A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.     

重组人p53腺病毒注射液联合顺铂与紫杉醇治疗晚期宫颈癌的疗效及安全性分析

目的探讨重组人p53腺病毒注射液联合顺铂与紫杉醇治疗晚期宫颈癌的疗效及安全性。方法 80例晚期宫颈癌患者随机分为两组各40例,对照组给予顺铂与紫杉醇治疗,研究组在对照组基础上给予重组人p53腺病毒注射液治疗。比较两组的治疗效果、不良反应以及复发率、转移率、死亡率。结果研究组的治疗总有效率高于对照组,1年内病死率、复发率及转移率均低于对照组(P <0.05)。两组的不良反应发生率比较,差异无统计学意义(P>0.05)。结论重组人p53腺病毒注射液联合顺铂与紫杉醇治疗晚期宫颈癌患者的疗效显著,安全性高,能够有效减少近期死亡、复发及转移。     

A Phase II Study of CLAG Regimen Combined With Imatinib Mesylate for Relapsed or Refractory Acute Myeloid Leukemia

IntroductionNo standard salvage chemotherapy regimen is available for relapsed or refractory (RR) acute myeloid leukemia (AML). Preclinical data have suggested synergy in vitro between cytarabine and imatinib mesylate (IM) on AML cell growth inhibition. After demonstrating the safety and feasibility in a phase I study, we conducted a phase II clinical study of CLAG (cladribine, cytarabine, granulocyte colony-stimulating factor) regimen combined with IM for patients with RR-AML.Patients and MethodsWe performed a single-institution 2-stage phase II study. The primary endpoint was the remission rate measured using the standard AML response criteria. The secondary endpoints included overall survival (OS) and progression-free survival (PFS).ResultsFrom August 2009 to April 2011, 38 patients were treated at the Moffitt Cancer Center. Their median age was 62 years (range, 26-79 years). Of the 38 patients, 7 (18%) had refractory AML, 19 (50%) had early relapse, and 12 (32%) had late relapse. At the original diagnosis, only 2 patients had favorable risk factors, 18 had intermediate risk, and 16 had poor risk; for 2 patients, the karyotype was missing. The overall response rate for all 38 evaluable patients was 37%. The median OS was 11.1 months (95% CI, 4.8-13.4 months), the median PFS was 4.9 months (95% CI, 1.6-11.7 months). Among the responders, 8 of 14 patients subsequently underwent allogeneic hematopoietic cell transplantation.ConclusionCLAG plus IM was well tolerated, with encouraging signs of activity in patients with poor-risk AML.