model. Notably, in addition to efficient anticancer activities, RGD-PDA-PHBV-PTX-NPs exhibited lower toxicity than PTX to normal hepatocytes and mouse in vitro and in vivo, respectively. These studies suggest the potential beneficial use of RGD-PDA-PHBV-PTX-NPs in future HCC-targeted therapy with drug-loaded nanocarriers. Citation Format: Mingfang Wu, Xinming Xia, Danna Sun, Chen Zhong. Surface modification of paclitaxel-loaded nanoparticles based on polydopamine with pH sensitive property for targeted therapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 303.","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"469 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76808368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-304
A. Hazelton, T. Samec, J. Boulos, S. Gilmore, Angela A Alexander-Bryant
{"title":"Abstract 304: Peptide-mediated delivery of siRNAs targeting CSNK2A1 decreases migration of ovarian cancer cellsin vitro","authors":"A. Hazelton, T. Samec, J. Boulos, S. Gilmore, Angela A Alexander-Bryant","doi":"10.1158/1538-7445.AM2021-304","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-304","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73860253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-280
Xiaowei Ma, Ping Zhang, Chao Cui, Chang-Chun Ling, Lina Cui
Systemic treatment of cancer using long-circulating nanomedicines is promising due to their passive tumor targeting ability to achieve higher and more selective accumulation in tumors with irregular vascularization, a phenomenon known as extended permeation and retention (EPR) effect.1,2 Clinical use of nanometer-sized carriers, such as Doxil and Abraxane, to deliver chemotherapeutics to solid tumors is proven effective in highly vascularized tumors such as breast cancer, ovarian cancer, multiple myeloma, and Kaposi9s sarcoma.3-5 Most nanomedicines that are being developed or approved so far have a diameter of around 100-200 nm for prolonged retention in highly angiogenic and densely vascularized tumors,6 however, they suffer from limited accumulation and poor penetration to the inner core of avascular or hypovascular tumors (such as prostate and pancreatic cancer),7-9 therefore nanomedicines small than 100 nm are more preferred for improved tumor penetration.10,11 Here we present our strategy to form cyclodextrin-based sub-30-nm nanocarriers, which allows easy drug encapsulation, and successful delivery of therapeutics to human tumor xenografts with significantly reduced tumor growth rates and improved survival rates. Citation Format: Xiaowei Ma, Ping Zhang, Chao Cui, Chang-Chun Ling, Lina Cui. Sub-30-nm capsules for drug delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 280.
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-273
Catherine M. Ade, Y. Qi, Sudipto Das, K. Hanada, Tapan Maity, Xu Zhang, T. Andresson, U. Guha, J. Yang
{"title":"Abstract 273: A mass spectrometry survey of frequent HLA alleles successfully presenting common tumor specific mutations for immune recognition","authors":"Catherine M. Ade, Y. Qi, Sudipto Das, K. Hanada, Tapan Maity, Xu Zhang, T. Andresson, U. Guha, J. Yang","doi":"10.1158/1538-7445.AM2021-273","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-273","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78974774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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