Enhancement of the theranostic efficiency for malignant brain tumor by using polymeric lipid-based micellar nanocarriers

Abstract

Malignant brain tumor (MBT), especially glioblastoma multiforme, is one of the most perplexing diseases which is regarded as incurable, up to the present. Standard treatment modalities of MBTs are surgical resection and following concurrent chemoradiation, but pro-longed mean survival of patients is limited up to 12-15 months. Accordingly, various alternatives have been introduced and developed to advance outcome. Theranosis is a combined concept of diagnosis and therapy. Because of the extent of removal and reduction of MBT decisively determine prognosis of the patients, and theranosis is able to maximize the performance of surgery, theranosis for MBT is in the limelight. Considerations to achieve enhancement of theranostic efficiencies are a good many, but one of the crucial factors that influence the results is drug delivery of theranostic agents to MBT. Nanomedicine is an emerging field that aspire toward innovative improvement of pharmacokinetics of a drug. Polymeric micelle, a nanocarrier, is suggested as an effective drug delivery system (DDS) for drug-hypopermeable cancers. Because of the presence of blood-brain or blood-brain tumor barriers in MBTs, fenestration size and permeation of a drug in MBTs are even more restricted than other cancers. So, I considered polymeric micelle as a good candidate DDS for the usage on theragnosis of MBT. I am trying to investigate possibility of polymeric lipid-based micelle, a nanoscale DDS, as an effective drug delivery method to enhance theranostic efficiency. After brief introduction of this thesis in chapter 1, enhancement of therapeutic efficiency of a drug with engineered polymeric micelles will be discussed in chapter 2. In brief, phototherapeutic sub-12-nm-sized polymeric micelles were engineered, and its therapeutic effects on MBT cells were evaluated. The engineered polymeric micelles enhanced photocytotoxic efficiency more than 2.5-fold in MBT cells, compared with parental and PEGylated drug formulations. With fluorescence imaging and analysis of the co-localization coefficient between intracellular organelles and drug, increased subcellular co-localization of a drug in mitochondria was ob-served, which is relevant to explain about the increment of cytotoxic efficiency. In chapter 3, accumulation of a drug with DDSs in tumoral tissue was evaluated in vi-vo. Because evaluation of the DDSs within blood-brain tumor barrier existing environment and preservation of the environment to secure relevant temporo-spatial resolution were essential, intravital imaging system with orthotopic xenograft chronic cranial window brain tumor models were established. With intravital two-photon laser scanning microscopy imaging, more than 1.4 fold increased average fluorescence intensity, which regarded as drug concentration, in tumoral tissue was identified with engineered nanocarriers. With the analysis of acquired images, implying findings of enhanced permeability and retention effect of nanocarriers were identified. In conclusion, enhancement of therapeutic efficiency and increment of drug delivery to MBT tissue were identified with engineered polymeric micelle. The drug used for the evaluations was a photosensitizer, hypericin, which is suggested as a potent candidate agent for the theranosis of MBTs. With consequent results, I expected this polymeric lipid-based micellar nanocarriers may act as an efficient assistant diagnostic and therapeutic modality for the theranosis of MBTs, and spur the application of sub-12-nm micelles for the theranostics.