Targeted Nanotechnology for Precise Delivery of Synergistic Combination Chemotherapy Exploiting Deficiencies in DNA Repair in High-Grade Serous Ovarian Cancers
Abstract
Ovarian cancer (OC) is the fourth cause of cancer death in women of developed countries, with minimal survival improvements achieved in the past 30 years. As OC often lacks perceptible symptoms until it has spread throughout the abdominal cavity and even beyond, most women are not diagnosed until the disease has reached advanced stages. In such cases, only 21% to 6% of patients will live to 10 years post-diagnosis. Since early disease detection is rare, focusing on developing effective treatments is a promising approach to fulfill Ovarian Cancer Research Program s (OCRP s) vision of eliminating OC. At present, initial treatment consists of surgery to remove visible tumors, followed by chemotherapy to treat microscopic tumor nodules. Most patients respond well to this therapy, but the disease returns in as many as 75% of women, often within 18 months, with tumors that become increasingly more resistant to chemotherapy. Given the ineffectiveness of current treatment, innovative treatment strategies directed at the unique characteristics of OC are urgently needed. Over the last decade, it has been discovered that a large portion of OCs lacks the ability to repair DNA damage. A relatively new class of drugs, termed PARP inhibitors, or PARPi, further impairs OC cells ability to repair damaged DNA. A promising strategy is to combine a PARPi with a drug that causes DNA damage. In fact, studies have shown that this type of combination has great potential in treating OC. Unfortunately, combining these two types of drugs has led to a high level of adverse effects in patients. This is likely because the two drugs have been administered to patients at the same high doses that are used when the drugs are given individually. Rather than simply giving these drugs at such high doses, it is important to understand how these drugs should be dosed to achieve the best possible outcome. Our own studies and others have shown that varying the proportion, or ratio, of one drug to the other can drastically change the outcome of the combination. A given combination ratio of two drugs can result in synergism (the effect of the two drugs together is greater than the sum of the individual effects of each drug), while a different ratio of the same two drugs can result in an additive effect (the effect of the two drugs together is the same as the sum of the individual effects of each drug) or even antagonism (the effect of the two drugs together is lower than the sum of the individual effects of each drug). Thus, identifying the optimal, synergistic ratio is imperative to maximize the effects of drug combinations. Once such a ratio is determined, one must devise a strategy to deliver the two drugs at that precise ratio to OC tumors. Our objective is to develop an innovative nanotechnology approach to deliver a specific synergistic ratio of the PARPi olaparib (OLP) and the DNA-damaging drug doxorubicin (DOX), which are both approved for OC therapy, to OC tumors. Simultaneous delivery of DOX with a PARPi using nanotechnology has never been reported. This particular combination has shown promise in OC treatment, but induces toxic adverse effects, as discussed earlier, due to a lack of understanding of how to best combine these drugs. The proposed nanotechnology is called a block copolymer micelle, which is a spherical structure into which drugs like OLP and DOX can be encapsulated at desired ratios. After injection, the micelles accumulate at tumor sites rather than healthy body tissues, and release the drugs after some time post-injection. We propose to affix a molecule on the surface of the micelles that will cause them to preferentially attach to OC cells rather than other cells in the body, a process termed active targeting. This nanotechnology will be administered directly into the abdominal cavity, where the majority of, if not all, OC tumors reside. The micelles will preferentially accumulate within tumors, and the surface mole
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610388
Entities
People
- Christine Allen
Organizations
- United States Army
- University of Toronto