Dataset Information

Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.

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.

SUBMITTER: Mensah LB

PROVIDER: S-EPMC6584097 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.

Mensah Lawrence B LB Morton Stephen W SW Li Jiahe J Xiao Haihua H Quadir Mohiuddin A MA Elias Kevin M KM Penn Emily E Richson Aysen K AK Ghoroghchian Paiman Peter PP Liu Joyce J Hammond Paula T PT

Bioengineering & translational medicine 20190501 2

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 ta ...[more]

PMID: 31249881

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Project description:Simple Summary Platinum-based chemotherapy and PARP inhibitors are two types of treatment that can benefit prostate cancer patients with mutations in genes that are involved in the repair of damage in the DNA. However, patients who receive one type of treatment may not respond as well to the other treatment later on. The optimal sequencing of these agents is still unclear. In this study, we looked at how 28 prostate cancer patients responded to both treatments. We found that patients generally responded best to the initially given treatment, but still over 40% of patients responded to the second treatment. We also found that the efficacy of the second given treatment was higher in the order of platinum-based chemotherapy first and PARP inhibitor second, compared to the opposite order. Abstract Patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair-related gene aberrations (HRRm) can derive meaningful benefits from both platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi). Cross-resistance between these agents is well-recognised in other tumour types but data on prostate cancer is lacking. In this retrospective pre-planned study, we assessed 28 HRRm mCRPC patients who received PlCh and PARPi. Progression-free survival (PFS) on initial therapy was longer than on subsequent therapy (median 5.3 vs. 3.4 months, p = 0.016). The median PFS of PlCh was influenced by the order of agents, with 3.6 months shorter PFS after PARPi than when administered first. The median PFS of PARPi was less influenced, with 0.9 months shorter PFS after PlCh than before. In the PARPi-first subgroup, six out of 16 evaluable patients (37.5%) had a >50% PSA decline to PlCh, and two of eight (25.0%) had a radiographic response to PlCh. In the PlCh-first subgroup, 6/10 (60.0%) had a >50% PSA decline, and 5/9 (55.6%) had a radiographic response to PARPi. These data show >40% of the cohort is sensitive to a subsequent HRR-targeting agent. PlCh appears to induce less cross-resistance than PARPi. Additional data on resistance mechanisms will be crucial in defining an optimal treatment sequence in HRRm mCRPC patients.

Dataset Information

Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.

Publications

Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.

Similar Datasets

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