Development of novel nanomedicines for treatment of primary and metastatic prostate cancer
Başlık çevirisi mevcut değil.
- Tez No: 403300
- Danışmanlar: Dr. MOHAMED E--SAYED
- Tez Türü: Doktora
- Konular: Biyomühendislik, Tıbbi Biyoloji, Bioengineering, Medical Biology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2016
- Dil: İngilizce
- Üniversite: University of Michigan
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 346
Özet
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Özet (Çeviri)
Prostate cancer is the 2nd most common cancer among men worldwide with an estimated 1.1 million men diagnosed with the disease in 2012 and accounting for more than 300,000 deaths in 2012. According to the GLOBOCAN 2012 report, it is estimated that prostate cancer will overtake lung cancer, which is currently the most common form of cancer affecting men globally, in the last ten years. This thesis focuses on the development of novel nanomedicine-based therapeutic approaches for focal ablation of primary prostate cancer and targeted chemotherapeutics of the treatment of metastatic prostate cancer lesions in bone. Focal prostate cancer therapy is an effective approach that can successfully eradicate single tumor lesions. However, the focal therapy approaches have limitations with regard to treating high-volume and multi-modal tumor lesions as well as lacks the ability to selectively ablate cancer lesions. To address these therapeutic limitations, we have developed nanodroplets (average diameter ~ 200nm) encapsulating perfluorocarbons (PFC's), namely perfluoropentane (PFP) and perfluorohexane (PFH), which can rapidly expand reaching > 500 μm in < 1μsecond when exposed to therapeutic ultrasound before they collapse. The pulsating microbubbles have proved successful in mechanically fractionating neighboring cells with significantly reduced cavitation parameter thresholds. To test the tumor ablation efficiency of the different PFC (PFP or PFH)-encapsulated nanodroplets, we developed 3D-prostate cancer spheroids from PC-3 and C4-2B cancer cells using aqueous-two-phase-systems (ATPS) on an agarose 3D tumor phantom model that mimicked the cells inside a tissue extracellular-matrix. The applied treatment groups included no ND with lower-pressure (13 MPa), no ND with high-pressure (28 MPa), PFP-loaded NDs with low-pressure (13 MPa), and PFH-loaded NDs with lower-pressure (13 MPa). During the treatments such high-pressure and low-pressure with nanodroplets, cavitation bubbles were observed at the transducer focus and cells were observed to be mechanically ruptured. After the treatments, we evaluated the ablated area of the spheroids. No nanodroplets at low-pressure could ablate less than 20 % area for both spheroid models. However, regular histotripsy with high-pressure ablated around 80 % of the spheroids. Whereas, PFP-nanodroplets with low-pressure destroyed 40 % of the spheroids, and PFH-nanodroplets could ablate almost 80 % of the spheroids. These results indicate both PFC-loaded nanodroplets significantly reduce the histotripsy threshold, and PFH-loaded nanodroplets with low-pressure can destroy cells as efficiently as high-pressure. The current bone metastases therapy modalities are riddled with its fair share of limitations such as their inability to efficaciously deliver the therapeutic concentrations of anti-cancer agents to the target site. To address these limitations, in the second part of this dissertation we designed bone-targeted nanoparticles that can encapsulate and deliver a high dose of Cabazitaxel (CTX) to prostate cancer lesions in bone. We further studied the targeted nanoparticles internalization profile into cancer cells as well as bone cells grown in a bone-like microenvironment. The project comprised of three major aims: i) We first designed non-targeted“smart”nanoparticles containing amphiphilic triblock copolymers, poly(ethylene)-b-poly(acrylic acid)-b-poly(methyl methacrylate), that have the ability to self-assemble in an aqueous medium to form nano-sized micelles that can encapsulate anti-cancer agents like CTX in their hydrophobic core. Cross-linkage of the PAA blocks using ketal-linkers resulted in an acid-labile shell that stabilized the drug-loaded micelles at physiologic pH, but allowed selective release of the loaded cargo in acidic environments. The in-vitro study of the non-targeted, CTX-loaded cross-linked nanoparticles exhibited a significantly higher therapeutic effect than free CTX without any cytotoxicity issues. Moreover, the particles did not have any biocompatibility issues based on the studies conducted such as, red blood cell hemolysis, protein adsorption, and platelet activation tests. Further, this non-targeted“smart”nanoparticle exhibited a limited macrophage uptake < 10% compared to cancer cells > 90%. ii) We conjugated the non-targeted nanoparticles with either a specific peptide sequence called pVTK or a small molecule bisphosphonate (BP) to actively target mineralizing or hydrolyzing bone surfaces in prostate cancer lesions, respectively. We characterized the size of the bone targeted particles (60-90 nm) and confirmed their binding affinity towards bone hydroxyapatite (HA) powder. Further, we examined both bone targeted nanoparticles uptake profiles into prostate cancer cell lines (PC-3 and C4-2B) and bone cell lines (MC3T3, RAW 264.7 bone macrophages, and RANKL activated RAW 264.7) on regular tissue culture plates as well as on bone-like surfaces (BLS). Results showed that increasing the number of BP-targeting copolymer in the particle formulation was able to augment the normalized particle fluorescence intensity in RAW 264.7 macrophages on regular culture plates. Additionally, the overall cellular uptake profile of bone-targeted nanoparticles trends was different in the presence of BLS compared to that of regular tissue culture plates. The results indicate that C4-2B and MC3T3 osteoblast cells were effectively targeted by pVTK bone-targeted nanoparticles. While, BP bone-targeted nanoparticles are capable of targeting PC-3 and RAW 264.7 macrophage cells. These results collectively indicate that pVTK- and BP-based bone targeting strategies can facilitate selective delivery of chemotherapeutic agents to metastatic prostate cancer in bone and the cross-talk between cancer cells and bone cells could be inhibited by using a specific targeting strategy (pVTK or BP), which opens doors to new personal bone metastasis therapies.
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