Anticancer efficacy and toxicokinetics of a novel paclitaxel-clofazimine nanoparticulate co-formulation

Koot, Dwayne; Cromarty, Allan Duncan

doi:10.1007/s13346-015-0222-6

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…In addition, clofazimine has been shown to exert an inhibitory action on ABCB1/MDR1/P-glycoproteins (Pgp) [58], although this aspect is particularly relevant when applied together with chemotherapeutics to chemo-resistant cells (e.g. [59]). Finally, clofazimine has been shown via bioinformatic screening to have the potential to inhibit p53–MDM2 interaction leading in turn to stabilization and activation of the tumor suppressor p53 [60, 61].…”

Section: Discussionmentioning

confidence: 99%

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Zaccagnino¹,

Managò

Leanza

et al. 2016

Oncotarget

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Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations. We provide evidence that clofazimine induces apoptosis in PDAC cells with an EC50 in the μM range via its specific inhibitory action on the potassium channel Kv1.3. Intraperitoneal injection of clofazimine resulted in its accumulation in the pancreas of mice 8 hours after administration. Using an orthotopic PDAC xenotransplantation model in SCID beige mouse, we show that clofazimine significantly and strongly reduced the primary tumor weight. Thus, our work identifies clofazimine as a promising therapeutic agent against PDAC and further highlights ion channels as possible oncological targets.

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Section: Discussionmentioning

confidence: 99%

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Zaccagnino¹,

Managò

Leanza

et al. 2016

Oncotarget

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“…Koot et al showed that Riminocelles™, a formulation of co-encapsulated paclitaxel and clofazimine, demonstrated superior efficacy in preclinical studies. 7 Batist et al demonstrated for the first time, that CPX-1, a liposome formulation co-encapsulated with irinotecan and floxuridine, was well tolerated and exhibited antitumor activity in patients with advanced solid tumors in a Phase 1 study. 8 Therefore, administering various chemotherapeutic drugs together as appropriate nanocarrier formulations may be a promising strategy for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles

Shin

Jin

et al. 2021

IJN

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We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles. Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles. Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration-time curve from 0 to 2 h (AUC 0-2 h ) and 0 to 8 h (AUC 0-8 h ) and plasma concentration at time zero (C o ) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEGb-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution. Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEGb-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.

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“…These differences highly complicate and make unlikely that the free drug combinations reach the target site at optimal ratios guaranteeing synergistic effects. However, the use of multifunctional nanocarriers that accommodate in their structure more than one drug at a fixed ratio appears a unique opportunity to overcome this problem. − …”

Section: Introductionmentioning

confidence: 99%

Co-delivery of Docetaxel and Disulfonate Tetraphenyl Chlorin in One Nanoparticle Produces Strong Synergism between Chemo- and Photodynamic Therapy in Drug-Sensitive and -Resistant Cancer Cells

et al. 2018

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Cancer therapies based on the combinations of different drugs and/or treatment modalities are emerging as important strategies for increasing efficacy and cure, decreasing unwanted toxicity, and overcoming drug resistance, provided that optimized drug concentration ratios are delivered into the target tissue. To these purposes, delivery systems such as nanoparticles (NPs) offer the unique opportunity to finely tune the drug loading and the release rate of drug combinations in the target tissues. Here, we propose double-layered polymeric NPs for the delivery of the chemotherapeutic docetaxel (DTX) and the photosensitizer disulfonate tetraphenyl chlorin (TPCS2a) coated with hyaluronic acid (HA), which allows cell targeting via CD44 receptors. The simultaneous delivery of the two drugs aims at killing DTX-sensitive (HeLa-P, MDA-MB-231) and DTX-resistant (HeLa-R) cancer cells by combining chemotherapy and photodynamic therapy (PDT). Using the Chou and Talalay method that analyses drug interactions and calculates combination index (CI) using the median-effect principle, we compared the efficiency of DTX chemotherapy combined with TPCS2a-PDT for drugs delivered in the standard solvents, coloaded in the same NP (DTX/TPCS2a-NP) or loaded in separate NPs (DTX-NPs + TPCS2a-NPs). Along with the drug interaction studies, we gained insight into cell death mechanisms after combo-therapy and into the extent of TPCS2a intracellular uptake and localization. In all cell lines considered, the analysis of the viability data revealed synergistic drug/treatment interaction especially when DTX and TPCS2a were delivered to cells coloaded in the same NPs despite the reduced PS uptake measured in the presence of the delivery systems. In fact, while the combinations of the free drugs or drugs in separate NPs gave slight synergism (CI < 1) only at doses killing more than 50% of the cells, the combination of drugs in one NPs gave high synergism also at doses killing 10-20% of the cells. Furthermore, the DTX dose in the combination DTX/TPCS2a-NPs could be reduced by ∼2.6- and 10.7-fold in HeLa-P and MDA-MB-231, respectively. Importantly, drug codelivery in NPs was very efficient in inducing cell mortality also in DTX resistant HeLa-R cells overexpressing P-glycoprotein 1 in which the dose of the chemotherapeutic can be reduced by more than 100 times using DTX/TPCS2a-NPs. Overall, our data demonstrate that the protocol for the preparation of HA-targeted double layer polymeric NPs allows to control the concentration ratio of coloaded drugs and the delivery of the transported drugs for obtaining a highly synergistic interaction combining DTX-chemotherapy and TPCS2a-PDT.

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Anticancer efficacy and toxicokinetics of a novel paclitaxel-clofazimine nanoparticulate co-formulation

Cited by 7 publications

References 46 publications

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles

Co-delivery of Docetaxel and Disulfonate Tetraphenyl Chlorin in One Nanoparticle Produces Strong Synergism between Chemo- and Photodynamic Therapy in Drug-Sensitive and -Resistant Cancer Cells

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