纳米颗粒介导的肿瘤-神经串扰破坏可增强胰腺癌治疗并缓解疼痛

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal prognosis. Dense fibrous tumor stroma creates a drug delivery barrier, cultivates aggressive tumor biology and immunosuppression in PDAC. A well-recognized hallmark of PDAC is nerve infiltration into tumors and cancer cells invading neurons, which correlate with local invasion and poor survival. Neural invasion leads to severe and intractable pain in PDAC patients, due to release neurotransmitters and pro-inflammatory responses. Sympathetic nerves release catecholamines interacting with beta-adrenergic receptors (beta-AR) to stimulate tumor cell proliferation and invasion, induce immunosuppression and increase pain sensation. Clinical studies revealed treatment with beta-AR inhibitors improved survival of PDAC patients. In this study, we have developed tumor cell, stroma, and cancer nerve targeted hyaluronic acid nanoparticles (HANPs) carrying SN-38 and beta-AR blocker (Propranolol, Pro) for targeted therapy of PDAC and mitigation of neuropathic pain. Methods: To enhance targeted delivery, we leveraged the biological properties of upregulation of urokinase plasminogen activator receptor (uPAR) and MMP14 in invasive tumor cells to developed a biomimetic nanoparticle drug delivery platform targeting to uPAR with MMP14 for stroma-penetration and drug delivery. The hydrophobic SN38 (an active metabolite of irinotecan) and Pro, were encapsulated into HANPs by self-assembling, resulting HANP/Pro+SN38 (HANP/PS). A uPAR targeted stroma penetrating recombinant ligand, ATFmmp14 was conjugated to HANP/PS to produce ATFmmp14-HANP/PS (AM-HANP/PS). Targeted delivery and therapeutic response were evaluated in an orthotopic PDAC patient derived xenograft model. Results: Our results showed that NIR 830 dye labeled-AM-HANP/PS led to a high tumor accumulation (46%) in a PANC XXIV PDX model. AM-HANP/PS treatment by co-delivery of SN38 (4 mpk) and Pro (10 mpk) resulted in significantly stronger inhibition of tumor growth (67%) compared with single drug delivery (40%) or free SN38+Pro (46%). Histological analysis revealed nearly complete elimination of sympathetic and sensory nerves in treated tumors, while other formulations showed a moderate level of nerve reduction. Pain evaluation showed decreased pain in AM-HANP/PS treated mice. The level of pain neurotransmitter, substance P, was significantly reduced in tumors. These findings support AM-HANP/PS as an effective tumor and nerve targeted therapy. Conclusion: AM-HANP/PS that targets PDAC tumor cells and cancer neurons achieved a high level of tumor accumulation. Co-delivery of SN38 and Pro significantly inhibits tumor growth, reduces density of sympathetic and sensory nerves, and relieves cancer-related pain. This dual-targeted strategy exhibited both antitumor efficacy and neuropathic pain mitigation in PDAC PDX model.