Abstract
Advanced staged high‐grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5‐year survival rates of only 25–30% due to late‐stage diagnosis and the shortcomings of platinum‐based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP‐ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum‐based therapy by developing a targeted delivery approach. Novel electrostatic layer‐by‐layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP‐encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44‐expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half‐life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.
Highlights
Epithelial ovarian cancer (EOC) is the second most common gynecological cancer and the leading cause of death from gynecologic malignancies in the developed world.[1,2] High-grade serous ovarian cancer (HGSOC) accounts for more than 70–80% of ovarian cancerassociated mortalities.[2,3] This high mortality rate is attributable to an aggressive phenotype, diagnosis at advanced stages, and the development of resistance against mainstay platinum-based therapies.[4]
In vivo preclinical testing and clinical trials have shown that the significant treatment response of cisplatin and PARPI combination therapy is accompanied by intolerable overlapping systemic toxicity, which requires a significant reduction of the dosing of either cisplatin or PARPI or their combination
6- to 8-week-old healthy immunocompetent BALB/c female mice were dosed with cisplatin, AZD2281, or BMN 673 individually or in combination as free drugs or encapsulated in NPs using the dosages previously described with moderate adjustment.[28]
Summary
Epithelial ovarian cancer (EOC) is the second most common gynecological cancer and the leading cause of death from gynecologic malignancies in the developed world.[1,2] High-grade serous ovarian cancer (HGSOC) accounts for more than 70–80% of ovarian cancerassociated mortalities.[2,3] This high mortality rate is attributable to an aggressive phenotype, diagnosis at advanced stages, and the development of resistance against mainstay platinum-based therapies.[4]. Rottenberg et al.[18] and Hay et al.[19] showed that the free-drug combination of AZD2281 with cisplatin or carboplatin significantly reduced resistance to platinum-based agents in BRCA1 mutated ovarian and breast cancer tumor-bearing mice and prolonged overall survival compared with either monotherapy. Cisplatin, which remains a key platinum agent for ovarian cancer therapy, is subject to the development of resistance in tumors and is typically administered at a high dose in the clinic, leading to its well-known systemic toxicity.[25,26] Third, the therapeutic combination of cisplatin and AZD2281 is poorly tolerated in patients due to the overlapping toxicities of the two drugs[27]; only reduced doses have been evaluated in clinical trials. We observed an overall increase in survival and improved treatment outcomes in mice treated with the LbLencapsulated drug combination compared with free drug combination therapy.[39,40]
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