Synergistic cytotoxicity of irinotecan and cisplatin in dual-drug targeted polymeric nanoparticles.
ABSTRACT Aim: Two unexplored aspects for irinotecan and cisplatin (I&C) combination chemotherapy are: actively targeting both drugs to a specific diseased cell type, and delivering both drugs on the same vehicle to ensure their synchronized entry into the cell at a well-defined ratio. In this work, the authors report the use of targeted polymeric nanoparticles (NPs) to coencapsulate and deliver I&C to cancer cells expressing the prostate-specific membrane antigen. Materials & method: Targeted NPs were prepared in a single step by mixing four different precursors inside microfluidic devices. Results: I&C were encapsulated in 55-nm NPs and showed an eightfold increase in internalization by prostate-specific membrane antigen-expressing LNCaP cells compared with nontargeted NPs. NPs coencapsulating both drugs exhibited strong synergism in LNCaP cells with a combination index of 0.2. Conclusion: The strategy of coencapsulating both I&C in a single NP targeted to a specific cell type could potentially be used to treat different types of cancer. Original submitted 24 February 2012; Revised submitted 21 June 2012.
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ABSTRACT: Microfluidic synthesis of nanoparticles (NPs) can enhance the controllability and reproducibility in physicochemical properties of NPs compared to bulk synthesis methods. However, applications of microfluidic synthesis are typically limited to in vitro studies due to low production rates. Herein, we report the parallelization of NP synthesis by 3D hydrodynamic flow focusing (HFF) using a multilayer microfluidic system to enhance the production rate without losing the advantages of reproducibility, controllability, and robustness. Using parallel 3D HFF, polymeric poly(lactide-co-glycolide)-b-polyethyleneglycol (PLGA-PEG) NPs with sizes tunable in the range of 13 - 150 nm could be synthesized reproducibly with high production rate. As a proof of concept, we used this system to perform in vivo pharmacokinetic and biodistribution study of small (20 nm diameter) PLGA-PEG NPs that are otherwise difficult to synthesize. Microfluidic parallelization thus enables synthesis of NPs with tunable properties with production rates suitable for both in vitro and in vivo studies.Nanomedicine: nanotechnology, biology, and medicine 08/2013; 10(2). DOI:10.1016/j.nano.2013.08.003 · 5.98 Impact Factor
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ABSTRACT: To summarize the most recent preclinical and clinical advancements in therapeutic nano-oncology. First-generation nanotherapies are well tolerated in humans and evidence shows that they are efficacious, while at the same time reducing the burden of side-effects. Most of these therapies are not specifically targeted, but take advantage of enhanced passive accumulation within tumors to preferentially deliver chemotherapies that demonstrate off-target toxicities when administered as free drugs. Also, actively targeted nanotherapies are entering the clinical arena and preliminary data are encouraging. Finally, a number of exciting preclinical developments in nanotechnology provide clear evidence that nanotherapies will continue to enter the clinic and will have a significant impact in oncology. A number of intriguing nanoparticle therapies are being tested in preclinical and clinical trials. Nanoparticles with increasing molecular sophistication, specific targeting properties, and unique mechanisms of action will find their way to the clinic. Certainly, nanoparticle-based therapies will be increasingly represented in drug development pipelines, and will continue to provide efficacious and well tolerated drug options for patients with cancer.Current opinion in oncology 10/2013; 25(6). DOI:10.1097/CCO.0000000000000012 · 3.76 Impact Factor
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ABSTRACT: Taking a nanoparticle (NP) from discovery to clinical translation has been slow compared to small molecules, in part by the lack of systems that enable their precise engineering and rapid optimization. In this work we have developed a microfluidic platform for the rapid, combinatorial synthesis and optimization of NPs. The system takes in a number of NP precursors from which a library of NPs with varying size, surface charge, target ligand density, and drug load is produced in a reproducible manner. We rapidly synthesized 45 different formulations of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) NPs of different size and surface composition and screened and ranked the NPs for their ability to evade macrophage uptake in vitro. Comparison of the results to pharmacokinetic studies in vivo in mice revealed a correlation between in vitro screen and in vivo behavior. Next, we selected NP synthesis parameters that resulted in longer blood half-life and used the microfluidic platform to synthesize targeted NPs with varying targeting ligand density (using a model targeting ligand against cancer cells). We screened NPs in vitro against prostate cancer cells as well as macrophages, identifying one formulation that exhibited high uptake by cancer cells yet similar macrophage uptake compared to nontargeted NPs. In vivo, the selected targeted NPs showed a 3.5-fold increase in tumor accumulation in mice compared to nontargeted NPs. The developed microfluidic platform in this work represents a tool that could potentially accelerate the discovery and clinical translation of NPs.ACS Nano 11/2013; 7(12). DOI:10.1021/nn403370e · 12.03 Impact Factor