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Nanoparticle-Mediated Targeting of MAPK Signaling Predisposes Tumor to Chemotherapy

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Nanoparticle-Mediated Targeting of MAPK Signaling Predisposes Tumor to Chemotherapy Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy Sudipta Basua,1, Rania Harfouchea,1, Shivani Sonia, Geetanjali Chimotea, Raghunath A. Mashelkara,b,2, and Shiladitya Senguptaa,2 aHarvard-MIT Division of Health Sciences and Technology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and bNational Chemical Laboratories, Pune 411008, India Contributed by Raghunath A. Mashelkar, March 19, 2009 (sent for review December 4, 2008) The MAPK signal transduction cascade is dysregulated in a majority gated a selective pharmacological inhibitor with a biodegradable of human tumors. Here we report that a nanoparticle-mediated polymer and engineered a nanoparticle that perturbs the MAPK targeting of this pathway can optimize cancer chemotherapy. We signaling pathway. The nanoparticles enable sustained drug engineered nanoparticles from a unique hexadentate-polyD,L- release, which results in inhibition of phosphorylation of ERK, lactic acid-co-glycolic acid polymer chemically conjugated to a downstream signal in the MAPK signal-transduction cascade. PD98059, a selective MAPK inhibitor. The nanoparticles are taken This translates into inhibition of cancer cell proliferation and up by cancer cells through endocytosis and demonstrate sustained induction of apoptosis. Furthermore, we demonstrate that a release of the active agent, resulting in the inhibition of phosphor- nanoparticle-enabled targeting of the MAPK pathway inhibits ylation of downstream extracellular signal regulated kinase. We tumor growth in vivo and enhances the anticancer activity of demonstrate that nanoparticle-mediated targeting of MAPK inhib- cisplatin, a first-line drug for the treatment of most cancers. Our its the proliferation of melanoma and lung carcinoma cells and results open up the possibility of harnessing nanovectors for induces apoptosis in vitro. Administration of the PD98059- modulating oncogenic pathways. nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Results and Discussion Our study shows the nanoparticle-mediated delivery of signal Synthesis and Characterization of Polylactic Acid Glycolic Acid- transduction inhibitors can emerge as a unique paradigm in cancer PD98059 Conjugates. Nanoparticles engineered from biodegrad- MEDICAL SCIENCES chemotherapy. able, biocompatible, and Food and Drug Administration- approved polymers offer the potential for rapid translation to the cancer ͉ signal transduction clinics. As a result, we adapted polylactic acid glycolic acid (PLGA) as the starting polymer to engineer the nanoparticles. ancer is the second leading cause of mortality in the United We selected PD98059 as the selective inhibitor to block MAPK CStates, with an estimated 1,444,180 new cases and 565,650 signaling (13). To avoid the characteristic burst release associ- deaths in 2008 (1). Standard chemotherapy nonspecifically tar- ated with nanoparticles and achieve a controlled release profile, ENGINEERING gets all dividing cells, resulting in dose-limiting toxicities. Con- PD98059 was conjugated to linear PLGA 5050 1, using amide- sequently, there is an urgent need to develop novel strategies that coupling reaction to obtain PLGA-PD98059 (1:1) conjugate 2 are more specifically targeted against the tumor. The MAPK (Fig. 1A). The loading of PD98059 in this conjugate was deter- ␮ pathway comprising of RAS, RAF, MEK, and ERK has been mined to be 3.0 g/mg of polymer. To increase the drug loading, implicated in a majority of human tumors, often through gain of we modified the native PLGA 1 to generate hexa-carboxylic function mutations in the RAS and RAF families (2, 3). Indeed, PLGA 8 using the scheme outlined in Fig. 1. The hexa-carboxylic RAS mutations occur in 30% of all cancer, and are particularly PLGA 8 enabled conjugation of 6 molecules of PD98059 9, which ␮ implicated in over 90% of pancreatic cancers (4) and 50% of increased the loading to 60 g/mg (see Fig. 1B). The structure colon cancers (5); RAF mutations are prevalent in over 60% of of molecules generated at each step was confirmed using spec- melanomas (6) and over 35% of ovarian cancers (7). As a result, troscopic and analytical methods [see supporting information the MAPK pathway has evolved as a focus of intense investi- (SI) Materials and Methods]. We used an emulsion-solvent gation for developing small molecule inhibitors as targeted evaporation method to formulate the nanoparticles from the therapeutics. conjugate 9 [PLGA-6(PD98059)] (14), which resulted in the Another emerging strategy for targeted chemotherapy is to formation of spherical nanoparicles with a median size distri- harness nanovectors for preferential delivery of drugs into the bution of 100 nm, as confirmed by transmission electron mi- tumor (8). A wide range of nanovectors, including liposomes, croscopy (TEM) and dynamic laser light scatter (DLS) (see micelles, polymeric nanoparticles, silicon and gold nanoshells, Fig. 1C). polymeric dendrimers, and carbon-based nanostructures, have been used for drug delivery to the tumor (9). It is well established Engineering PEG Functionalized PD98059-Loaded Nanoparticles. Na- that nanoparticles preferentially localize at the tumors as a result ked nanoparticles are rapidly cleared by the macrophages fol- of the enhanced permeation and retention effect (10, 11). lowing opsonization. Surface modification of the nanoparticle Indeed, a nanoliposomal formulation of cisplatin was shown to with PEG has been reported to decrease surface interactions attain 10- to 200-fold increased drug concentration in tumors during a Phase-I clinical trial (12). However, standard liposomal Author contributions: S.B., R.H., S. Soni, G.C., R.A.M., and S. Sengupta designed research; or protein carrier-based nanoplatforms have limited control over S.B., R.H., S. Soni, and G.C. performed research; S.B. contributed new reagents/analytic drug release. In contrast, controlled-release drug delivery sys- tools; S.B., R.H., S. Soni, G.C., and S. Sengupta analyzed data; and S.B., R.H., S. Soni, R.A.M., tems have the potential to induce standardized and durable and S. Sengupta wrote the paper. clinical responses. The authors declare no conflict of interest. Interestingly, while extensive studies have been done on 1S.B. and R.H. contributed equally to this work. delivering cytotoxic agents to solid tumors using nanovectors, no 2To whom correspondence may be addressed. E-mail: [email protected] or [email protected]. report exists on combining targeted therapeutics with nanopar- This article contains supporting information online at www.pnas.org/cgi/content/full/ ticle-based tumor targeting. In this study, we chemically conju- 0902857106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0902857106 PNAS Early Edition ͉ 1of5 Downloaded by guest on September 23, 2021 A B 75 50 g/mg μ 25 0 279 C 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.) with opsonins through steric repulsion (15), thereby conferring PEG-biotin conjugate 11 (Fig. S1) and PLGA. The nanoparticles long-circulating property to the nanoparticles (16). PEG has were then probed with streptavidin-gold nanoparticles (5 nm), excellent biocompatibility and is already approved by the Food cross-sectioned, stained with uranyl acetate, and visualized using and Drug Administration for human use (17). To develop the TEM. As seen in Fig. S1, the complexation of the gold nano- ‘‘stealth’’ nanoparticles (i.e., to mask them from tissue macro- particles at the periphery of the cross-section of PLGA-PEG- phages or the reticuloendothelial system), we synthesized a nanoparticles clearly demonstrates that the PLGA-nanoparticle PLGA-b-PEG block copolymer 10 by amide coupling of the was surface coated with PEG. No such binding was observed carboxylic acid of PLGA with the amine group of 2 KDa amine with nanoparticles that were constructed with nonpegylated ethylene glycol using the coupling reagent HBTU with diiso- PLGA. propylethyl amine (DIPEA) as base (Fig. 2A). To optimize the size and surface coverage of the nanoparticles by PEG we used In Vitro-Release Kinetics of PD98059 from Nanoparticles. We next studied the controlled-release kinetics of PD98059 from the varying ratios of PLGA-b-PEG: PLGA-6(PD98059). Light scat- nanoparticles. To mimic the clinical situation, we incubated the ter and TEM revealed that the PLGA-b-PEG: PLGA- nanoparticles with tumor-cell lysates, and dialyzed the released 6(PD98059) in 1:5 ratio gave the most optimal size distribution PD98059 against PBS buffer (pH ϭ 7). We used 3 different for further studies (see Fig. 2A). cancer-cell lines for this study, the B16/F10 melanoma cells, the To test whether a ratio of 1:5 of PLGA-b-PEG: PLGA- MDA-MB-231 breast-cancer cells, and Lewis lung carcinoma 6(PD98059) confers optimal surface coverage of the nanopar- (LLC) cells. As shown in Fig. 2B, incubation with lysates of ticles by PEG, we developed a method based on the well- MDA-MB-231, B16/F10, and LLC cells resulted in a sustained validated streptavidin-biotin binding to visualize the PEG chains release of PD98059 from the nanoparticles, with a faster release on the surface of the nanoparticles using TEM. Biotinylated evident with the MDA-MB-231 cell lysate as compared with nanoparticles were engineered from a 1:5 mixture of PLGA-b- B16/F10 and LLC cells. A B 600 release kinetics 500 400 MDA g μ 300 LLC B16/F10 200 100 0 100 1000 0 100 1000 0 100 1000 0 PLGA-PEG:PLGA-6[PD] PLGA-PEG:PLGA-6[PD] PLGA-PEG:PLGA-6[PD] 0 50 100 150 200 250 300 400 500 (10:1) (5:1) (1:1) hours 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 ϭ intensity; x-axis ϭ size in nm).
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