Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-310
Parmandeep Kaur, D. Choudhury
The oral route is the most convenient route of drug administration and almost 80 % of the drugs are administered through this route. Despite many advantages like self-administrable, convenient, economic, pain-free, non-invasive, etc, the oral route is a major challenge for drugs which has low permeability through the GI tract leading to absorption of only 3-10% of the administered dose and reduced bioavailability. Therefore, due to limited half-life (~30 mins) in the stomach and small intestine, to achieve effective response excess of drugs need to be administrated through an oral route which causes many side effects including irritable bowel syndrome, hemorrhoids, gastrointestinal ulcers, and cancer, Cohn9s disease, ulcerative colitis, etc. Besides mixing of the un-metabolized drug to the environment like soil and drinking water causes bio-magnifications and infer the development of antibiotic resistance in microorganisms. Therefore, an increase of half-life in the GI tract would be a great solution to solve this problem. Here in this work, we show the use of surface encapsulated mesoporous (2-3 nm) carbohydrate nanoparticles of (15-25 nm in size) on metabolically active Lactobacillus reuteri, a GRAS bacterium, as a drug carrier vehicle suitable for oral administration. We have further demonstrated the use of bacteria mediated drug delivery system for enhancing the potency of 5-fluorouracil against Sarcoma-180 cancer. The bacterial surface encapsulated nanoparticles particles showed 12-15% drug loading capacity of its dry weight. The particles also showed excellent stability up to 48 h in simulated gastric and intestinal fluid. Further, the particles showed sustained release of the drug for up to 16 h, where after an initial blast (release up to 30 %) between 30 min-1 h a steady release of drug was obtained for up to 6.5 to 7 h, where 95% of the drug got released within that window. The pre-clinical study showed anchorage of drug-loaded surface encapsulated microbes to the mice intestinal alveolar regions after feeding through the oral route. Further, a study using murine Sarcoma-180 tumor model showed enhancement of life span and enhanced shrinkage of the Sarcoma-180 solid tumor volume (up to -95%) at optimal dose 50 mg/Kg dose, in comparison with control only ~75% throughout 10 days9 treatment. Up to 75 % reduction of tumor volume was also observed in suboptimal dose (25 mg/kg) using the microbial vehicle. Reduction of hepatic and nephrotic toxicity was also evident from the blood parameters analysis and histological analysis was also prominent using this delivery tool. This novel design and development make this system ideal for use in orally administrable drug shaving low solubility or permeability or both. Citation Format: Parmandeep Kaur, Diptiman Choudhury. Gut microflora mediated novel oral drug delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. P
{"title":"Abstract 310: Gut microflora mediated novel oral drug delivery system","authors":"Parmandeep Kaur, D. Choudhury","doi":"10.1158/1538-7445.AM2021-310","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-310","url":null,"abstract":"The oral route is the most convenient route of drug administration and almost 80 % of the drugs are administered through this route. Despite many advantages like self-administrable, convenient, economic, pain-free, non-invasive, etc, the oral route is a major challenge for drugs which has low permeability through the GI tract leading to absorption of only 3-10% of the administered dose and reduced bioavailability. Therefore, due to limited half-life (~30 mins) in the stomach and small intestine, to achieve effective response excess of drugs need to be administrated through an oral route which causes many side effects including irritable bowel syndrome, hemorrhoids, gastrointestinal ulcers, and cancer, Cohn9s disease, ulcerative colitis, etc. Besides mixing of the un-metabolized drug to the environment like soil and drinking water causes bio-magnifications and infer the development of antibiotic resistance in microorganisms. Therefore, an increase of half-life in the GI tract would be a great solution to solve this problem. Here in this work, we show the use of surface encapsulated mesoporous (2-3 nm) carbohydrate nanoparticles of (15-25 nm in size) on metabolically active Lactobacillus reuteri, a GRAS bacterium, as a drug carrier vehicle suitable for oral administration. We have further demonstrated the use of bacteria mediated drug delivery system for enhancing the potency of 5-fluorouracil against Sarcoma-180 cancer. The bacterial surface encapsulated nanoparticles particles showed 12-15% drug loading capacity of its dry weight. The particles also showed excellent stability up to 48 h in simulated gastric and intestinal fluid. Further, the particles showed sustained release of the drug for up to 16 h, where after an initial blast (release up to 30 %) between 30 min-1 h a steady release of drug was obtained for up to 6.5 to 7 h, where 95% of the drug got released within that window. The pre-clinical study showed anchorage of drug-loaded surface encapsulated microbes to the mice intestinal alveolar regions after feeding through the oral route. Further, a study using murine Sarcoma-180 tumor model showed enhancement of life span and enhanced shrinkage of the Sarcoma-180 solid tumor volume (up to -95%) at optimal dose 50 mg/Kg dose, in comparison with control only ~75% throughout 10 days9 treatment. Up to 75 % reduction of tumor volume was also observed in suboptimal dose (25 mg/kg) using the microbial vehicle. Reduction of hepatic and nephrotic toxicity was also evident from the blood parameters analysis and histological analysis was also prominent using this delivery tool. This novel design and development make this system ideal for use in orally administrable drug shaving low solubility or permeability or both. Citation Format: Parmandeep Kaur, Diptiman Choudhury. Gut microflora mediated novel oral drug delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. P","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":"83073340","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.AM2021-316
B. Manfredi, R. Hohl
{"title":"Abstract 316: Effect of schweinfurthins on malignant plasma cells","authors":"B. Manfredi, R. Hohl","doi":"10.1158/1538-7445.AM2021-316","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-316","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83178282","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.AM2021-330
J. Oyer, Johnson Ted William, Andrew C. Wang, M. Maestre, Ana Flores-Bojorquez, R. Melnychuk, Sergei L Timofeevski, Sherry L. Niessen, Zhenxiong Wang, Jian Li, Wade Diehl, Koleen Eisele, N. Lee, A. Zou, Carl Davis, Eric C Greenwald, Jacob C. DeForest, Martha A. Ornelas, Bryan Li, S. Scales, Penney Khamphavong, C. Ambler, Yun Huang, Romelia Salomón-Ferrer, S. Greasley, Ben Bolanos, N. Grodsky, L. Lum, T. Vanarsdale, Indrawan J. McAlpine
{"title":"Abstract 330: Engineering electrophile-sensitive kinase mutants to accelerate oncology target validation","authors":"J. Oyer, Johnson Ted William, Andrew C. Wang, M. Maestre, Ana Flores-Bojorquez, R. Melnychuk, Sergei L Timofeevski, Sherry L. Niessen, Zhenxiong Wang, Jian Li, Wade Diehl, Koleen Eisele, N. Lee, A. Zou, Carl Davis, Eric C Greenwald, Jacob C. DeForest, Martha A. Ornelas, Bryan Li, S. Scales, Penney Khamphavong, C. Ambler, Yun Huang, Romelia Salomón-Ferrer, S. Greasley, Ben Bolanos, N. Grodsky, L. Lum, T. Vanarsdale, Indrawan J. McAlpine","doi":"10.1158/1538-7445.AM2021-330","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-330","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81749827","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.AM2021-306
S. Gardner, K. L. Alatise, E. Miller, E. Grant, Angela A Alexander-Bryant
Introduction: Ovarian cancer is the fifth leading cause of cancer mortality in women, with nearly 75% of women who respond to initial platinum-based chemotherapy experiencing relapse due to drug resistance [1,2]. Liposomes are a promising solution to overcoming drug resistance due to their biocompatibility and capacity to encapsulate hydrophilic and hydrophobic drugs as well as complex small interfering RNA (siRNA), which have the potential to downregulate the expression of genes related to drug resistance [3]. We aim to synthesize and characterize a cationic liposomal system to deliver siRNA and paclitaxel (PTX) to ovarian cancer cells. Methods: Cholesterol (CHOL) liposomes were synthesized by the thin-film hydration method. Dynamic light scattering (DLS) was used to determine the size, polydispersity index (PDI), and zeta potential of the liposomes. Uptake of liposomes into OVCAR3 and OVCAR3-T40, a wild-type and a paclitaxel-resistant human adenocarcinoma cell line, was examined using fluorescence microscopy. The cytotoxicity of unloaded CHOL liposomes was evaluated through MTS assay on OVCAR3 and OVCAR3-T40 cells. Results: PTX- and siRNA-loaded CHOL liposomes had an average diameter of 114.9 ± 10.35 nm and a zeta potential of 27.6 ± 1.79 mV. Blank CHOL liposomes had an average diameter of 123.0 ± 2.49 nm and zeta potential of 32.3 ± 2.16 mV. All formulations of liposomes were cationic and formed monodisperse nanoparticles. The encapsulation efficiency of siRNA and PTX was 99.8% and 80.4% respectively. Coumarin 6, a hydrophobic model drug, was loaded into liposomes to verify cellular uptake through fluorescent imaging. Results demonstrated that the liposomal system was efficiently delivered intracellularly. Blank liposomes were used to determine the toxicity of the delivery system. The unloaded liposomes were not cytotoxic to both the wild-type and drug-resistant cell lines at concentrations up to 75 µg/mL, and therefore, cytotoxicity of drug-loaded liposomes can be attributed to paclitaxel, siRNA, or combination treatment. Conclusions: Liposomes were successfully formed with a monodisperse size, exhibited effective drug and siRNA loading, and were internalized into OVCAR3 and OVCAR3-T40 cells. Future work includes investigating the efficacy of the liposomal system in mediating gene silencing. Acknowledgements: This work was supported in part by the National Science Foundation EPSCoR Program under NSF Award # OIA-1655740 and Clemson Creative Inquiry. References: [1] Torre, L. A., CA Cancer J Clin. 2018;68(4):284-296, [2], Norouzi-Barough L., J Cell Physiol.2018;233(6):4546-4562, [3] Farra R., Pharmaceutics. 2019;11(10):547. Citation Format: Samantha Gardner, Kharimat L. Alatise, Emily Miller, Emily Grant, Angela Alexander-Bryant. Cationic cholesterol liposomes for combination therapy to treat drug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-2
{"title":"Abstract 306: Cationic cholesterol liposomes for combination therapy to treat drug-resistant ovarian cancer","authors":"S. Gardner, K. L. Alatise, E. Miller, E. Grant, Angela A Alexander-Bryant","doi":"10.1158/1538-7445.AM2021-306","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-306","url":null,"abstract":"Introduction: Ovarian cancer is the fifth leading cause of cancer mortality in women, with nearly 75% of women who respond to initial platinum-based chemotherapy experiencing relapse due to drug resistance [1,2]. Liposomes are a promising solution to overcoming drug resistance due to their biocompatibility and capacity to encapsulate hydrophilic and hydrophobic drugs as well as complex small interfering RNA (siRNA), which have the potential to downregulate the expression of genes related to drug resistance [3]. We aim to synthesize and characterize a cationic liposomal system to deliver siRNA and paclitaxel (PTX) to ovarian cancer cells. Methods: Cholesterol (CHOL) liposomes were synthesized by the thin-film hydration method. Dynamic light scattering (DLS) was used to determine the size, polydispersity index (PDI), and zeta potential of the liposomes. Uptake of liposomes into OVCAR3 and OVCAR3-T40, a wild-type and a paclitaxel-resistant human adenocarcinoma cell line, was examined using fluorescence microscopy. The cytotoxicity of unloaded CHOL liposomes was evaluated through MTS assay on OVCAR3 and OVCAR3-T40 cells. Results: PTX- and siRNA-loaded CHOL liposomes had an average diameter of 114.9 ± 10.35 nm and a zeta potential of 27.6 ± 1.79 mV. Blank CHOL liposomes had an average diameter of 123.0 ± 2.49 nm and zeta potential of 32.3 ± 2.16 mV. All formulations of liposomes were cationic and formed monodisperse nanoparticles. The encapsulation efficiency of siRNA and PTX was 99.8% and 80.4% respectively. Coumarin 6, a hydrophobic model drug, was loaded into liposomes to verify cellular uptake through fluorescent imaging. Results demonstrated that the liposomal system was efficiently delivered intracellularly. Blank liposomes were used to determine the toxicity of the delivery system. The unloaded liposomes were not cytotoxic to both the wild-type and drug-resistant cell lines at concentrations up to 75 µg/mL, and therefore, cytotoxicity of drug-loaded liposomes can be attributed to paclitaxel, siRNA, or combination treatment. Conclusions: Liposomes were successfully formed with a monodisperse size, exhibited effective drug and siRNA loading, and were internalized into OVCAR3 and OVCAR3-T40 cells. Future work includes investigating the efficacy of the liposomal system in mediating gene silencing. Acknowledgements: This work was supported in part by the National Science Foundation EPSCoR Program under NSF Award # OIA-1655740 and Clemson Creative Inquiry. References: [1] Torre, L. A., CA Cancer J Clin. 2018;68(4):284-296, [2], Norouzi-Barough L., J Cell Physiol.2018;233(6):4546-4562, [3] Farra R., Pharmaceutics. 2019;11(10):547. Citation Format: Samantha Gardner, Kharimat L. Alatise, Emily Miller, Emily Grant, Angela Alexander-Bryant. Cationic cholesterol liposomes for combination therapy to treat drug-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-2","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87601962","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.AM2021-312
Hyung-Gyoo Kang, J. Nagy, Bryon Upton, R. Upton, T. Triche
The tumor-targeted, nanoparticle delivery technology has shown the possibility of increasing the delivered dose of virtually any small therapeutics to tumor cells while limiting the drug uptake by normal tissues, thereby greatly increasing the effective MTD. By refining the early formulations and after extensive testing, we developed a novel targeted liposomal nanoparticle, Targeted NanoSpheres (TNS). We showed this novel nano-formulated platform can overcome many deficiencies of conventional nanoparticles and therefore has enhanced potential as an effective delivery vehicle for virtually any type of cancer for which a suitable tumor cell surface antigen is present. We have developedNV103, a first-in-class anti-CD99 TNS (CD99-TNS/Irinotecan), for the treatment of Ewing Sarcoma (EWS), a highly lethal pediatric and young adult bone and soft tissue tumor driven by a fusion protein, typically EWS/FLI1 in over 85% of cases. Cancer cells have the ability to develop resistance to the chemotherapy. Our present salvage/rescue study with NV103 showed that NV103 can overcome irinotecan resistance of Ewing tumor with simple change of dose schedule (dose intensification), not increasing the dose. The results from our salvage/rescue studies with NV103 suggested that successful dose intensification schedules with NV103 could be used to treat relapsed or resistant patients in future clinical trials. Furthermore, Targeted Nanosphere (TNS) can be used to overcome drug resistance of various cancers.This platform is also being investigated for other types of cancer that either express CD99, or other tumor antigens like GD2 and B7-H3. Citation Format: HyungGyoo Kang, Jon Nagy, Bryon Upton, Racheal Upton, Timothy Triche, Timothy Triche. Targeted NanoSpheres (TNS) [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 312.
以肿瘤为靶点的纳米颗粒给药技术表明，在限制正常组织对药物的摄取的同时，几乎可以增加任何小剂量治疗药物对肿瘤细胞的递送剂量，从而大大提高有效MTD。通过改进早期配方并经过广泛的测试，我们开发了一种新的靶向脂质体纳米颗粒，靶向纳米球(targeted NanoSpheres, TNS)。我们证明了这种新型纳米配方平台可以克服传统纳米颗粒的许多缺陷，因此具有增强的潜力，作为一种有效的递送载体，几乎可以用于任何类型的肿瘤细胞表面抗原存在的癌症。我们已经开发了nv103，一种一流的抗cd99 TNS (CD99-TNS/伊立替康)，用于治疗Ewing肉瘤(EWS)， EWS是一种由融合蛋白驱动的高度致命的儿童和年轻人骨骼和软组织肿瘤，典型的EWS/FLI1在超过85%的病例中。癌细胞有能力对化疗产生耐药性。我们目前对NV103的抢救研究表明，NV103只需改变剂量计划(剂量增强)，而不增加剂量，即可克服Ewing肿瘤的伊立替康耐药。我们对NV103的抢救/抢救研究结果表明，在未来的临床试验中，NV103成功的剂量强化方案可用于治疗复发或耐药患者。此外，靶向纳米球(TNS)可用于克服各种癌症的耐药。该平台也正在研究用于表达CD99或其他肿瘤抗原(如GD2和B7-H3)的其他类型的癌症。引用格式:HyungGyoo Kang, Jon Nagy, Bryon Upton, Racheal Upton, Timothy Triche, Timothy Triche。靶向纳米微球(TNS)[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):312。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-277
Duaa Kanan, Tarek Kanan, Berna Dogan, S. Durdağı
{"title":"Abstract 277: Discovery of promising antineoplastic drugs against the USP7 deubiquitinating enzyme: A pharmacophore-based FDA-approved and investigational drugs repurposing study","authors":"Duaa Kanan, Tarek Kanan, Berna Dogan, S. Durdağı","doi":"10.1158/1538-7445.AM2021-277","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-277","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75958335","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.AM2021-302
Sagun Poudel, G. Mattheolabakis
Oral delivery of nucleic acids has been challenging, due to unfavorable physiological factors that do not comply with the nucleic acids9 properties. Firstly, nucleic acids break down in the harsh acidic gastric environment. Secondly, they are hydrophilic, negatively charged, large-molecular-weight molecules, unable to efficiently penetrate through the mucus membrane and enter the epithelial intestinal wall. We developed a novel nano delivery system of nucleic acids complexed with mannosylated PEI encapsulated in PEG-PCL matrix. We will use this carrier to overcome the above-mentioned limitations of oral nucleic acid delivery aiming for colon cancer treatment. We synthesized the mannosylated PEI with the objective to target colon cancer cells. We will use active targeting as these cells overexpress mannose receptors. We complexed a model nucleic acid, the PGL-3 luciferase expressing plasmid, with mannosylated PEI at the optimal N/P ratio of 20:1. We transfected cancer cells in vitro and analyzed the luciferase expression. Furthermore, we analyzed the cytotoxicity of PCL-PEG nanoparticles containing mannosylated PEI/PGL-3 complexes, as well as the nanoparticles capacity to protect nucleic acids and release their load. Mannosylated PEI successfully complexed with the nucleic acids, protecting from degradation against nucleases. Mannosylated PEI/PGL-3 complexes transfected colon cancer cells and the luciferase expression was significantly higher when compared to PEI alone, at 24 and 48 h. The complexes were successfully up taken by cell lines in a time dependent manner. Competitive transfection assay with free mannose demonstrated the active targeting effect caused due to the mannose receptors. Similarly, the PCL-PEG nanoparticles with mannose PEI/PGL-3 complexes had a limited cytotoxicity. Most importantly, the carrier successfully protected the mannose PEI/PGL-3 complexes in a simulated gastric fluid environment and released them in a simulated intestinal fluid environment. This indicates that the nanocarriers can potentially protect the nucleic acids in an acidic environment, such as the stomach, and release their mannosylated PEI/PGL-3 in a neutral environment, such as in the intestines. Such a behavior would indicate a passive targeting to the small and large intestines. We can conclude that the formulated polymeric nanoparticles were successful in protecting the nucleic acids. The mannosylated PEI was able to completely complex with nucleic acids and actively target colon cancer. This promising nanocarrier and our approach merits further evaluation for the oral administration of nucleic acids in therapeutic applications of passive and active targeting against colon cancer. Citation Format: Sagun Poudel, George Mattheolabakis. Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2
由于不符合核酸特性的不利生理因素，核酸的口服递送一直具有挑战性。首先，核酸在恶劣的酸性胃环境中分解。其次，它们是亲水、带负电、大分子量分子，不能有效地穿透黏液膜进入上皮性肠壁。我们开发了一种新型的核酸与甘露糖基PEI配合的纳米递送系统，该系统被包裹在PEG-PCL基质中。我们将利用这种载体来克服上述针对结肠癌治疗的口服核酸递送的局限性。我们合成了甘露糖基PEI，目的是靶向结肠癌细胞。我们将使用主动靶向，因为这些细胞过表达甘露糖受体。我们将表达PGL-3荧光素酶的模型核酸与甘露糖基化PEI以20:1的最佳N/P比络合。我们在体外转染癌细胞，分析荧光素酶的表达。此外，我们分析了含有甘露糖基化PEI/PGL-3复合物的PCL-PEG纳米颗粒的细胞毒性，以及纳米颗粒保护核酸和释放其负载的能力。甘露糖基化PEI成功地与核酸络合，防止核酸酶降解。甘露糖基化PEI/PGL-3复合物转染结肠癌细胞后，在24和48 h时，荧光素酶的表达明显高于单纯PEI。这些复合物以时间依赖性的方式被细胞系成功吸收。游离甘露糖竞争性转染实验证实了甘露糖受体的活性靶向作用。同样，带有甘露糖PEI/PGL-3复合物的PCL-PEG纳米颗粒具有有限的细胞毒性。最重要的是，载体在模拟胃液环境中成功保护了甘露糖PEI/PGL-3复合物，并将其释放到模拟肠液环境中。这表明纳米载体可以潜在地在酸性环境(如胃)中保护核酸，并在中性环境(如肠道)中释放甘露糖基化的PEI/PGL-3。这样的行为表明是对小肠和大肠的被动攻击。我们可以得出结论，配制的聚合物纳米颗粒成功地保护了核酸。甘露糖基化PEI能够与核酸完全复合物并积极靶向结肠癌。这种有前景的纳米载体和我们的方法值得进一步评估核酸口服给药在被动和主动靶向治疗结肠癌中的应用。引文格式:Sagun Poudel, George Mattheolabakis。一种新型口服纳米载体对结肠癌细胞的被动和主动核酸递送[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302期。
{"title":"Abstract 302: Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration","authors":"Sagun Poudel, G. Mattheolabakis","doi":"10.1158/1538-7445.AM2021-302","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-302","url":null,"abstract":"Oral delivery of nucleic acids has been challenging, due to unfavorable physiological factors that do not comply with the nucleic acids9 properties. Firstly, nucleic acids break down in the harsh acidic gastric environment. Secondly, they are hydrophilic, negatively charged, large-molecular-weight molecules, unable to efficiently penetrate through the mucus membrane and enter the epithelial intestinal wall. We developed a novel nano delivery system of nucleic acids complexed with mannosylated PEI encapsulated in PEG-PCL matrix. We will use this carrier to overcome the above-mentioned limitations of oral nucleic acid delivery aiming for colon cancer treatment. We synthesized the mannosylated PEI with the objective to target colon cancer cells. We will use active targeting as these cells overexpress mannose receptors. We complexed a model nucleic acid, the PGL-3 luciferase expressing plasmid, with mannosylated PEI at the optimal N/P ratio of 20:1. We transfected cancer cells in vitro and analyzed the luciferase expression. Furthermore, we analyzed the cytotoxicity of PCL-PEG nanoparticles containing mannosylated PEI/PGL-3 complexes, as well as the nanoparticles capacity to protect nucleic acids and release their load. Mannosylated PEI successfully complexed with the nucleic acids, protecting from degradation against nucleases. Mannosylated PEI/PGL-3 complexes transfected colon cancer cells and the luciferase expression was significantly higher when compared to PEI alone, at 24 and 48 h. The complexes were successfully up taken by cell lines in a time dependent manner. Competitive transfection assay with free mannose demonstrated the active targeting effect caused due to the mannose receptors. Similarly, the PCL-PEG nanoparticles with mannose PEI/PGL-3 complexes had a limited cytotoxicity. Most importantly, the carrier successfully protected the mannose PEI/PGL-3 complexes in a simulated gastric fluid environment and released them in a simulated intestinal fluid environment. This indicates that the nanocarriers can potentially protect the nucleic acids in an acidic environment, such as the stomach, and release their mannosylated PEI/PGL-3 in a neutral environment, such as in the intestines. Such a behavior would indicate a passive targeting to the small and large intestines. We can conclude that the formulated polymeric nanoparticles were successful in protecting the nucleic acids. The mannosylated PEI was able to completely complex with nucleic acids and actively target colon cancer. This promising nanocarrier and our approach merits further evaluation for the oral administration of nucleic acids in therapeutic applications of passive and active targeting against colon cancer. Citation Format: Sagun Poudel, George Mattheolabakis. Passive and active nucleic acid delivery against colon cancer cells using a novel nanocarrier aimed for oral administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"165 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74121388","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.AM2021-16
Y. Geffen, Shankara K. Anand, Yoshihisa Akiyama, Tommer M. Yaron, A. Kerelsky, Jared L. Johnson, Karsten Krug, David I Heiman, S. Satpathy, K. Clauser, Michael A. Gillette, D. Mani, Chet Birger, Steve Carr, L. Cantley, F. Aguet, G. Getz
{"title":"Abstract 16: Patterns and regulation of post translational modifications in cancer","authors":"Y. Geffen, Shankara K. Anand, Yoshihisa Akiyama, Tommer M. Yaron, A. Kerelsky, Jared L. Johnson, Karsten Krug, David I Heiman, S. Satpathy, K. Clauser, Michael A. Gillette, D. Mani, Chet Birger, Steve Carr, L. Cantley, F. Aguet, G. Getz","doi":"10.1158/1538-7445.AM2021-16","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-16","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"333 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79730970","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.AM2021-272
M. Rasheduzzaman, Xi Zhang, R. Dolcetti, L. Kenny, N. Johnson, D. Kolarich, C. Punyadeera
{"title":"Abstract 272: Glycomics: Protein glycosylation changes in the pathogenesis of head and neck cancer","authors":"M. Rasheduzzaman, Xi Zhang, R. Dolcetti, L. Kenny, N. Johnson, D. Kolarich, C. Punyadeera","doi":"10.1158/1538-7445.AM2021-272","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-272","url":null,"abstract":"","PeriodicalId":9563,"journal":{"name":"Cancer Chemistry","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81883190","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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