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Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy.

ABSTRACT: Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with sterically stabilized liposome (SSL)-DXR. Using data extracted from diverse literature sources, Cremophor-paclitaxel (Taxol(®)) PK was described by a carrier-mediated dispositional model and SSL-DXR PK was described by a two-compartment model with first-order drug release. A hybrid-physiologic, well-stirred model with partition coefficients (Kp) captured intratumor concentrations. Apoptotic responses driving tumor priming were modeled using nonlinear, time-dependent transduction functions. The tumor growth model used net first-order growth and death rate constants, and two transit compartments that captured the temporal displacement of tumor exposure versus effect, and apoptotic signals from each agent were used to drive cytotoxic effects of the combination. The final model captured plasma and intratumor PK data, apoptosis induction profiles, and tumor growth for all treatments/sequences. A feedback loop representing PAC-induced apoptosis effects on Kp(_DXR) enabled the model to capture tumor-priming effects. Simulations to explore time- and sequence-dependent effects of priming indicated that PAC priming increased K(p_DXR) 3-fold. The intratumor concentrations producing maximal and half-maximal effects were 18 and 7.2 ?g/ml for PAC, and 17.6 and 14.3 ?g/ml for SSL-DXR. The duration of drug-induced apoptosis was 27.4 h for PAC and 15.8 h for SSL-DXR. Simulations suggested that PAC administered 24 h before peak priming could increase efficacy 2.5-fold over experimentally reported results. The quantitative approach developed in this article is applicable for evaluating tumor-priming strategies using diverse agents.

SUBMITTER: Ait-Oudhia S

PROVIDER: S-EPMC3533406 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy.

Ait-Oudhia Sihem S Straubinger Robert M RM Mager Donald E DE

The Journal of pharmacology and experimental therapeutics 20121031 1

Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with sterically stabilized liposome (SSL)-DXR. Using data extracted from diverse literature sources, Cremophor-paclitaxel (Taxol(®)) PK was described by a carrier-mediated dispositional model and SSL-D ...[more]

PMID: 23115220

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Project description:Most pancreatic adenocarcinoma patients present with unresectable disease and benefit little from chemotherapy. Poor tumor perfusion and vascular permeability limit drug deposition. Previous work showed that Smoothened inhibitors of hedgehog signaling (sHHI) promote neovascularization in spontaneous mouse models of pancreatic cancer (PaCA) and enhance tumor permeability to low-molecular weight compounds. Here, we tested the hypothesis that sHHI can enhance tumor deposition and efficacy of drug-containing nanoparticles consisting of 80 to 100 nm sterically-stabilized liposomes (SSL) containing doxorubicin (SSL-DXR). SCID mice bearing low-passage patient-derived PaCA xenografts (PDX) were pretreated p.o. for 10 days with 40 mg/kg/d NVP-LDE225 (erismodegib), followed by i.v. SSL-DXR. Microvessel density, permeability, perfusion, and morphology were compared with untreated controls, as was SSL deposition and therapeutic efficacy. The sHHI alone affected tumor growth minimally, but markedly increased extravasation of nanoparticles into adenocarcinoma cell-enriched regions of the tumor. Immunostaining showed that sHHI treatment decreased pericyte coverage (α-SMA(+)) of CD31(+) vascular endothelium structures, and increased the abundance of endothelium-poor (CD31(-)) basement membrane structures (collagen IV(+)), suggesting increased immature microvessels. SSL-DXR (15 mg/kg) administered after sHHI pretreatment arrested tumor volume progression and decreased tumor perfusion/permeability, suggesting an initial vascular pruning response. Compared with controls, one cycle of 10-day sHHI pretreatment followed by 6 mg/kg SSL-DXR doubled median tumor progression time. Three cycles of treatment with sHHI and SSL-DXR, with a 10-day between-cycle drug holiday, nearly tripled median tumor progression time. Based upon these data, short-term sHHI treatment sequenced with nanoparticulate drug carriers constitutes a potential strategy to enhance efficacy of pancreatic cancer therapy.

Project description:Cancers originating from the digestive system account for 290,000 or ~20% of all new cancer cases annually in the US. We previously developed paclitaxel-loaded tumor-penetrating microparticles (TPM) for intraperitoneal (IP) treatment of peritoneal tumors (Lu et al., 2008; Tsai et al., 2007; Tsai et al., 2013). TPM is undergoing NIH-supported IND-enabling studies for clinical evaluation. The present study evaluated the hypothesis that TPM, via inducing apoptosis and expanding the interstitial space, promotes the delivery and transfection of lipid vectors containing siRNA. The in vivo model was the metastatic human Hs766T pancreatic tumor that, upon IP injection, produced widely distributed solid tumors and ascites in the peritoneal cavity in 100% of animals. The target gene was survivin, an anti-apoptotic protein induced by chemotherapy and associated with metastases and poor prognosis of patients with gastric and colorectal cancers. The siRNA carrier was pegylated liposomes comprising cationic and neutral lipids plus a fusogenic lipid (PCat). PCat-loaded with survivin siRNA (PCat-siSurvivin) was active in cultured cells (decreased survivin mRNA and protein levels, reduced cell clonogenicity, enhanced paclitaxel activity), but lost its activity in vivo; this difference is consistent with the well-known problem of inadequate delivery and transfection of siRNA in vivo. In comparison, single agent TPM prolonged animal survival and, as expected, induced survivin expression in tumors. Addition of PCat-siSurvivin reversed the TPM-induced survivin expression and enhanced the antitumor activity of TPM. The finding that in vivo survivin knockdown by PCat-siSurvivin was successful only when it was given in combination with TPM provides the proof-of-concept that tumor priming promotes the delivery and transfection of liposomal siRNA. The data further suggest the TPM/PCat-siSurvivin combination as a potentially useful chemo-gene therapy for peritoneal cancer.

Project description:Drug development for first-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anticancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including ALDH1A and CD133, also known as PROM1 Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel HR compared with vehicle (HR = 0.037) and paclitaxel (HR = 0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with first-line chemotherapy in primary and chemotherapy-refractory EOC.Significance: This study highlights the use of an in vitro spheroid 3D drug screening model to identify new therapeutic approaches to reverse chemotherapy resistance in ovarian cancer. Cancer Res; 78(15); 4370-85. ©2018 AACR.

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Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy.

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Systems pharmacological analysis of paclitaxel-mediated tumor priming that enhances nanocarrier deposition and efficacy.

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