Multi-functional nanocarriers for drug delivery The combination of photodynamic therapy and chemotherapy with anti-angiogenesis in the treatment of cancers)
Date Issued
2009
Date
2009
Author(s)
Peng, Cheng-Liang
Abstract
In recent years, the nanomaterials, such as polymer-drug conjugates, nanoparticles, and polymeric micelles, have been considered as potential carriers for hydrophobic drug delivery that may resolve the mentioned problems. The combination of photodynamic therapy, chemotherapy, or anti-angiogenesis had been a development tendencies for the cancer treatments.his dissertation was divided into three parts. The first part is synthesis of photosensitizers and their conjugates for photodynamic therapy. There are two topics of research in this part. The first topic is to synthesis and evaluate the asymmetric porphyrins on intracellular uptake, subcellular localization and phototoxicity in cancer cells. The second topic is synthesis and evaluate of PAMAM- porphyrin conjugates for photodynamic therapy and gene transfection. In first study, we prepared a series of asymmetric porphyrins with varying proportion of substituents, such as 4-hydroxyphenyl, 4-aminophenyl, and 4-pyridine, with a varied degree of hydrophobic/hydrophilic substitution as model compounds for localization studies of photosensitizers and its photodynamic activity in tumor cells. In addition, we conjugated photosensitizers (TAMCPP, P35) with PAMAM dendriers to increase the hydrophilicity for clinical applicaion. And G4-TAMCPP became less aggregation, more photocytotoxitic efficacy, and lysosomal targeting that could be applied on delivery system for the photochemical internalization.he second part is to prepare the dual functionalized micellar delivery system for the combination of photodynamic therapy and chemotherapy. This part has two topics of research, the first is to synthesis and evaluate the self-assembled chlorin-cored poly(ε-caprolactone)-poly(ethylene glycol) diblock copolymer (CSBC) micelles for paclitaxel-based chemotherapy combinated with photodynamic therapy in MCF-7 breast cancer cells. The second topics is to use CSBC micelles for SN-38 delivery and evaluate its combination efficacy effects in a HT-29 human colon cancer xenograft model. Combined SN-38/CSBC-mediated PDT synergistically inhibited tumor growth, resulting in up to 60% complete regression of well-established tumors after 3 treatments. These treatments also decreased the microvessel density (MVD) and cell proliferation within the subcutaneous tumors. he third part is Anti-angiogenesis therapy combinated with photodynamic therapy or nanomedicines. The first topic is anti-angiogenic treatment (Bevacizumab) enhances the responsiveness of photodynamic therapy in a HT-29 human colon cancer xenograft mode. Our results demonstrated that combination therapy protocol of PDT then bevacizumab exhibited greater tumor response in comparison with other treatment protocols. The last topic is to investigate the relationship between angiogenesis and nanomedicines on the therapeutic efficacy in colon cancer. he vascular-targeting PDT induce the loss of vascular barrier function and increase in vascular permeability. In this study, we demonstrated that alteration in tumor vascular barrier by vascular-targeting PDT, which enhances the delivery of macromolecules. It also demonstrated whether pretreatment with bevacizumab (anti-angiogenesis) or vascular-targeting PDT (pro-angiogenesis) influence the efficacy of systemically administered nanomedicines in mice bearing human colon HT-29 adenocarcinoma, and to investigate the optimal conditions (time window, particle size) of anti-angiogenesis and pro-angiogenesis and their effects on the delivery and efficacy of nanomedicines. Bevacizumab had been shown to decrease microvessel density (MVD) and vascular perfusion in solid tumours. However, the effects of bevacizumab on the delivery of micellar SN-38 formulations therapeutic efficacy are not effected, because of the larger size of SN-38/micelles.
Subjects
Photodyamic therapy
chemotherapy
anti-angiogenesis
photosensitizers
micelles
nanomedicine
cancer
SDGs
Type
thesis
File(s)![Thumbnail Image]()
Loading...
Name
ntu-98-D93548014-1.pdf
Size
23.53 KB
Format
Adobe PDF
Checksum
(MD5):d307982ee6b9bd80c9a4848e9cda1745