Therapeutic Effect And Mechanism Of ATP Responsive Cationic Polymer Gene Vector On Solid Tumor

Malignant tumors are one of the most common lethal diseases in the world,with more than 10 million new cases each year.Currently,the preferred treatment for solid malignancies is surgery,followed by radiation therapy and chemotherapy.In recent years,with the rapid development of biomedical science technology such as gene sequencing,gene therapy of tumors has received more and more attention.However,its use in the clinic is limited due to the difficulty of gene delivery.Nanocarriers have advantages in histocompatibility,tissue toxicity,tumor targeting and material plasticity,making them the most promising for gene delivery.One of the common features of the cationic polymer is that it contains a large amount of amino groups,which are protonated at physiological p H;When the RNA is incubated with the cationic polymer,negative charge of RNA interacts with protonated amino groups,forming a relatively small volume of RNA particles.This ultimately allows the RNA-cationic polymer to evade the degradation of RNase and achieve safe delivery of RNA in vivo.At the same time,due to the strong electrostatic interaction between the cationic polymer carrier and the RNA,the capacity of the RNA and the stability of the polymer are greatly improved.ATP is one of the most abundant intracellular molecules in the cell.Its concentration in cells is 1-10 m M,which is thousands of times coparing to extracellular.The difference in concentration of ATP provides an effective condition for designing ATP-responsive nanocarriers.In this paper,we designed and prepared two ATP responsiveness cationic polymer gene vectors for androgen-independent prostate cancer and drug-resistant breast cancer,respectively,and systematically explored its therapeutic effects and possible mechanisms.Based on the characteristics of androgen-independent prostate cancer,we designed and synthesized intelligent dual-stimulus-responsive PEI-PBA-mi R146a/PEI-MAH-C225 nanomicelles.This nanomicelles are homogeneous spheres with a diameter of 100-200 nm.It can be rapidly dissociated in an acidic environment and intracellular ATP concentration.In both in vivo and in vitro experiments,the PEI-PBA-mi R146a/PEI-MAH-C225 nanomicelles can successfully carry mi R146 a into androgen-independent prostate cancer cells with high transfection efficiency,while achieving a good inhibitory effect and no significant toxic effects have been observed.To further extend the usage of ATP responsiveness cationic polymer gene vectors,we designed ATP-responsive doxorubicin-loaded nano-polymer HA/Bcl-2 si RNA-PLL-PBAp-gp si RNA-DOX for the treatment of drug-resistant breast cancer.The ATP-responsive doxorubicin-loaded nano-polymers HA/Bcl-2 si RNA-PLL-PBA-p-gp si RNA-DOX are homogeneous spheres with a diameter of 100 nm.Tt can be rapidly dissociated at intracellular ATP concentration.In both in vivo and in vitro experiments,the HA/Bcl-2si RNA-PLL-PBA-p-gp si RNA-DOX nano-polymers can safely carry both Bcl-2 si R NA and p-gp si RNA into resistant breast cancer cells and achieve high transfection efficiency.It can reverse the resistance of drug-resistant breast cancer to doxorubicin,restore the inhibitory effect of doxorubicin on tumor,and no obvious toxic effect was observed.In this study,the two ATP responsiveness cationic polymer gene vectors we designed have achieved high stability,tumor targeting,high gene carrying capacity and high transfection efficiency,while having low cytotoxicity.It provides new idea and direction for utilizing ATP as a nanocarrier stimulation-response trigger.