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a Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, P. R. China

b Department of Clinical Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

c CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
E-mail: [email protected], [email protected], [email protected]

d University of Chinese Academy of Sciences, Beijing 100049, P. R. China

Abstract

The synergistic combination of microRNA (miRNA) modulation and chemotherapy has emerged as an effective strategy to combat cancer. Irinotecan (IRI) is a potent antitumor chemotherapeutic in clinical practice and has been used for treating various malignant tumors, including colorectal cancer (CRC). However, IRI is not effective for advanced CRC or metastatic behavior. Herein, novel polymeric hybrid micelles were engineered based on two different amphiphilic copolymers, polyethyleneimine-poly(D,L-lactide) (PEI-PLA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethyleneglycol) (DSPE-PEG), in which IRI and a tumor suppressive microRNA-34a (miR-34a) gene were efficiently co-loaded (MINPs) to achieve a chemo-miRNA combination therapy against CRC. MINPs were successfully constructed by two-step film dispersion and electrostatic interaction methods. IRI and miR-34a could be efficaciously encapsulated as MINPs and transferred to CRC cells. After encapsulation, MINPs would then upregulate miR-34a expression and regulate miR-34a-related downstream genes, which in turn led to enhanced cell cytotoxicity and apoptosis ratios. MINPs presented an excitation-dependent multi-wavelength emission feature due to the intrinstic fluorescence properties of PEI-PLA and could be utilized for in vitro/vivo imaging. According to the in vivo experimental results, MINPs possess the great characteristic of accumulating in situ in a tumor site and lightening it after intravenous administration. Furthermore, MINPs presented extraordinary antitumor efficacy owing to the combined therapy effects of IRI and miR-34a with good biocompability. Overall, our findings validated MINPs-mediated miR-34a replenishment and IRI co-delivery to serve as an effective theranostic platform and provided an innovative horizon for combining chemo-gene therapy against CRC.

The synergistic combination of microRNA (miRNA) modulation and chemotherapy has emerged as an effective strategy to combat cancer. Irinotecan (IRI) is a potent antitumor chemotherapeutic in clinical practice and has been used for treating various malignant tumors, including colorectal cancer (CRC). However, IRI is

Tim Richmond, 34, Auto Racer

Tim Richmond, a former Indianapolis 500 rookie-of-the-year driver whose subsequent stock-car racing career was cut short by controversy and illness, died Sunday. He was 34 years old.

Dr. David Dodson, Mr. Richmond’s physician, said today that Mr. Richmond died at Good Samaritan Hospital in West Palm Beach, Fla. Citing the wishes of the family, Dr. Dodson declined to give the cause of death.

Mr. Richmond led the Nascar Winston Cup circuit with seven victories in 1986. A year later, he said he had contracted pneumonia.

His career ended when Nascar suspended him before the 1988 season-opening Daytona 500 after a drug test showed excessive amounts of two nonprescription drugs found in over-the-counter remedies for allergies and respiratory conditions. He passed a subsequent drug test and was reinstated, but was not able to get a car. Recently in Motorcycle Accident

Mr. Richmond, who lived in southern Florida, had been hospitalized recently for injuries sustained in a motorcycle accident, according to Dr. Jerry Punch, a friend of the driver.

Mr. Richmond drove Indy cars and was the Indy 500 rookie of the year in 1980 before switching to stock cars. He had 13 career victories, including two immediately after returning from a layoff due to illness in 1987.

He sued the stock-car sanctioning body in April 1988 for suspending him after a drug test. An out-of-court settlement was reached later that year.

In his last public appearance, at a news conference at Daytona Beach, Fla., in February 1988, Mr. Richmond denied having abused drugs and said a mistake had been made in the test he failed. Mr. Richmond’s last race was the Champion Spark Plug 400 at Michigan International Raceway in August 1987.

Tim Richmond, 34, Auto Racer Tim Richmond, a former Indianapolis 500 rookie-of-the-year driver whose subsequent stock-car racing career was cut short by controversy and illness, died Sunday. He