function ali zed radioactive gold

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Advanced Review

Functionalized radioactive goldnanoparticles in tumor therapyRaghuraman Kannan, 1 Ajit Zambre, 1 Nripen Chanda, 1 RajeshKulkarni, 1 Ravi Shukla, 1 Kavita Katti, 1 Anandhi Upendran, 2 CathyCutler, 3 Evan Boote 1 and Kattesh V. Katti 1

The development of new treatment modalities that offer clinicians the ability toreduce sizes of tumor prior to surgical resection or to achieve complete ablationwithout surgery would be a signicant medical breakthrough in the overall careand treatment of prostate cancer patients. The goal of our investigation is aimedat validating the hypothesis that Gum Arabic-functionalized radioactive goldnanoparticles (GA- 198AuNP) have high afnity toward tumor vasculature. Wehypothesized further that intratumoral delivery of the GA- 198AuNP agent within

prostate tumor will allow optimal therapeutic payload that will signicantlyor completely ablate tumor without side effects, in patients with hormonerefractory prostate cancer. In order to evaluate the therapeutic efcacy of thisnew nanoceutical, GA- 198AuNP was produced by stabilization of radioactive goldnanoparticles ( 198Au) with the FDA-approved glycoprotein, GA. This reviewwill describe basic and clinical translation studies toward realization of thetherapeutic potential and myriad of clinical applications of GA- 198AuNP agentin treating prostate and various solid tumors in human cancer patients. 2011 WileyPeriodicals, Inc.

How to cite this article:

WIREs Nanomed Nanobiotechnol 2012, 4:4251. doi: 10.1002/wnan.161

INTRODUCTION

P rostate cancer in men is the second deadliestcancer after lung cancer. Approximately 217,730men are diagnosed with prostate cancer resulting inloss of life for 32,050 men. 1 Prostate cancer diagnosisbegins either with a digital rectal exam during whicha doctor feels the prostate to check for irregularity ora blood test to check the level of prostate-specic an-tigen (PSA) or both. 2,3 Recent studies have shown thatregular PSA screening did not increase the survivalrate over a period of 10 years. 4,5 Early detectionof prostate tumor by common imaging modalitiessuch as ultrasound (US), computer tomography (CT)is difcult, as the prostate is deep inside the pelvisand harder to access. These clinical impediments will

Correspondence to: [email protected],[email protected] of Radiology, University of Missouri, Columbia, MO,USA2Nanoparticle Biochem, Inc., Columbia, MO, USA3Missouri University Research Reactor, University of Missouri,Columbia, MO, USA

continue to hinder accurate and early detection of prostate cancer resulting in more cases of androgendependent and hormone independent prostate cancersand thus posing some of the most vexing questionsin medicine. 6 The widely used brachy therapy utilizeagents of 50100 m in size including 125 I or 103 Pdradioactive seeds, and Y-90 immobilized glassmicrospheres (Therasphere ) to achieve selective in-ternal radiation therapy (SIRT). 79 The limitednatural afnity of these microspheres towardtumor vasculature coupled with signicantly larger

(50100 m) sizes as compared to the porosityof tumor vasculature (150300 nm) causes limitedretention and signicant leakage of therapeutic dosesaway from the tumor site. These problems result indecreased efcacy, acute toxic side effects and lowertumoricidal activity of brachy therapy agents.

A central goal of chemo or radiation therapywhile treating patients with prostate (and othersolid tumors) cancer is to achieve maximum doseintensity at the tumor site while managing drug-related toxicities to the minimum to non-target

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WIREs Nanomedicine and Nanobiotechnology GA-198AuNP in tumor therapy

organs. For a vast majority of chemo therapeutic-and radiation-induced agents, it is still a signicantchallenge to optimize critically important clinicalparameters such as plasma concentration and the timeof exposure to the diseased tissue to chemotherapyor radiotherapy agents as the manipulation of

variables such as dose regimens of drugs and dosingschedules have often failed to achieve the optimumtherapeutic payloads. Various targeted strategiesbeing currently employed are of limited benet asthe drugs used are rapidly eliminated from the plasmacompartment, metabolized into inactive species thusobliterating therapy, and rapidly released fromtumor cells due to poor tumor cell/tissue specicity.Therefore, concerted efforts are being focused onthe development of clinical modalities to maximizedrug exposure to tumor sites following systemicor intratumoral administration. Recently, newapproaches using nanoparticle-based delivery systemsfor the administration of inherently therapeuticradioactive isotopes are being explored. 1012 Wanget al. have demonstrated therapeutic effects of -emission of 186 Re carried by liposomes into the tumorremnants in a nude rat squamous cell carcinomaxenograft model. 13 Following the partial resection of tumor xenografts, the animals were intratumorallyinjected with 186 Re-labeled or unlabeled (control)and neutrally charged or positively charged 100-nm-diameter liposomes. Tumor efcacy studies indicatedthat the neutral ( n = 4) and cationic ( n = 4) liposometreated control groups showed an increase in tumorgrowth, whereas the 186 Re-neutral-liposome group(n = 8) and the 186 Re-cationic-liposome group (n = 8)presented with a signicantly reduced average naltumor volume at the end of the study (Day 35).These results demonstrate that the intraoperativeuse of liposomal therapeutic radionuclides mayplay an important role in the management of positive surgical margins in advanced head andneck squamous cell carcinoma. French et al. havepresented another example of the utility of liposomesas delivery vehicles for radioactive nuclides whichinvolves the application of liposome carrying -

emitting186

Re to treat head and neck cancer bydirect intratumoral infusion in nude rats. In thisstudy, the authors report average tumor volumereduction for the 186 Re-liposome group on post-treatment on Day 14 to 87.7%. 14 This study furtherprovides hope that liposomal 186 Re particles canbe effectively used for treating head and neckcancer with minimal side effects after convection-enhanced interventional delivery. Zavaleta et al. havereported biodistribution and pharmacokinetics of 186 Re encapsulated in biotin-liposomes containing

patent blue dye, and injected intraperitoneally (IP)with avidin in an OVCAR-3 ovarian cancer xenograftmodel. This study has demonstrated a 30% decreasein the growth of tumor volumes as compared tocontrol groups. This is a compelling evidence forthe potential of 186 Re-blue-biotin-liposome/avidin

system in treating advanced ovarian cancer involvingperitoneal carcinomatosis. 15

Amplication of therapeutic doses of X-rays dueto encapsulation of tissue mimics on gold foil appearsto provide clinical benets. Recent studies have shownradiation dose enhancement up to more than afactor of 100 in an environment of tissue-equivalentpolymethylmethacrylate (PMMA) close to the surfaceof a thin metallic gold foil. These studies involvedevaluation of enhancement factors for heavily lteredX-rays (40120 kV tube potential) under backscatterconditions, using thin-lm radiation detectors with

sub-micrometer resolution. Under in vitro models,enhanced biological effects have been observed usingmonolayers of C3H 10T1/2 mouse embryo broblastsexposed in intimate contact with the gold surface.Dosimetry calculations have indicated that a dose of 100 mGy, 80 kV X-rays (measured in homogeneousPMMA) caused a frequency at an inserted gold surfacecomparable to that obtained with a dose of about4.5 Gy of 60 Co rays in homogeneous PMMAsuggesting that nanoparticles of gold which offersuperior surface area may show even better dosimetrycharacteristics. 16 Recently, Balogh and coworkers

have reported the development of poly {198

Au}radioactive gold dendrimer composite nanodevices of sizes between 10 and 29 nm and demonstrated theirutility in targeted radiopharmaceutical dose deliveryto tumor. 17 Their studies have shown that singleintratumoral injection of poly {198 Au0 }d = 22 nmcomposite nanodevices in phosphate-buffered saline(PBS) delivering a dose of 74 Ci, after 8 days,resulted in a statistically signicant 45% reductionin tumor volume when compared with untreatedgroups.

As part of our ongoing efforts toward the appli-

cation of nanotechnology for the design and develop-ment of sophisticated molecular imaging and therapyagents, we have recently discovered biocompatibleradioactive gold nanoparticles. 1836 The developmentof the -emitting radioactive Gum Arabic glycopro-tein stabilized biocompatible gold nanoparticulateagent (GA- 198 AuNP) is an innovative approach foruse in treating hormone refractory prostate and otherinoperable cancers. 37 Nanoparticles of gold are inher-ently multifunctional in their diagnostic and thera-peutic capabilities. 30,38 198 Au, provides a desirable

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-energy emission and half-life for effective destruc-tion of tumor cells/tissue ( max = 0.96 MeV; half-lifeof 2.7 days). 37 The range of the 198 Au -particle is suf-ciently long to provide cross-re effects of radiationdose delivered to cells within the prostate gland andshort enough to minimize signicant radiation dose

to critical tissues near the periphery of the capsule.The 2.7 day half-life of 198 Au allows time for trans-port of the doses of the GA- 198 AuNP agent fromcentral radiopharmacies to the clinical sites and isamenable for delivery of single GA- 198 AuNP admin-istered doses to provide a 105 Gy dose to prostatetumor. In this review, we will discuss the overall clin-ical translation efforts of GA- 198 AuNP therapeuticagent including (1) production of therapeutic radioac-tive gold nanoparticles; (2) intra-prostate tumoraldelivery, retention, and therapeutic efcacy studies;(3) 198 AuNP dosimetry considerations; and (4) theoverall oncological relevance of this new GA- 198 AuNPtherapeutic agent in the context of its potential appli-cations in treating prostate and various other solidtumors.

PRODUCTION OF THERAPEUTICRADIOACTIVE GOLDNANOPARTICLES

A novel approach for manufacturing therapeuticradioactive AuNPs has been developed at the Uni-versity of Missouri Research Reactor (MURR).Traditional production methods for AuNPs do notwork at tracer levels for the generation of cor-responding radioactive gold nanoparticles. Eachgold nanoparticle contains several atoms of gold, anumber of which could be radioactive 198 Au/ 199 Au.This should result in a substantial increase in thera-peutic dose to the tumor site. In addition, they canbe easily tagged with oligonucleotides, tumor-specicproteins, and peptides that are selective for receptorsover expressed by cancerous cells/tissue.

Traditional gold nanoparticle formulationmethods utilize interaction of gold salts withsodium borohydride (NaBH 4), hydrazine, and other

reducing agents for the production of AuNPs atmacroscopic levels. Because of kinetic considerations,such methods fail when used at the tracer level to pro-duce radioactive gold nanoparticles. A recent discov-ery in our laboratory has demonstrated that a trimericalanine conjugate (P(CH 2NHCH(CH 3)COOH) 3 ;THPAL) upon mixing with NaAuCl 4 results in the for-mation of gold nanoparticles of well-dened particu-late size (1520 nm) (Figure 1). 28,33 The nanoparticleinitiator (P(CH 2NHCH(CH 3)COOH) 3 ; THPAL) isnontoxic and the gold nanoparticle formation by this

PO

CH 3

N

NHH

O

O

OH

HO

CH 3

CH 3

NHO

THPAL(Initiator)

Gum Arabic (stabilizer)

NaAuCI 4 GA-AuNP TEM of GA-AuNP

H

F IG U R E 1 | Synthesis of GA-AuNP.

method proceeds in aqueous media resulting in bio-logically benign alanine and phosphoric acid as byproducts. It is important to note that the reactionoutlined in Figure 1 is efcient for the productionof nanoparticulate gold using radioactive precursors(198 Au/ 199 Au) at signicantly low concentrations.

For the production of 198 Au, gold foil 530 mgare irradiated at a ux of 8 1013 n/cm2 /s. Theradioactive foil is subsequently dissolved with aquare-gia, dried down, and reconstituted in 0.51 mL of 0.05 N HCl to form H 198 AuCl4 . The radioactivegold solution is added to aqueous solutions of GA,followed by solution of reducing agent, THPAL(P(CH 2NHCH(CH 3)COOH) 3), for formation of radioactive gold nanoparticles of well-dened parti-cle sizes (1520 nm). 28,33 The change in color from

pale yellow to purple is diagnostic of plasmonplasmon transition and characteristic of radioac-tive gold nanoparticle formation, and the solutionsat the tracer levels are characterized by UVVisspectrophotometry.

198 AuNP DOSIMETRYCONSIDERATIONS

Nanoparticles based on -particle emitting isotopesof gold offer a possible means by which effectiveradiotherapy may be performed for the treatment

of prostate cancer without complicating effects andurinary morbidity. For 198 Au, the combination of

TABLE 1 Dosimetry for Different Radioactive Isotopes

Isotope T 1/ 2 Emission Principle125I 59.4 days EC, 2735 keV photons103Pd 17 days EC, 21 keV photons131Cs 9.7 days EC, 434 keV photons198Au 2.7 days (mean energy= 312 keV), 412 keV photon



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TABLE 2 Effectiveness of 198Au Therapy Compared with OtherIsotopes Used for Prostate Brachy therapy

Radioisotope

Indices 125I 103Pd 131Cs 198Au

Target dose,D total (Gy) 145.0 125.0 120.0 105.0

BED (Gy) 101.7 112.7 115.7 124.33TCP (%) 79 95.5 97.1 99.2T eff (day) 236.2 94.1 61 21.358D (T eff ) (Gy) 135.8 122.3 118.5 104.6Wasted dose (%) 6.36 2.15 1.27 0.41

-particle emission with relatively high energy raysresults in a low dose, because the short range of theelectrons in tissue restricts the dose to the local vol-ume of tissue. In addition, the relatively short half-lifeof 198 Au (Table 1) presents some intriguing possi-bilities for increased relative biological effectiveness(RBE). These properties are compared with otherradioisotopes used for either low dose rate (LDR)or high dose rate (HDR) prostate brachy therapy inTable 1. 198 Au had been used as early as the 1950s forclinical brachy therapy. 39 The effectiveness of 198 Auis shown in Table 2. 198 Au isotope offers superiorradiation dose rate as compared to the slower (longerT 1/ 2) isotopes. 125 I and 103 Pd are commonly used seedimplanted emitters with relatively low ( < 100 keV) rays.

In Table 2, wasted dose is the difference

between the total dose delivered ( D total ) and the doseover the effective treatment time ( T eff ) versus thetotal dose delivered, e.g. the dose that is the resultof the total decay of radioisotope after it has beenimplanted in the tumor. There is an obvious inversecorrelation between BED/TCP and T 1/ 2 .

In clinical applications, radioactive gold isencapsulated within 0.1 mm thick platinum, whichattenuates the -particle spectrum and thus the dose isdue to the high energy emissions. Our new approachwhich involves implementation of radioactive goldnanoparticles for therapy is reliant upon in vivo sta-bilization through nanoparticle formation. Therefore,the energy of the -emission by gold is unaffected andleads to high dose rates in vivo. The ability to reliablyand accurately predict dose to tissues is a critical aspectin the successful implementation of radiation therapy.Restriction of dose to relevant tumor tissues is impor-tant to avoid undesirable side effects. Calculations of dose and dose rate in the treatment volume is vitalin understanding the biological effective dose (BED),effective dose( D(T eff ), T 1/ 2 dependent) and the tumorcontrol probability (TCP) based on radiobiologicalsurvival models.

DOSIMETRY FOR PROSTATE TUMORTREATMENT USING RADIOACTIVEGOLD NANOPARTICLES

Brahme 40 provides a rationale for an energy-independent stopping power for low energy relativistic

electrons, therefore, the range of the electrons islimited by the stopping power in water (1 g/cm 3).For a maximum -energy of 0.96 MeV (for 198 Au),the maximum range is 4 mm (0.4 g/cm 2)/(1 g/cm3).A simple approach to 198 Au dosimetry would beto assume a uniform distribution of activity withina volume that has a diameter greater than thecompletely slowing down approximation (CDSA) of 4 mm. With such a distribution, charged particleequilibrium is achieved. The dose rate within thevolume is then a summation of deposited energy fromall the nanoparticles in the volume, which will, in turn,be dependent upon the total activity per unit mass.A dose rate for 198 Au particles will be based onthe 0.317 MeV average energy. Assume that a volumeof water is approximately 1 cm in diameter; the totalmass will be 4/3 r3 0.5 g.

On the basis of Attix 41 effective dosecalculations, the dose rate is

D = 3600 s/ h (3.7 10 7disintigrations/s)

0.317 MeV

0.5 g(1.602 10 10 Gyg/MeV)

12 Gy / h/ mCi

The total dose is then:

D total = 1.44D0T 1/ 2

where D0 is the initial dose rate, D total is the totaldose. The initial dose rate will be based on the size of the prostate volume under treatment.

Another helpful means to compare radiationtreatment is to employ biophysical models. For per-manent prostate implants (using gold nanoparticles),the tumor cells are subjected to continuous irradi-ation during the period which activity is present.The instantaneous dose rates will vary over time.Parameters for prostate cancer are applied for cal-culations of the radiobiological indices based on thelinear-quadratic cell-inactivation model. In this case,we use the recommended values by Wang et al. 42 = 0.15/Gy, = 0.05/Gy 2 , Tp = 42 days and therepair half-life = 0.27h. T p is the potential doublingtime for prostate tumor cells.

T eff = T avg ln D total T D

T 1/ 2



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T eff is dened as the time at which the cell-inactivation rate equals the rate of cell repopulationfor any hypothetically remaining cell.

The Dale BED model 43 uses a two-critical targetof repair of sublethal radiation damage. The repaircapability is modeled by a time constant for sublethal

damage repair (this is inversely proportional to therepair half-time), and used in the following equationfor repair effectiveness (RE). In this equation, is thedecay constant for the radionuclide in question.

RE(T eff ) = 1 +

D0( )

1

1 e T eff

1 e 2T eff 2

+ (1 e ( + )T eff )

The repair effectiveness is then used to calculate theBED:

BED = D(T eff ) RE(T eff ) ln 2T eff T p

In this model, any dose deposited after T eff is considered to be a wasted dose. The differencebetween D total and D(T eff ) is the amount of wasteddose andshould be as small as possible. Tumor controlprobability (TCP) is determined by the Poisson prob-ability of inactivating all tumor cells. The BED is themore accepted model in the community, based on the

fact that a general TCP formalism tends to underes-timate tumor cure rate when tumor cell repopulationoccurs during treatment. As this is less likely to hap-pen with the high dose rates seen in 198 AuNP therapy,we present TCP here as one more possible parameterto consider.

TCP = exp[N 0e( BED)]

N 0 is the number of tumor cells initially present(e.g., 10 6 cells in a tumor).

IN VIVO TUMOR RETENTIONCHARACTERISTICS OF GA- 198 AuNP

In order to understand the retention and clearancecharacteristics of radioactive GA- 198 AuNP withintumor, we have performed a detailed in vivo inves-tigation involving intratumoral administration of GA198 AuNP (3.5 Ci/tumor) in SCID mice ( n = 5)bearing human prostate cancer xenografts (Figure 2).These studies involved analysis of 198 Au in variousorgans post euthanasia of animals at 30 min, 1, 2,4, and 24 h. The blood, various organs, and tumorswere collected and counted to measure the amount of radioactivity (Figure 2). Analysis of 198 Au radioactiv-ity revealed that over 75% of the injected dose (ID) of GA-198 AuNP was retained in prostate tumors at 24 h,

0

Organs

B l o o d

H e a r t L u

n g L i v e r

S p l e e

n

S t o m a

c h K i d

n e y

M u s c l

e B o

n e

B l a d d

e r B r a

i n

P a n c

r e a s

T u m o

r A

T u m o

r B

50

100

150

A v g

% D / g m

200

250

300

30 min 1 hour 2 hour 4 hour 24 hour

F IG U R E 2 | Biodistribution prole showing retention of GA-198AuNP in prostate tumor after intratumoral injection.



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and was nearly constant from 30 min to 24 h. TheGA-198 AuNP nanoparticles exhibited slow clearance(leakage) into the blood with only 0.06%ID/g at 24 h.The uptake of GA- 198 AuNP agent in various organs,as shown in Figure 2, at different postinjection timepoints have further indicated that there is a signicant

accumulation of nanotherapeutic agent in the kid-neys (10 .68 1.72%ID/g) after 24 h, and the mainclearance route of 198 Au activity was via urine with16 .77 0.13%ID at 24 h. Lungs, pancreas, and liverexhibited very low uptake at 24 h. These pharmacoki-netics features conrmed the excellent retention of therapeutic payloads of GA- 198 AuNP nanoparticleswithin prostate tumors with only minor leakage tonon-target organs.

Intratumoral administrations of the nonradioac-tive surrogate of GA- 198 AuNP agent (GA-AuNP) invery low concentrations have been investigated inorder to ascertain if GA- 198 AuNP agent distributeshomogeneously within the prostatic tumor (Figure 3).In these experiments, nonradioactive analog, GA-AuNP, was administered at 12 g/g of prostate

Pre-scan 1 hour post dose 24 hours post dose

F IG U R E 3 | CT imaging of tumors in pre and post intratumoral

administration of GA-AuNP in prostate tumor bearing mice. Red Arrowindicates the homogeneity in distribution of GA-AuNP agent in prostatetumor within 1 h and 24 hrs post administration.

tumor in mice with prostate tumor xenografts. Post-intratumoral administration of GA-AuNP, homo-geneity in distribution of this agent was monitoredby CT imaging of tumor regions at various timespostinjection. The pre- and postadministration imagesshown in Figure 3 clearly demonstrate that GA-198

AuNP agent permeates and distributes homoge-neously in prostate tumors within 1 h postadministra-tion and the injected dose (ID) of optimum therapeuticpayloads resides within tumors for over 24 h. Encour-aged by the excellent tumor retention features of GA-198 AuNP, we have explored therapeutic efcacystudies in order to evaluate tumor ablation properties.

TUMOR ABLATIONCHARACTERISTICS OF GA- 198 AuNP

The therapeutic efcacy of GA- 198 AuNP has beenevaluated using prostate tumor-bearing SCID micemodels. In this in vivo investigation, solid tumorswere allowed to grow for 3 weeks, and animals wererandomized (denoted Day 0) into control and treat-ment groups ( n = 7) with no signicant differences intumor volume. On Day 8, 408 Ci (30 L) of GA-198 AuNP was directly administered into the prostatetumor to deliver an estimated dose of 70 Gy. ControlSCID mice received 30 L Dulbeccos PBS. Tumorgrowth was monitored twice each week. Completein vivo therapeutic data are depicted in Figure 4. 37

Tumor growth in the treated animals showed a dras-tic decrease within 1 week (Day 14) post-treatmentwith respect to the control group. Tumor volumes

F IG U R E 4 | Therapeutic efcacy studies of GA-198AuNP in prostate tumor-bearing SCIDmice. (Reprinted with permission from Ref 37.Copyright 2010 Elsevier)

Tumor

Treatment vs. Control

Day 8

Tumor

** * * *

Control

Controlgroup

Treatment

Treatedgroup

0.41 mCiAu-198 NP, i.t.

00.0

0.2

0.4

0.6

P C 3 t u m o r v o

l u m e

( c m

3 ) 0.8

1.0

5 10 15Days after palpable tumors randomized

20 25 30

** p = 0.005; Day 17* p < 0.0001; Day 2128

n = 57; means sem



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were twofold lower ( P < 0.005) for the treated ani-mals compared with the control group; 9 days post-treatment with GA- 198 AuNP (Day 17).This signicanttherapeutic effect was maintained throughout the30 days long study. 37 Three weeks after GA- 198 AuNPadministration, tumor volumes for the control ani-

mals were vefold greater with respect to those forthe radiotherapy group ( P < 0.0001; 0 .86 0.08 vs0.17 0.02 cm3). Several animals in the control grouphad to be euthanized because of continued weight loss,deteriorating overall health status, and risk of tumorulceration. By contrast, none of the seven animalsin the treatment group reached early termination cri-teria. They did exhibit a transient weight loss thatpeaked at 17 .6 2.4% on Day 17, but recov-ered to 10 .6 2.9% by Day 31. Liver contained0.91 0.26%ID, kidney 0 .13 0.01%ID, and smallintestines 0 .09 0.00%ID. Levels of radioactivitynoted forblood, heart, lung, spleen, stomach, and pan-creas were barely distinguishable from background.Insignicant/no radioactivity in liver, intestine, andvarious nontarget organs unequivocally establishedthat the therapeutic payload indeed resided within thetumor site throughout the 30-day long treatment regi-men. The therapeutic efcacy and concomitant in vivotolerance of GA- 198 AuNP further provides evidenceon the potential for clinical translation of this agent.Reduction in tumor volume has a direct bearing on theefcacy of chemotherapy and immunotherapy and hasbeen shown to stimulate a natural immune response.The signicant reduction in tumor volume ( > 70%),as shown by GA- 198 AuNP in prostate tumor-bearingSCID mice indicates the potential for clinical trans-lation of this new nanotherapeutic agent for clinicalapplications in reducing the size of tumor prior to sur-gical resection, and perhaps to reduce/eliminate theneed for surgical resection in certain circumstances.

ROLE OF LOCALIZED THERAPYTO DECELERATE METASTASES

It is important to note that the residual tumor tissue

samples from the above studies contained 52.3% of the ID of GA- 198 AuNP after 28 days. The tumors har-vested from the treatment group consisted largely of necrotic tissue, indicating extensive tumor cell kill. Thepropensity with which GA- 198 AuNP ablates prostatetumors (Figure 4) is directly related to the excellenttumor retention characteristics of radioactive goldnanoparticles (Figure 2). The unprecedented payloadof inherent therapeutic agent within tumor cells has adirect way of curative prospects in achieving desirablenecrotic outcomes. As discussed in the therapeutic

efcacy studies section, intratumoral delivery of GA-198 AuNP nanoparticles within prostate tumors in micenot only resulted in effective control on the growth of tumors, the analysis of tumor tissue unambiguouslydemonstrated necrotic features. Therefore, the ultraefcient retention of GA- 198 AuNPs within prostate

tumors has the potential to effectively destroy tumorcells within localized areas and thus may prevent cellpropagation and recruitment of tumor cells (and stemtumor cells) into bone marrowa pathway to decel-erate and stop metastases of prostate and other solidtumors.

CONCLUSIONS AND OVERALLONCOLOGICAL IMPLICATIONSOF GA- 198 AuNP AGENT

The development and commercialization of the -emitting GA- 198 AuNP agent is an innovative approachin cancer therapy because of the inherent high afn-ity of such agents to tumor vasculature. For futureapplications of this new therapeutic agent in humans,it is important to recognize that intratumoral injec-tions of GA- 198 AuNP will not interfere with systemicadministration of other therapeutic agents. Therefore,even the large tumors can be effectively treated withhomogeneously dispersed injectable radioactive goldnanoparticles. The results of preclinical studies inprostate tumor-bearing mice, as described above, haveshown the clinical capabilities of the readily injectablenanotherapeutic agent, GA- 198 AuNP in providingoptimum therapeutic payloads at the tumor site withno associated side effects. Detailed toxicology studiesof GA-AuNP, in small (mice) and large animals (pigs),have clearly demonstrated the nontoxic characteristicsof this new therapeutic agent. The in vivo therapeu-tic efcacy results obtained to date present realisticprospects toward the development of a new generationof homogeneously dispersed radioactive nanoparticlesof 198 Au embedded within the nontoxic Gum Arabicplant source (GA- 198 AuNP). The clinical applicationsand oncological relevance of homogeneously dis-

tributed and readily injectable nanoparticulate agentsgo beyond treating prostate cancers. Indeed, theimmediate impact of this intratumorally injectabletherapeutic agent will have signicant benets to alarge number of inoperable human tumors includ-ing: cancers of the head and neck, lip, mouth, buccalmucosa, nasopharyngeal, salivary gland, soft palate,tonsilar fossa/pillar, esophageal, respiratory and diges-tive tract, genitourinary, bladder, urethral, endome-trial, cervix, vaginal, retinal, brain, breast, pancre-atic, liver, lung cancers, and soft tissue sarcomas.



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A number of clinical trials for establishing safetyand tolerance using intratumoral administration of chemotherapeutic agents including 2-hydroxyuta-mide (Licroca Depot), 44 -Gal Glycosphingolipids 45 ,and Ad5CMV-NIS 46 administered intraprostaticallyfollowed by radioiodine treatment in patients with

locally recurrent adenocarcinoma of the prostate arecurrently in progress within the National Cancer

Institute and other clinical centres across the world.In this context, GA- 198 AuNP agent represents a newnanotechnological approach to oncology as it presentsan effective clinical pathway to reduce tumor vol-ume through intratumoral administration of predeter-mined doses in order to achieve optimum therapeuticpayloads at the tumor sites.

ACKNOWLEDGMENTS

The work reported in this review has been supported by grants from the National Institutes of Health(NIH)/National Cancer Institute under the Cancer Nanotechnology Platform program (Grant 5R01CA119412-01 and NIH 1R21CA128460-01 and NIH-Small Business Innovation Research Contract 241) and by theUniversity of Missouri-Research Board Program C8761 RB 06-030. Some of the results reported in thisreview are taken from the graduate research project of Rajesh Kulkarni which would be used toward partialfulllment of his PhD degree program. Continuing collaborative support and encouragement from various

faculty colleagues including Jeffrey C Smith, John Lever, Silvia Jurrison, Wynn Volkert, and Timothy Hoffmanare gratefully acknowledged.

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