Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy - PubMed (original) (raw)

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

Sudipta Basu et al. Proc Natl Acad Sci U S A. 2009.

Abstract

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Development of PD98059 loaded nanoparticles. (A) Synthetic scheme for different PLGA-(PD98059)x conjugates. (B) Loading of PD98059 in mono (2)-, tri (7)- and hexa (9)- dentate PLGA expressed as microgram per milligram of polymer. (C) Representative transmission electron microscopy image of nanoparticles synthesized from hexadentate PLGA-(PD98059)6 conjugate. (Scale bar, 100 nm.)

Fig. 2.

Fig. 2.

Engineering pegylated nanoparticles. (A) Synthetic scheme for PEG-_b_-PLGA conjugate for engineering pegylated nanoparticles. Different ratio of PLGA-PEG: PLGA-[PD98059]6 results in nanoparticles of different size distribution, as measured by DLS (_y_-axis = intensity; _x_-axis = size in nm). (B) Graph shows physicochemical release kinetics of PD98059 when the nanoparticles are incubated with MDA-MB231, LLC, and B16/F10 cell lysates.

Fig. 3.

Fig. 3.

Effect of PD98059-loaded nanopaticles on cell proliferation. B16/F10 melanoma and MDA-MB-231 breast-cancer cells were incubated with free PD98059 (PD), PD98059-nanoparticle (PD-NP), or vehicle (control), for 24 or 72 h. MTS assays were used to determine the temporal cytotoxicity of increasing concentrations of free PD98059 and PD98059-nanoparticles (NP). Data are expressed as percent of vehicle-treated control (considered as 100%), and represents mean ± SEM from at least triplicates. *, P < 0.05 vs. vehicle control (ANOVA followed by Dunnet's post hoc test).

Fig. 4.

Fig. 4.

Combination therapy of PD98059-NP with cisplatin inhibits B16/F10 melanoma in xenograft mouse model. (A) Graph shows tumor volume of B16/F10 melanoma in different treatment groups, comparing the effects of PD98059-nanoparticle (PD-NP) + cisplatin, PD-NP, free PD98059, cisplatin, and free PD90859 + cisplatin. The control group received saline. Animals were treated with PD98059 (free or NP-conjugated) at a dose of 5 mg/kg through the tail vein. Cisplatin (1.25 mg/kg) was administered i.p. 1 day after the PD98059 dosing. Animals were killed on day 14. Each animal received 3 doses of the treatments. (B) Mean body weight of animals in different treatments as a measure of gross toxicity. All results are mean ± SEM (n = 6–8 per treatment group). *, P < 0.05 vs. vehicle (ANOVA followed by Newman Keul's post hoc test). (C) Representative images showing histological staining of the cross section of the excised tumors in different treatments at 20× magnifications. (Left) H&E staining of representative tumor cross-sections. (Middle) Tumor cross-section was immunostained for phospho-ERK (green), and counterstained with propidium iodide (red). (Right) Tumor sections were TUNEL-labeled for apoptosis with the use of Texas Red-labeled nucleotide. Images were captured using a Nikon Eclipse epifluorescence microscope.

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