Date of Award

2019

Embargo Period

8-1-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Dieter Haemmerich

Second Advisor

Patrick M. Woster

Third Advisor

Eduardo N. Maldonado

Fourth Advisor

Yuri K. Peterson

Fifth Advisor

Ann-Marie Broome

Abstract

Liposomes and nanoparticles have been used in the clinic to treat cancer for the past 30 years due to their reduced toxicity though there is no increase in treatment efficacy. Thermosensitive liposomes (TSLs) have been developed to release the encapsulated payload when exposed to hyperthermic temperatures (40–42°C). Combined with imaging and localized hyperthermia, TSLs are capable of delivering a large quantity of free drug to the target tissue. There have been several clinical trials employing TSL's and different hyperthermia modalities with limited success. Two unanswered questions remain in the realm of TSLs and their clinical use. There is no clinical approved way of knowing how much drug was delivered in real time. Once the hyperthermia is concluded, a large proportion of the infused TSLs are present in the blood that is slowly cleared away leading to unwanted off-target issues. We focused on these two issues and developed technologies that would address these problems. For the first aim, we used TSLs encapsulating the chemotherapeutic agent doxorubicin which is intrinsically fluorescent. We used the innate fluorescent ability of doxorubicin to monitor the delivery of the drug in real time using fluorescence in vivo imaging in a mouse model. Nude mice carrying Lewis lung carcinoma tumors on both flanks were infused with TSL-dox at a dosage of 5mg/kg. Hyperthermia was applied by a lab made device on one of the tumors in an in vivo imaging system. Blood sampling was done immediately post infusion and at the end of hyperthermia. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). Tumor drug concentration was tied to hyperthermia duration, at 4.2±1.3 μg/g (no HT), 7.1±5.9 μg/g (15 min HT), 14.1±6.7 μg/g (30 min HT), and 21.4±12.6 μg/g (60 min HT). There was good correlation (R^2=0.67) between fluorescence of the tumor region and tumor drug uptake. For the second aim, we tried to the remove the undelivered drug in the circulation at the end of hyperthermia. We used a rat model carrying sarcoma tumors, to deliver TSL-dox mediated localized drug delivery using a microwave probe. At the end of the hyperthermia, we established an extracorporeal circuit (ECC) for removing the TSL-dox that was undelivered. We used fluorescence imaging to monitor and quantify the drug being removed in real-time. We were able to remove 29.7±3.7% of the infused dose with 60 min of ECC consistently.

Rights

All rights reserved. Copyright is held by the author.

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