Article

Synergistic cytotoxicity of irinotecan and cisplatin in dual-drug targeted polymeric nanoparticles.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Nanomedicine (Impact Factor: 5.26). 10/2012; DOI: 10.2217/nnm.12.134
Source: PubMed

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.

0 Bookmarks
 · 
198 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The adjustable microfluidic droplet generator (ADG) described herein successfully uses a micro-mixer and a flow-focusing device to produce water droplets with eleven different trypan blue concentrations under various flow rate ratios of the trypan blue solution (sample phase 1, w1) and D.I. water (sample phase 2, w2) and uses these chitosan microparticles to encapsulate the magnetic nanoparticles. These eleven trypan blue/water droplet variations are uniform in size, with a coefficient of variation less than 10%, and can be precisely controlled by adjusting the sum of the sample phase flow rates (w1+w2) and the oil phase flow rate. Chitosan emulsions with eleven different Fe3O4 nanoparticle concentrations are used for magnetic targets, with the chitosan microparticles ranging from 44 to 83 ┬Ám in diameter. The ADG has the advantages of active droplet diameter control, the generation of droplets of uniform and specific size with different concentrations and the simplicity of the process. This preparation approach for chitosan microparticles with eleven different concentrations has many potential applications in drug delivery and pharmaceuticals.
    Journal of Micromechanics and Microengineering 12/2013; 23(12):5025-. · 1.73 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 12.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intelligent nanomaterials that are able to respond to environmental stimuli for sequential release of multiple payloads are highly desirable in applications of drug delivery systems. In this study, a core/shell-structured nanocarrier with an acid-dissolvable magnetic supraparticle (MSP) as core and a redox-degradable poly(methylacrylic acid-co-N,N-bis(acryloyl)cystamine) (P(MAA-Cy)) as shell was prepared using the distillation-precipitation polymerization technique, in which the magnetic core and the polymer shell were loaded with different guest molecules. Under physiological conditions similar to the cytoplasm of tumour cells, this MSP@P(MAA-Cy) microsphere showed a sequential degradation profile of the shell and the core. With dyes of fluorescein isothiocyanate (FITC) loaded in the core and rhodamine in the shell, the produced MSP-FITC@P(MAA-Cy)-Rho microspheres were applied in HeLa cell and HEK 293T cell cultures, showing selective degradation of the microspheres in HeLa cells to release the rhodamine and FITC dyes in sequence. When two anticancer drugs, i.e., paclitaxel (TXL) and doxorubicin (DOX), were loaded separately into the core and the shell domains of the microspheres, the experimental results showed that the MSP-TXL@P(MAA-Cy)-DOX nanodrug exhibited better inhibitive efficacy than the free drugs under the same dosing level, demonstrating the great potential of this stimuli-sensitive drug delivery system for programmed and stimuli-responsive drug release characteristics.
    J. Mater. Chem. B. 07/2014; 2(32).