Text

theses

Ductal carcinoma in situ (DCIS) is characterized by the abnormal proliferation of luminal epithelial cells in mammary ducts without invasion into the surrounding stroma. In the last two decades, DCIS incidence has substantially increased due to widespread breast cancer screening. Most DCIS patients are treated with lumpectomy plus radiation therapy or mastectomy. Approximately 50% of patients who are treated with surgery alone will suffer from invasive tumor recurrence. Additionally, surgical treatment is always associated with significant adverse effects and cosmetic issues that impact both the emotional status and quality of life of patients. As a result, clinicians and oncologists are deeply concerned about the overtreatment of DCIS and therefore, investigating alternate non-surgical treatment options is warranted.

Parenterally or orally administered systemic therapy is not effective for treating DCIS due to the lack of direct blood circulation in and to the mammary duct. Local therapy is an attractive option since the doses required to achieve therapeutic efficacy are significantly lower than systemic therapy due to the lack of dilution in the blood. Compared to systemic therapy, local therapy reduces systemic drug exposure due to the fact that the required efficacious doses are expected to be significantly lower. Local therapy can be achieved using transpapillary (i.e., through the nipple) administration directly into the mammary ductal system. One key challenge facing direct intraductal therapy is the rapid diffusional clearance of small molecule drugs into the mammary tissue and systemic circulation since the ducts are highly permeable, which limits efficacy and ultimately requires more frequent administration. Therefore, an important goal of local intraductal therapy is to increase drug persistence in the mammary tissue.

The objective of this thesis project is to develop a locally administered nanoscale drug delivery system for treating DCIS that delivers a synergistic combination of one or more drugs in a controlled manner in order to increase mammary tissue exposure and efficacy while minimizing the administered dose and potential for side effects. There are currently no first-line pharmacotherapy options for treating DCIS. Ciclopirox (CPX) was used along with gedatolisib (GTB), a phosphatidylinositol 3-kinase and mammalian target of rapamycin dual inhibitor, as the primary therapeutic agents. CPX has demonstrated antitumor activity by downregulating and inhibiting several oncogenic targets and pathways frequently associated with the development and progression of DCIS. First, a drug delivery system was designed and fabricated using ciclopirox zinc complex or an esterase responsive ciclopirox prodrug in order to evaluate the role of slowing drug release and increasing drug persistence in mammary tissue on anti-tumor efficacy in an orthotopic rat model of breast cancer. Second, in order to reduce the administered drug doses and resulting systemic exposure as well as to determine the optimal order of drug presentation, synergy and co-delivery strategies were investigated and evaluated.

The first study was performed to evaluate the effectiveness of delivering CPX in a non-stimuli responsive manner. This was achieved by preparing a hydrophobic ion pair, a zinc complex, to slow CPX release. The CPX zinc complex was successfully synthesized and characterized by several spectral analytical methods. An orthotopic rat DCIS-tumor model was successfully established based on histological findings and was used in all studies. CPX zinc complex loaded in polymeric nanoparticles demonstrated longer mammary persistence and better therapeutic efficacy than either CPX or CPX zinc complex nanosuspensions. A direct correlation between CPX mammary retention and in vivo efficacy was observed.

In the next study, a prodrug strategy was used to alter the physicochemical properties of CPX, enabling the fabrication of stable nanoscale drug delivery systems with controllable esterase responsive release properties. The efficacy of intraductal CPX nanosuspension administration was found to be dose dependent in suppressing tumor initiation. Both prodrug nanosuspension and a combination of prodrug nanosuspension with prodrug loaded in poly (lactic-co-glycolic acid) nanoparticles (1:1) demonstrated higher mammary persistence and better therapeutic efficacy than CPX nanosuspension at the same equivalent dose of CPX.

In the last study, two concepts were explored – synergy and co-delivery. The first involved using drug synergy to reduce the required dose(s) of drugs while maintaining efficacy. Reduced drug dosages would result in less systemic drug exposure when the drugs are eventually cleared from the mammary duct into the general circulation. The second involved exploring the role of drug presentation order on efficacy. An in vitro evaluation of the combination of CPX with GTB, and the antitumor activity of lipid-polymer hybrid nanoparticles (LPNPs) co-loaded with a fixed ratio of CPX prodrug and hydrophobic ion-pairing of GTB in three human triple-negative cell lines was evaluated. Significant increases in the calculated synergy scores, combination indices and dose reduction values for both drugs were observed when co-loaded in LPNPs compared to co-administering the free drug combination. It was also observed that the order of presentation of the drugs to the targets was important with optimal efficacy achieved when CPX was delivered first and followed by GTB. Overall, these results confirm that both synergy and co-delivery are important features that should be designed into future drug delivery systems for locally treating DCIS.

In conclusion, both the zinc complexation and prodrug approaches were highly efficient in improving the stability and physicochemical properties of CPX and GTB, thus enabling the development of nanoscale delivery systems without compromising biological activity. This study undoubtedly demonstrates the feasibility of using nanoscale delivery systems for prolonging mammary tissue persistence and improving therapeutic efficacy in locally treating DCIS in an orthotopic rat model. In addition, feasibility results demonstrate that synergy and co-delivery may improve delivery system performance and anti-tumor efficacy while minimizing adverse effects.

ETD_10570

Ph.D.

Includes bibliographical references

doi:10.7282/t3-6vkx-8q86

ETD doctoral

The author owns the copyright to this work.