Systemic RNA Delivery to Tumors
全身性 RNA 递送至肿瘤
基本信息
- 批准号:10297216
- 负责人:
- 金额:$ 58.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-12-21 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdjuvantAftercareAgonistAmerican Cancer SocietyAnimal ModelApoptosisAutophagocytosisBiodistributionBiological MarkersBlood CirculationCancer PatientCellsCessation of lifeChargeCombined Modality TherapyCytotoxic T-LymphocytesDevelopmentDiseaseDrug KineticsEconomic BurdenEngineeringExcretory functionFaceFormulationFoundationsFundingGene ExpressionGenerationsGenetically Engineered MouseGoalsGrowthHMGB1 ProteinHybridsImmuneImmune checkpoint inhibitorImmune responseImmunocompetentImmunologic MemoryIn VitroIndividualInjectionsKidneyLightLipidsMalignant NeoplasmsMalignant neoplasm of prostateMediatingMessenger RNAModalityModelingMolecularMolecular WeightMusMutateMutationNatureNeoplasm MetastasisNon-Small-Cell Lung CarcinomaOncogenesPTEN genePatternPharmaceutical PreparationsPhenotypePolymersPredispositionProstate Cancer therapyRNARNA deliveryRegulatory T-LymphocyteResearch Project GrantsRoleSafetySeriesSmall Interfering RNASolid NeoplasmSurfaceSystemT cell responseTLR9 geneTP53 geneTechnologyTestingTherapeuticTherapeutic EffectTransfectionTransgenic ModelTranslationsTumor Cell LineTumor ImmunityTumor Suppressor ProteinsUnited StatesValidationWorkanti-PD1 antibodiesanti-PD1 therapyanti-tumor immune responsebasecancer cellcancer therapycancer typeclinical developmentcytokinecytotoxiccytotoxicityimmune checkpointimmune checkpoint blockadeimmunogenic cell deathimprovedin vivometastasis preventionnanomedicinenanoparticlenanoparticle deliverynanotherapyneoplastic cellnovelnovel strategiesnovel therapeuticsnucleaseprogrammed cell death protein 1prostate cancer cellprostate cancer modelprotein expressionrestorationsocialsubcutaneoustumortumor growthtumor microenvironmenttumor-immune system interactionsuptake
项目摘要
ABSTRACT
The use of RNA technologies to specifically target genetic alterations in tumor cells has shown great potential of
becoming a novel therapy modality for cancer treatment. Nevertheless, systemic delivery of RNA agents such
as messenger RNA (mRNA) to tumor cells in vivo commonly faces multiple barriers, including low stability, rapid
elimination by renal excretion, insufficient cellular uptake, poor endosomal escape, and transient activities. Our
long-term objective is to develop robust nanoparticle (NP) platforms for effective and safe RNA delivery to solid
tumors, and along with cancer target validation in vivo, to eventually transition the RNA nanomedicines into
clinical development. In the last funding cycle, a lipid-polymer hybrid RNA NP system has been engineered with
favorable features, such as small size, high RNA encapsulation, efficient cytosolic translocation, and relatively
long blood circulation. We have also pioneered the application of these hybrid NPs for mRNA delivery to restore
tumor suppressors (e.g., PTEN) in different cancer types including prostate cancer (PCa) and non-small cell lung
cancer, which represents a novel approach to cancer treatment that is independent of oncogene antagonism. In
our latest work, we further reveal that PTEN restoration in PTEN-null/mutated murine tumor cell lines can induce
immunogenic cell death (ICD). Preliminary in vivo studies show that PTEN mRNA NP treatment triggers cytotoxic
T cell responses, modulates the immunosuppressive tumor microenvironment, and improves the responses of
immune checkpoint blockade therapy. In this renewal application, we propose to i) address the unique challenge
of transient bioactivity in mRNA delivery by developing a new generation of hybrid mRNA NPs, and ii) apply the
new hybrid mRNA NPs to explore PTEN restoration-induced ICD and evaluate the anti-tumor efficacy of PTEN
restoration along with immune checkpoint blockade. Specifically, the three Aims underlying the proposal are: 1)
To optimize the new generation of hybrid NPs and study the NP-mediated long duration of mRNA bioactivity with
the goal of achieving prolonged PTEN expression in PCa tumors using as infrequent injections as possible; 2)
To apply the optimized mRNA NPs to investigate the mechanisms underlying PTEN-mediated ICD and anti-
tumor immune responses and to evaluate the therapeutic effect and safety in subcutaneously grafted, orthotopic,
and transgenic models of PCa; and 3) To expand the new hybrid mRNA NPs to systemic co-delivery of PTEN
mRNA and CpG oligodeoxynucleotide (a toll-like receptor-9 agonist) for stronger ICD and to test the co-delivery
NPs for PCa treatment together with immune checkpoint inhibitors. We expect that successful completion of this
project will lead to development of a novel synthetic mRNA nanotherapy that could benefit cancer patients with
loss/mutation of PTEN. Moreover, this NP delivery strategy could be readily expanded to other tumor suppressor-
encoding mRNAs for various malignancies.
摘要
项目成果
期刊论文数量(0)
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Jinjun Shi其他文献
Jinjun Shi的其他文献
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{{ truncateString('Jinjun Shi', 18)}}的其他基金
A New Lipid Nanoparticle Technology Enabling Long-acting mRNA Therapy
新型脂质纳米颗粒技术实现长效 mRNA 治疗
- 批准号:
10669826 - 财政年份:2023
- 资助金额:
$ 58.56万 - 项目类别:
Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance
长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗
- 批准号:
10424582 - 财政年份:2021
- 资助金额:
$ 58.56万 - 项目类别:
Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance
长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗
- 批准号:
10631236 - 财政年份:2021
- 资助金额:
$ 58.56万 - 项目类别:
Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance
长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗
- 批准号:
10277786 - 财政年份:2021
- 资助金额:
$ 58.56万 - 项目类别:
Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers
纳米粒子联合递送 RNAi 和化疗治疗多重耐药癌症
- 批准号:
8689250 - 财政年份:2013
- 资助金额:
$ 58.56万 - 项目类别:
Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers
纳米粒子联合递送 RNAi 和化疗治疗多重耐药癌症
- 批准号:
8707222 - 财政年份:2013
- 资助金额:
$ 58.56万 - 项目类别:
Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers
纳米粒子联合递送 RNAi 和化疗治疗多重耐药癌症
- 批准号:
8916630 - 财政年份:2013
- 资助金额:
$ 58.56万 - 项目类别:
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