Drug-based polycations for combination drug-gene delivery

描述（由申请人提供）：为了充分发挥药物-基因联合治疗的潜力，需要改进药物和基因同时传递的方法。我们的长期目标是建立一类新的可生物降解基因传递载体，能够在细胞内降解后作为(i)基因传递载体和（ii）活性药物双重功能。本提案的目的是设计创新的可生物降解的树突状BENSpm多阳离子（BDBP），能够作为基因传递载体和针对癌症中失调的多胺代谢的活性抗癌剂双重功能。我们将以阳离子药物N1， n11 -双（乙基）去精胺（BENSpm）为基础，开发可生物降解的树突状前药，将肿瘤坏死因子相关凋亡诱导配体（TRAIL）基因高效递送至三阴性乳腺癌细胞，并分解为原药BENSpm，从而增强TRAIL的治疗效果。我们假设，根据我们的初步数据，由于BDBP释放的BENSpm的协同增强，联合药物-基因递送将提高TRAIL的抗癌活性。我们的总体目标将通过追求两个具体目标来实现：1)合成可生物降解的树突状BENSpm聚合物；2)确定BDBP联合TRAIL是否能增强人乳腺癌模型体内的抗肿瘤活性。在目标1中，申请人已确定可行的合成方法将用于制备在细胞内还原环境中可降解并能够释放完整的BENSpm的BDBP。在目的2中，BDBP将在三阴性乳腺癌肿瘤模型MDA-MB- 231中传递TRAIL-GFP质粒，并评估细胞内BDBP降解和BENSpm释放对表达的TRAIL-GFP抗肿瘤活性的影响。该方法的创新之处在于其递送载体的设计新颖，不仅可以递送治疗基因，还可以通过发挥其自身的药理作用来增强治疗基因的活性。该研究将为非病毒基因传递系统的同时药物基因传递建立一个广泛适用的设计范式，从而改善基因治疗策略的结果。

DESCRIPTION (provided by applicant): Improved methods to simultaneously deliver drugs and genes are needed to fully realize the potential of drug- gene combination therapies. Our long-term goal is to establish a new class of biodegradable gene delivery vectors capable of functioning dually as (i) gene delivery vectors and (ii) active pharmacologic agents after intracellular degradation. The objective of this proposal is to design innovative biodegradable dendritic BENSpm polycations (BDBP) capable of functioning dually as a gene delivery vector and an active anticancer agent targeting dysregulated polyamine metabolism in cancer. We will develop biodegradable dendritic prodrugs based on a cationic drug N1,N11-bis(ethyl) norspermine (BENSpm) that will efficiently deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene to triple negative breast cancer cells and then decompose into the original drug BENSpm, thus augmenting the therapeutic effect of TRAIL. We hypothesize that the combined drug-gene delivery will improve TRAIL anticancer activity due to synergistic enhancement by BENSpm released from BDBP, as suggested by our preliminary data. Our overall objective will be achieved by pursuing two specific aims: 1) synthesize biodegradable dendritic BENSpm polycations; 2) determine whether BDBP combined with TRAIL enhances antitumor activity in human breast cancer model in vivo. In aim 1, a synthetic methodology, which has been established as feasible by the applicant will be used to prepare BDBP that are degradable in a reducing intracellular environment and capable of releasing intact BENSpm. In aim 2, the BDBP will be used to deliver TRAIL-GFP plasmid in triple-negative breast cancer tumor model, MDA-MB- 231, and to evaluate the effect of intracellular BDBP degradation and BENSpm release on the antitumor activity of expressed TRAIL-GFP. The approach is innovative because of the novel design of delivery vectors that not only deliver therapeutic genes but also augment the activity of the therapeutic gene by exerting its own pharmacologic effect. The proposed research is significant because it will establish a widely applicable design paradigm for non-viral gene delivery systems for simultaneous drug-gene delivery and thus it will improve outcome of gene therapy strategies.