Antitumor efficacy of liposome-encapsulated NVP-BEZ 235 in combination with irreversible electroporation

Tian, Li; Qiao, Yanjiang; Lee, Patrick; Wang, Lucas; Chang, Ashley; Ravi, Saisree; Rogers, Thomas A.; Lu, Linfeng; Singhana, Burapol; Zhao, Jun; Melancon, Marites P.

doi:10.1080/10717544.2018.1444683

Cited by 16 publications

(18 citation statements)

References 34 publications

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“…More recently, studies have shown that mild hyperthermia results from IRE [19,27,[52][53][54]. However, hyperthermia is a desirable treatment characteristic and has been utilized to enhance the efficacy of IRE when combined with chemotherapeutics to prevent recurrence [55][56][57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Combinatorial effect of radium-223 and irreversible electroporation on prostate cancer bone metastasis in mice

Rojo

Perez

Damasco

et al. 2021

International Journal of Hyperthermia

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Background: Metastatic prostate cancer in bone is difficult to treat as the tumor cells are relatively resistant to hormonal or chemotherapies when compared to primary prostate cancer. Irreversible electroporation (IRE) is a minimally invasive ablation procedure that has potential applications in the management of prostate cancer in bone. However, a common limitation of IRE is tumor recurrence, which arises from incomplete ablation that allows remaining cancer cells to proliferate. In this study, we combined IRE with radium-223 (Ra-223), a bone-seeking radionuclide that emits short track length alpha particles and thus is associated with reduced damage to the bone marrow and evaluated the impact of the combination treatment on bone-forming prostate cancer tumors. Methods: The antitumor activity of IRE and Ra-223 as single agents and in combination was tested in vitro against three bone morphogenetic protein 4 (BMP4)-expressing prostate cancer cell lines (C4-2B-BMP4, Myc-CaP-BMP4, and TRAMP-C2-BMP4). Similar evaluation was performed in vivo using a bone-forming C4-2B-BMP4 tumor model in nude mice. Results: IRE and Ra-223 as monotherapy inhibited prostate cancer cell proliferation in vitro, and their combination resulted in significant reduction in cell viability compared to monotherapy. In vivo evaluation revealed that IRE with single-dose administration of Ra-233, compared to IRE alone, reduced the rate of tumor recurrence by 40% following initial apparent complete ablation and decreased the rate of proliferation of incompletely ablated tumor as quantified in Ki-67 staining (53.58 ± 16.0% for IRE vs. 20.12 ± 1.63%; for IRE plus Ra-223; p ¼ 0.004). Histological analysis qualitatively showed the enhanced killing of tumor cells adjacent to bone by Ra-223 compared to those treated with IRE alone. Conclusion: IRE in combination with Ra-223, which enhanced the destruction of cancer cells that are adjacent to bone, resulted in reduction of tumor recurrence through improved clearance of proliferative cells in the tumor region.

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Section: Discussionmentioning

confidence: 99%

Combinatorial effect of radium-223 and irreversible electroporation on prostate cancer bone metastasis in mice

Rojo

Perez

Damasco

et al. 2021

International Journal of Hyperthermia

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“…Our previous study also used DPPC and DSPE-PEG liposomes encapsulating BEZ. Their combination with IRE showed antiproliferation efficacy on Hep3B xenografts after a single treatment [11].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous in vitro results [11] for electroporation of Hep3B cells suggests that electroporation in the RE range leads to higher cell viability than does IRE. The same results were observed on HN5 cells (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…A tumor may receive IRE to the treatment center, but RE at the margins. Furthermore, our previous results in Hep3B hepatocellular carcinoma cells suggest that RE leads to greater viability of cancer cells in vitro and to higher proliferation, as shown in the increased Ki67 staining of the tumor margin in vivo [11]. Clinical results also suggest that more than 10% of local tumor recurrences occur at the ablated site for patients treated with IRE [12].…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Efficacy of Liposome-Encapsulated NVP-BEZ235 Combined with Irreversible Electroporation for Head and Neck Cancer

et al. 2019

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Irreversible electroporation (IRE) kills tumor cells by the delivery of short pulses of strong electric fields. However, the field strength decreases with distance from the treatment center. When IRE cannot eradicate the entire tumor mass, the surviving tumor cells can regrow. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that has been administered orally in clinical trials. However, its hydrophobicity and poor water solubility make NVP-BEZ235 difficult to deliver to target areas. To improve its pharmacokinetics and therapeutic efficacy, we have encapsulated NVP-BEZ235 in a liposome (termed as L-BEZ). Our current study focuses on the long-term antitumor efficacy of IRE and intratumoral injection of L-BEZ in HN5 head and neck cancer xenografts in nude mice. We compared in vitro efficacy, as well as the effect on tumor size and growth rate in vivo, between IRE alone, IRE + oral BEZ, and IRE + L-BEZ over the course of two months. All animals in the control group were sacrificed by day 36, due to excess tumor burden. Tumors treated with IRE alone grew faster and larger than those in the control group. IRE + oral BEZ suppressed tumor growth, but the growth rate increased to that of the controls toward the end of 21 days. Only IRE + L-BEZ eradicated the tumor masses, with no palpable or extractable tumor mass observed after two months. The combination of IRE and L-BEZ could effectively eradicate tumors and prevent recurrence.

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“…MTT assay was used to determine the cytotoxic effects of nano-systems against cancer or normal cells. 38 Briefly, after 24 hours of culture, the cells were treated with drug-loaded nano-systems and free drugs at certain concentrations for 24 hours. Subsequently, MTT was added to the treated cells for 3 hours, with added DMSO, and then placed in the cells for 15 minutes.…”

Section: Mtt Assay and Combination Index Calculationmentioning

confidence: 99%

<p>Synergistic Effect of Tangeretin and Atorvastatin for Colon Cancer Combination Therapy: Targeted Delivery of These Dual Drugs Using RGD Peptide Decorated Nanocarriers</p>

He¹,

Zheng

Li³

et al. 2020

DDDT

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Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the fourth leading cause of cancer death over the world. Nano-sized drug delivery systems are used for the treatment of cancers. The aim of this study was to develop a tangeretin (TAGE) and atorvastatin (ATST) combined nano-system decorated with RGD (RGD-ATST/TAGE CNPs) for colon cancer combination therapy. Materials and Methods: In this study, cyclized arginine-glycine-aspartic acid sequences (RGD) contained ligand was synthesized by conjugating cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) with D-α-tocopheryl succinate dichloromethane (TOSD) using polyethylene glycol (PEG) as a linker to obtain cRGDfK-PEG-TOSD. ATST and TAGE combined nanosystems: RGD-ATST/TAGE CNPs were prepared. The combination effects as well as antitumor effects of these two agents were evaluated on colon cancer cells and mice bearing cancer models. Results: Drug entrapment efficiencies of nano-systems were high (around 90%), suggesting the good loading capacity. The release profiles of ATST or TAGE from RGD-ATST/TAGE CNPs followed Higuchi model. The RGD-decorated nano-system showed more obvious cytotoxicity on HT-29 cells than the undecorated nano-system, but no obvious difference was found on normal CCD-18 cells. The strongest synergism was observed when the weight ratio of ATST to TAGE was 1:1. In vivo biodistribution of RGD-ATST/TAGE CNPs in the tumor site is high and prominently inhibited the in vivo tumor growth. Conclusion: The results demonstrated that RGD-ATST/TAGE CNPs showed the most significant synergistic therapeutic efficacy, exhibited no significant toxicity to major organs and tissues, and body weight of the treated mice was stable. Therefore, the combination nano-system is a promising platform for colon cancer therapy.

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Antitumor efficacy of liposome-encapsulated NVP-BEZ 235 in combination with irreversible electroporation

Cited by 16 publications

References 34 publications

Combinatorial effect of radium-223 and irreversible electroporation on prostate cancer bone metastasis in mice

Combinatorial effect of radium-223 and irreversible electroporation on prostate cancer bone metastasis in mice

Antitumor Efficacy of Liposome-Encapsulated NVP-BEZ235 Combined with Irreversible Electroporation for Head and Neck Cancer

<p>Synergistic Effect of Tangeretin and Atorvastatin for Colon Cancer Combination Therapy: Targeted Delivery of These Dual Drugs Using RGD Peptide Decorated Nanocarriers</p>

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