Page - 50 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Cooperet al. Nanoparticles for radiation therapy Surprisingly, unconjugated particles showed a greater radiosen- sitizing effect than thioglucose-conjugated particles, which the authorsattributedtopossibleabsorbanceofsingletoxygenbythe thioglucoseshell. Another study used the humanized anti-HER2 antibody Trastuzumab (Herceptin), PEGylated and conjugated to 30nm Au particles, for delivery to MDA-MB-361 breast cancer (Chattopadhyayetal.,2013)(Figure1B).Both invitroand invivo studieswere performed. In vitro, an effective dose enhancement factorof1.6wasseeninthepresenceof2.4mg/mLparticlesusing 100kVpX-rays.Delivery toMDA-MB-361 xenografts was done intratumorally, with ∼0.8mg total Au used (4.8mg/g tumor). 11Gyof 100kVp imageguidedX-ray irradiationwasperformed 24hafter injection.This subtoxicdose led toa46%reduction in tumorsizerelativetoirradiationalone,withnodamagetonormal tissueorsystemic toxicity. Folicacidisanothernutrientforwhichtheneedis increasedin cancercells.Conjugationtofolatehasbeenusedforawidevariety of targeting applications for cancer and inflammatory diseases; a reviewmay be found here (Low et al., 2008). Intra-operative tumor imaging using folate targeting has recently moved to the clinic for ovarian cancer (van Dam et al., 2011). In terms of GNRT, one study reported the use of silica-modified Au nanorods(∼50nmlong)conjugatedtofolate(Huangetal.,2011) (Figure1C). The rods were taken up byMGC803 human gas- tric carcinoma cells. 6GyofX-irradiation led to a 60%decrease in cell viability in the presence of 12.5μMrods relative to cells without Au. The study also demonstrated uptake of the rods by MGC803 xenografts in nude mice, with contrast sufficient for X-ray imaging. No radiation experiments on animals were reported. Cancers are also often distinguished by a lower pH than healthy cells due tohypoxia and resulting anaerobicmetabolism within tumors. The pH-sensitive pHLIP peptide was used in one study to target Au nanoparticles to mice bearing HeLa tumors (Yao et al., 2013). Although radiation was not per- formed,accumulationofAuintumorssufficientforradiotherapy enhancementwasdemonstrated,withthestatedgoalofusingthe construct for thispurpose. Prostate cancer is an excellent target for nanoparticle- enhancedradiation, since it isoftentreatedbybrachytherapyand is accessible to intratumoral injection. Choline is a ubiquitous molecule inall cells forwhichoveractivityofprocessingenzymes (choline kinase) has been found in prostate tumors. One study reporteddevelopmentofpolyethylene imine (PEI)- andcholine- conjugatedAunanoparticles for thepurposeof targetingprostate cancer for GNRT (Razzak et al., 2013) (Figure1D). While no radiation experiments were performed in this study, favorable pharmacokineticswereshowninmice. These studies illustrate that targeted GNRT remains an area requiring substantial further investigation. While one or more targeting agents may be conjugated to Au nanoparticles, and while thesemay improve delivery in vitro and even in vivo, it is not fully establishedwhether these formulations improve tumor responsetoradiationtherapy.Thepossibilitythatanorganicshell can absorb reactive oxygen species deserves further inquiry. The size of the nanoparticles used, the density of targeting ligands, and the deliverymethod (IV, intratumoral, concentration, tim- ing)allneedtobeoptimized.Thegoodnewsisthatmanyofthese formulations use FDA-approved ingredients, some ofwhich are currentlyintheclinicforimaging.Optimizationinanimalstudies shouldthus leadtorapidclinical translation. IMPROVINGGNRTBYADDITIONOFPHOTOTHERMALTHERAPY Hyperthermiatherapyisaminimally invasive treatment inwhich the temperature is increased locally (up to 44◦C) to kill malig- nant cells. Even though hyperthermia can kill cells on its own, it ismoreoftenused in combinationwithother treatments such as radiotherapyor chemotherapy (Wust et al., 2002); such com- binations are in clinical trials (Vernon et al., 1996; van der Zee et al., 2000; Zagar et al., 2010). An increase in nuclear damage is one of the mechanisms through which cells are radiosensi- tized after hyperthermia (Wust et al., 2002;Kampinga, 2006). In addition, thehighertemperaturecausesdilationof thebloodves- sels, increasing oxygenation of the tumor (Griffin et al., 1996; Song et al., 2009). Since oxygen is a potent radiosensitizer, it can increase thedamage to the tumor throughgenerationof free radicals. Methods to locally heat the tumor region includehigh inten- sity focused ultrasound (HIFU), microwave heating, magnetic hyperthermia, andphotothermal therapy. Inphotothermal ther- apy, a light source (usually infrared) is used to deliver heat to the tumor.Suchapproachesaredifficult to target, butdeliveryof nanomedicinestothetumorcouldimprovethelocalheatingpro- file.Moststudieshave lookedatgoldnanoparticlesandnanorods for thispurpose,becauseexposureofAunanoparticles toIRlight causes a local temperature increase due to surface plasmon res- onance (El-Sayed et al., 2006; Huang et al., 2006; Gobin et al., 2007;Hainfeldet al., 2010;Vermaet al., 2014).Bymodifying the size and shapeof thesenanoparticles, the resonancepeak canbe tunedtodifferentwavelengths in theIR. Delivery of gold followed by heating and ionizing radiation has proved to be a promising approach in pre-clinical studies. Gold nanoshells with a 120nm silica core and a 12–15nm shell were used in one study (Diagaradjane et al., 2008) to treat a murine xenograft model of human colorectal cancer. Localized hyperthermic treatment followed 5min later by a 10Gy X-ray dosewere given 20–24h after IVdelivery of the nanoshells. The tumor volume doubling time was significantly greater for the treatedmice.Twomechanismswere identifiedas contributing to the treatment’s efficacy: an increase in perfusion resulting in a decrease in tumor hypoxia, and vascular collapse in the tumor due to accumulation of nanoparticles around the blood ves- sels. Another study confirmed these results using similar gold nanoshells in twomurine breast cancermodels (Atkinson et al., 2010). Another study used gold nanorodsmodified with silica and conjugated to folic acid (Huang et al., 2011) to test the effects of photothermal and radiation therapy onMGC803 gastric cancer cells. The two treatments were tested separately and not com- bined. For the radiation treatment, a 6MeV sourcewas used to deliverdosesofupto10Gy.Cellsurvivalwithradiationdecreased in a concentration-dependent fashion with nanoparticle addi- tion; the particles were non-toxic in the absence of radiation. www.frontiersin.org October2014 |Volume2 |Article86 | 50