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Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice.

ABSTRACT: To determine aerosol administration capability and therapeutic efficacy of the new formulation of hyaluronan cisplatin conjugates, HylaPlat™ (HA-Pt), for lung cancer treatment.In vitro formulation stability test, 2D and 3D spheroid cell culture and in vivo efficacy studies using mouse orthotopic allograft models were conducted.The HA-Pt effectively attenuated cell growth in 2D and 3D cultures with IC50 of 2.62 and 5.36 ?M, respectively, which were comparable to those with unconjugated control cisplatin-dependent growth inhibition (IC50 1.64 and 4.63 ?M, respectively). A single dose of either 7.5 or 15 mg/kg HA-Pt (cisplatin equivalent) by intratracheal aerosol spray 7 days after Lewis lung carcinoma (LLC) cell inoculation markedly inhibited growth of LLC allografts in mouse lungs and resulted in a 90 or 94% reduction of tumor nodule numbers, respectively, as compared to those from the PBS control. Cancer stem cells and cisplatin resistant cells marker, CD44 expression decreased in the tumor nodules of the HA-Pt but not in those of cisplatin treated groups.The current study suggests that an intratracheal aerosol administration of the HA-Pt nanoparticles offers an effective strategy for lung cancer treatment and this treatment may induce only limited cisplatin resistance.

SUBMITTER: Ishiguro S

PROVIDER: S-EPMC5007205 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice.

Ishiguro Susumu S Cai Shuang S Uppalapati Deepthi D Turner Katie K Zhang Ti T Forrest Wai Chee WC Forrest M Laird ML Tamura Masaaki M

Pharmaceutical research 20160622 10

<h4>Purpose</h4>To determine aerosol administration capability and therapeutic efficacy of the new formulation of hyaluronan cisplatin conjugates, HylaPlat™ (HA-Pt), for lung cancer treatment.<h4>Methods</h4>In vitro formulation stability test, 2D and 3D spheroid cell culture and in vivo efficacy studies using mouse orthotopic allograft models were conducted.<h4>Results</h4>The HA-Pt effectively attenuated cell growth in 2D and 3D cultures with IC50 of 2.62 and 5.36 μM, respectively, which were ...[more]

PMID: 27335023

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Project description:BackgroundAcute lung injury (ALI) is a common lung disorder that affects millions of people every year. The infiltration of inflammatory cells into the lungs and death of the alveolar epithelial cells are key factors to trigger a pathological cascade. Trophoblast stem cells (TSCs) are immune privileged, and demonstrate the capability of self-renewal and multipotency with differentiation into three germ layers. We hypothesized that intratracheal transplantation of TSCs may alleviate ALI.MethodsALI was induced by intratracheal delivery of bleomycin (BLM) in mice. After exposure to BLM, pre-labeled TSCs or fibroblasts (FBs) were intratracheally administered into the lungs. Analyses of the lungs were performed for inflammatory infiltrates, cell apoptosis, and engraftment of TSCs. Pro-inflammatory cytokines/chemokines of lung tissue and in bronchoalveolar lavage fluid (BALF) were also assessed.ResultsThe lungs displayed a reduction in cellularity, with decreased CD45+ cells, and less thickening of the alveolar walls in ALI mice that received TSCs compared with ALI mice receiving PBS or FBs. TSCs decreased infiltration of neutrophils and macrophages, and the expression of interleukin (IL) 6, monocyte chemoattractant protein-1 (MCP-1) and keratinocyte-derived chemokine (KC) in the injured lungs. The levels of inflammatory cytokines in BALF, particularly IL-6, were decreased in ALI mice receiving TSCs, compared to ALI mice that received PBS or FBs. TSCs also significantly reduced BLM-induced apoptosis of alveolar epithelial cells in vitro and in vivo. Transplanted TSCs integrated into the alveolar walls and expressed aquaporin 5 and prosurfactant protein C, markers for alveolar epithelial type I and II cells, respectively.ConclusionIntratracheal transplantation of TSCs into the lungs of mice after acute exposure to BLM reduced pulmonary inflammation and cell death. Furthermore, TSCs engrafted into the alveolar walls to form alveolar epithelial type I and II cells. These data support the use of TSCs for the treatment of ALI.

Dataset Information

Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice.

Publications

Intratracheal Administration of Hyaluronan-Cisplatin Conjugate Nanoparticles Significantly Attenuates Lung Cancer Growth in Mice.

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