Targeted Nanotherapy for Pancreatic Cancer
胰腺癌靶向纳米治疗
基本信息
- 批准号:9186665
- 负责人:
- 金额:$ 34.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-24 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AbraxaneAdverse effectsAlbumin-Stabilized Nanoparticle PaclitaxelAlbuminsAntibodiesAntibody-drug conjugatesAntineoplastic AgentsApoptoticAttenuatedBindingBiodistributionBiological AvailabilityCXCL12 geneCXCR4 geneCancer PatientCell LineCell membraneCessation of lifeClinicalCoupledDataDepositionDevelopmentDiagnosisDiseaseDrug Delivery SystemsDrug EffluxDrug TransportDrug resistanceEngineeringEnvironmentExhibitsExtracellular MatrixFDA approvedFibrosisFormulationGoalsGrowthIn VitroInvestigationKineticsLeadLegal patentLipidsMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMethodsMicroRNAsModalityMolecularMucin 1 proteinNeoplasm MetastasisOncogenicPaclitaxelPathway interactionsPatientsPharmaceutical PreparationsPluronicsProteinsPublishingRegulationResearch ProposalsResistanceSHH geneSafetySignal PathwaySiteStromal NeoplasmSurvival RateSystemTestingTherapeuticTransgenic MiceTransgenic OrganismsTranslationsTreatment EfficacyTreatment ProtocolsXenograft ModelXenograft procedurebasecancer therapychemotherapyclinically relevanteffective therapygemcitabineimprovedin vivoinnovationintravenous administrationlipid structuremouse modelnanoformulationnanoparticlenanotherapyneoplastic cellnoveloverexpressionpancreatic cancer cellspancreatic neoplasmparacrineresistance mechanismresponsetargeted deliverytargeted treatmenttherapy outcometreatment choicetumortumor growthtumor microenvironmenttumor progressionuptake
项目摘要
The long-term goal of the proposed research proposal is to develop a targeted paclitaxel nanotherapy that
can be used for the treatment of pancreatic cancer (PanCa) in combination with Gemcitabine (GEM).
Although many conventional and combinational chemotherapies exist to treat PanCa, significant side
effects occur without increasing the survival of patients (not even 2 additional months). Desmoplasia
(characterized by excessive fibrosis and extracellular matrix deposition) causes suboptimal drug delivery in
tumors and thus induces chemo-resistance. Additionally, certain signaling pathways, abnormal tumor cell
membrane lipid structure/composition and restricted drug uptake due to overexpression of drug efflux
associated proteins also lead to cancer progression/metastasis and drug resistance. A recent FDA-
approved (on Sept. 6, 2013) combination treatment regimen [nab-nanoparticles (i.e., paclitaxel nanoparticles,
Abraxane®) plus GEM] has marginally improved (only 1.8 months) overall survival (8.5 months vs. 6.7 months
with GEM alone). Studies have also shown that PTX altered tumor microenvironment (TME) and reduced
desmoplasia, thus improved GEM uptake in pancreatic tumors. We believe that this PTX-mediated
marginally improved therapeutic outcome can be further enhanced by using an inimitable tumor specific
antibody targeted PTX nanoparticle formulation. We hypothesize that antibody-guided, tumor specific
targeted delivery of PPNPs will enhance the bioavailability of PTX in pancreatic tumors and macro/
micro metastatic lesions to attenuate tumor growth and sensitize tumor cells to GEM via decreased
desmoplasia, altered TME and SHH/CXCL12/CXCR4, miR-21 mediated oncogenic signaling pathways.
This proposal examines two levels of targeting PanCa. The first is MUC13 targeted delivery of PTX to
pancreatic tumors as our PPNPs selectively/preferentially reach and accumulate in the tumors/metastatic
lesions. Our preliminary data demonstrates that MUC13 targeted nanoparticles effectively target pancreatic
tumors. The second level of treatment is intravenous administration of GEM. The first level of targeting will
considerably alter TME which will thus promote a better response to GEM. This novel combination therapeutic
modality will enhance drug loading specifically to the tumor site, inducing greater anti-cancer effects while
minimizing side effects. To achieve these goals, three specific aims are proposed: AIM 1: To Evaluate Chemo-
sensitization and TME of PPNPs in PanCa Cells. AIM 2: To Investigate Pharmaco-kinetics/dynamics (PK/PD)
and Safety of PPNPs/GEM in a stromal component containing PanCa xenograft mouse model. AIM 3: To
Evaluate the Therapeutic Efficacy of MUC13 Targeted PPNP Formulation in clinically relevant transgenic
mice and patient derived xenograft (PDX) models. This proposal leads to a better treatment modality by
altering tumor-stromal (paracrine) cross-talk and chemo-sensitization in PanCa which are considered to be
major roadblocks in PanCa therapeutics. The proposed studies are based on recent clinical observations,
thus clinical translation of this approach will be easy and quick.
拟议研究提案的长期目标是开发一种靶向紫杉醇纳米疗法,
可与吉西他滨(GEM)联合用于治疗胰腺癌。
虽然存在许多常规和联合化疗方法来治疗胰腺癌,但重要的是
效果的发生不会增加患者的存活率(甚至不会增加2个月)。结缔组织发育不全
(以过度纤维化和细胞外基质沉积为特征)导致在
肿瘤,从而诱导化疗耐药。此外,某些信号通路,异常的肿瘤细胞
膜脂结构/组成与药物外排过表达所致的药物摄取受限
相关蛋白还导致癌症进展/转移和耐药性。最近的FDA-
批准(于9月9日6,2013)联合治疗方案[NaB-纳米粒(即,紫杉醇纳米粒,
Abraxane®)加GEM]略微改善了(仅1.8个月)总生存期(8.5个月与6.7个月
仅用宝石)。研究还表明,PTX改变了肿瘤微环境(TME),并减少了
促结缔组织增生症,从而改善了胰腺肿瘤对GEM的摄取。我们认为这种PTX介导的
通过使用无与伦比的肿瘤特异性药物可以进一步提高略微改善的治疗结果
抗体靶向PTX纳米粒制剂。我们假设抗体引导的、肿瘤特异性的
靶向递送PPNPs将提高PTX在胰腺肿瘤和宏细胞肿瘤中的生物利用度
微转移灶通过减少抑制肿瘤生长和增加肿瘤细胞对GEM的敏感性
促结缔组织增生、TME改变和SHH/CXCL12/CXCR4、miR-21介导的致癌信号通路。
这项提案考察了两个层次的目标panca。第一种是MUC13靶向传递PTX至
胰腺肿瘤作为我们的PPNPs选择性/优先到达并积聚在肿瘤/转移性肿瘤中
损伤。我们的初步数据表明,MUC13靶向纳米粒有效地靶向胰腺
肿瘤。第二个层次的治疗是静脉注射GEM。第一级目标将是
显著改变TME,从而促进对创业板的更好反应。这是一种新型的联合疗法
这种方法将提高药物对肿瘤部位的特异性载药量,从而产生更好的抗癌效果
将副作用降至最低。为了实现这些目标,提出了三个具体目标:目标1:评估化学药物
PPNPs在Panca细胞中的敏化和TME。目的2:研究药代动力学/动力学(PK/PD)
PPNPs/GEM在含有PANCA的异种移植小鼠模型中的安全性。目标3:实现
MUC13靶向PPNP制剂在临床相关转基因中的疗效评价
小鼠和患者来源的异种移植(PDX)模型。这一建议通过以下方式带来了更好的治疗方式
改变肿瘤间质(旁分泌)的串扰和化疗敏化,这被认为是
潘卡疗法的主要障碍。建议的研究是基于最近的临床观察,
因此,这种方法的临床翻译将是容易和快速的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Subhash C. Chauhan其他文献
Dietary mung bean as promising food for human health: gut microbiota modulation and insight into factors, regulation, mechanisms and therapeutics—an update
- DOI:
10.1007/s10068-023-01495-8 - 发表时间:
2024-01-17 - 期刊:
- 影响因子:3.100
- 作者:
Nirmala Sehrawat;Mukesh Yadav;Anil Kumar Sharma;Varruchi Sharma;Deepak Chandran;Sandip Chakraborty;Abhijit Dey;Subhash C. Chauhan;Kuldeep Dhama - 通讯作者:
Kuldeep Dhama
Structural insights into small-molecule KRAS inhibitors for targeting KRAS mutant cancers
针对 KRAS 突变型癌症的小分子 KRAS 抑制剂的结构见解
- DOI:
10.1016/j.ejmech.2024.116771 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:5.900
- 作者:
Divya Pandey;Subhash C. Chauhan;Vivek K. Kashyap;Kuldeep K. Roy - 通讯作者:
Kuldeep K. Roy
Emerging role of mucins in antibody drug conjugates for ovarian cancer therapy
- DOI:
10.1186/s13048-024-01485-2 - 发表时间:
2024-08-08 - 期刊:
- 影响因子:4.200
- 作者:
Shabnam Malik;Mohammed Sikander;Natasha Bell;Daniel Zubieta;Maria C. Bell;Murali M. Yallapu;Subhash C. Chauhan - 通讯作者:
Subhash C. Chauhan
Protein subunit vaccines: Promising frontiers against COVID-19
蛋白质亚单位疫苗:对抗 COVID-19 的有希望的前沿领域
- DOI:
10.1016/j.jconrel.2024.01.017 - 发表时间:
2024-02-01 - 期刊:
- 影响因子:11.500
- 作者:
Vivek P. Chavda;Eswara Naga Hanuma Kumar Ghali;Pankti C. Balar;Subhash C. Chauhan;Nikita Tiwari;Somanshi Shukla;Mansi Athalye;Vandana Patravale;Vasso Apostolopoulos;Murali M. Yallapu - 通讯作者:
Murali M. Yallapu
Bioactive compounds from high altitude lake <em>Arthrospira platensis</em> HANL01: Antioxidant property, thermal stability and antibacterial assessment against multiple antibiotics resistant bacteria
- DOI:
10.1016/j.biteb.2023.101398 - 发表时间:
2023-06-01 - 期刊:
- 影响因子:
- 作者:
Ritu Chauhan;Ashutosh Tripathi;Abhishek Chauhan;Rupesh Kumar Basniwal;Anuj Ranjan;Arpna Kumari;Vishnu D. Rajput;Evgeniya V. Prazdnova;Tatiana Minkina;Subhash C. Chauhan;Tanu Jindal;Ram Prasad - 通讯作者:
Ram Prasad
Subhash C. Chauhan的其他文献
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{{ truncateString('Subhash C. Chauhan', 18)}}的其他基金
International Conference on Cancer Health Disparities
国际癌症健康差异会议
- 批准号:
10606212 - 财政年份:2023
- 资助金额:
$ 34.77万 - 项目类别:
MUC13 Mucin in Colerectal Cancer Health Disparity
MUC13 粘蛋白在结肠直肠癌健康差异中的作用
- 批准号:
10016192 - 财政年份:2019
- 资助金额:
$ 34.77万 - 项目类别:
Development of Targeted Nanotechnology Platform for Pancreatic Cancer
胰腺癌靶向纳米技术平台的开发
- 批准号:
9318460 - 财政年份:2016
- 资助金额:
$ 34.77万 - 项目类别:
Development of Targeted Nanotechnology Platform for Pancreatic Cancer
胰腺癌靶向纳米技术平台的开发
- 批准号:
9931148 - 财政年份:2016
- 资助金额:
$ 34.77万 - 项目类别:
MUC13 Mucin in Colorectal Cancer Health Disparity
MUC13 粘蛋白在结直肠癌健康差异中的作用
- 批准号:
9313845 - 财政年份:2016
- 资助金额:
$ 34.77万 - 项目类别:
Development of Targeted Nanotechnology Platform for Pancreatic Cancer
胰腺癌靶向纳米技术平台的开发
- 批准号:
9188609 - 财政年份:2016
- 资助金额:
$ 34.77万 - 项目类别:
Etiology of cervical cancer health disparity in American Indian women
美洲印第安女性宫颈癌健康差异的病因学
- 批准号:
8287944 - 财政年份:2012
- 资助金额:
$ 34.77万 - 项目类别:
Etiology of cervical cancer health disparity in American Indian women
美洲印第安女性宫颈癌健康差异的病因学
- 批准号:
8737805 - 财政年份:2012
- 资助金额:
$ 34.77万 - 项目类别:
Etiology of cervical cancer health disparity in American Indian women
美洲印第安女性宫颈癌健康差异的病因学
- 批准号:
8495289 - 财政年份:2012
- 资助金额:
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