review article solid tumor-targeting theranostic polymer nanoparticle in...

Review ArticleSolid Tumor-Targeting Theranostic Polymer Nanoparticle inNuclear Medicinal Fields

Akira Makino12 and Shunsaku Kimura3

1 Biomedical Imaging Research Center (BIRC) University of Fukui Fukui 910-1193 Japan2 Research and Education Program for Life Science University of Fukui Fukui 910-1193 Japan3Department of Material Chemistry Graduate School of Engineering Kyoto University Kyoto 615-8510 Japan

Correspondence should be addressed to Akira Makino amakinou-fukuiacjp

Received 27 June 2014 Revised 8 August 2014 Accepted 11 August 2014 Published 14 October 2014

Academic Editor Masashi Ueda

Copyright copy 2014 A Makino and S Kimura This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Polymer nanoparticles can be prepared by self-assembling of amphiphilic polymers and various types of molecular assemblieshave been reported In particular in medicinal fields utilization of these polymer nanoparticles as carriers for drug deliverysystem (DDS) has been actively tried and some nanoparticulate drugs are currently under preclinical evaluations A radionuclideis an unstable nucleus and decays with emission of radioactive rays which can be utilized as a tracer in the diagnostic imagingsystems of PET and SPECT and also in therapeutic purposes Since polymer nanoparticles can encapsulate most of diagnosticand therapeutic agents with a proper design of amphiphilic polymers they should be effective DDS carriers of radionuclides inthe nuclear medicinal field Indeed nanoparticles have been recently attracting much attention as common platform carriers fordiagnostic and therapeutic drugs and contribute to the development of nanotheranostics In this paper recent developments ofsolid tumor-targeting polymer nanoparticles in nuclear medicinal fields are reviewed

1 Introduction

Nanoparticles have been actively examined as carriers fordrug delivery system (DDS) which make it possible toimprove therapeutic efficacy and to suppress side effectsof the parent drug [1ndash5] Among various types of nano-ordered carriers including inorganic and lipid particles poly-meric micelles and vesicles which are prepared from self-assembling process of amphiphilic polymers can encapsulatein general hydrophobic and hydrophilic compounds in thehydrophobic core and inner aqueous cavity regions respec-tively [6ndash10] Further not only surface modification but alsofunctionalization of these nanoparticles is possible with easeby using suitably designed amphiphilic polymers Thereforepolymeric nanoparticles have received much attention as theDDS carriers

Additionally nanoparticles are originally accumulated atthe region where cells are rapidly proliferating because leak-age of nanoparticles can occur through the holes on imma-ture blood vessels Combined with the effect of undeveloped

lymph system at tumor region nanoparticles are retainedthere leading to the passive accumulationThis phenomenonis called the enhanced permeability and retention (EPR)effect and is one of the most frequently utilized method-ologies of nanoparticles for DDS [11ndash13] On the basis ofthese reasons polymeric nanoparticle is a suitable carrier forsolid tumors-targeting DDS [8 14] In fact various tumor-targeting DDS carriers have been developed and somepolymeric nanoparticles encapsulating antitumor drugs arecurrently under clinical trials [15]

Recently polymeric nanoparticles are also applied ascarriers for contrast agents in the field of in vivo imaging [16ndash18] Among various modalities such as near-infrared fluore-scence (NIRF) imaging magnetic resonance imaging (MRI)positron emission tomography (PET) and single photonemission computed tomography (SPECT) systems the invivo near-infrared fluorescence (NIRF) imaging system hasshown amazing progresses This is because handling of theNIRF compounds is relatively easy and its biodistributioncan be directly visualized However penetration depth of

Hindawi Publishing Corporatione Scientific World JournalVolume 2014 Article ID 424513 12 pageshttpdxdoiorg1011552014424513

2 The Scientific World Journal

Table 1 Representative radionuclides used for imaging and radiotherapy

Radionuclide Emission type Half-life Usage111C 120573+ (998) 120574 (02) 2039min I13N 120573+ (998) 120574 (02) 9965min I15O 120573+ (999) 120574 (01) 2037min I18F 120573+ (967) 120574 (33) 1098min I32P 120573minus (100) 1424 day T64Cu 120573+ (174) 120574 (436) 1270 h TI

120573minus (390)89Sr 120573minus (100) 5053 day T90Y 120573minus (100) 6400 h T99mTc 120574 (gt999) 6015 h TI111In 120574 (100) 2805 day TI123I 120574 (100) 1322 h I125I 120574 (100) 5940 day TI131I 120573minus 8021 day TI186Re 120573minus 120574 3718 day TI188Re 120573minus 120574 1700 h T211At 120572 7214 h T213Bi 120572 214min T225Ac 120572 100 day T1Radionuclide usage for imaging and therapy are abbreviated as ldquoIrdquo and ldquoTrdquo respectively

near-infrared light in tissue is limited to a few centimeters[19] Therefore the NIRF imaging system is suitable for invivo experiments using small animals but its applicative areain human clinical uses is limited to near the surface wherefluorescent signal can be detectable On the other handin general sensitivity of nuclear imaging is high Furtherquantitative analyses are available by using PET imagesWhen it comes to the quantitative performance SPECT isless competitive than PET but has been improved by recentmechanical developments [20] Positron emitters such as 11C13N 15O 18F and 64Cu are used for PET imaging as signalsources and 120574-ray emitters such as 99mTc 111In and 123I arefor SPECT imaging (Table 1) For preparation of nanoparticletype probes for nuclear imaging techniques strategies onhow to encapsulate these radioisotopes into nanoparticlesare important There are considerable approaches for theencapsulation which can be classified into three categories(1) hydrophobized radionuclides are encapsulated into thehydrophobic core region of polymeric micelle (2) radionu-clide solution is encapsulated into the inner cavity of vesicularassemblies and (3) metal radionuclides such as 64Cu and99mTc can be attached to the nanoparticles as chelates bymod-ifying constituent amphiphilic polymers with appropriatechelators About the inner radiation therapy 120573minus ray emitterssuch as 90Y and 131I are generally used In addition attemptsto utilize radionuclides emitting120572-ray (211At 213Bi) and augerelectron (99mTc 111In and 125I) are also performed (Table 1)[21ndash25] Any radionuclides labeled nanoparticle can be pre-pared by selecting appropriate methods for encapsulation aswritten above

In this review recent research developments on solidtumor-targeting DDS using polymer nanoparticle carriers innuclear medicinal fields are summarized

2 Polymeric Micelles

21 Importance of Surface Modification withPoly(ethylene glycol) (PEG)

211 Poly(methyl acrylate)-b-poly(acrylic acid) One of theinitial trials to utilize polymeric micelle as a carrier for PETtracer agent was performed in 2005 by Rossin et al [26]Polymeric micelle was prepared from amphiphilic poly(methyl acrylate)-b-poly(acrylic acid) (PMA

164

-b-PAA93

)which was synthesized via sequential atom transfer radicalpolymerization (ATRP) [27] As illustrated in Figure 1PMA-b-PAA in the micelle was cross-linked between thecarboxyl acid group of PAA and the amine functionalitiesof 221015840-(ethylenedioxy)diethylamine poly(acrylic acid) toform shell cross-linked (SCK) nanoparticles Folate receptor(FR) is well-known molecular target for tumor therapies[28] and therefore folate-poly(ethylene glycol)-amine wasconjugated to the surface of the micelle Further 14811-tetra-azacyclotetradecane-1198731015840 11987310158401015840 119873101584010158401015840 1198731015840101584010158401015840-tetra-aceticacid (TETA) was also modified to the micelle surface for64Cu chelate formation

Using tumor transplanted mice biodistribution of themicelle was examined by organ harvesting method Themicelle was recognized by reticuloendothelial system (RES)which is self-defense system of living organisms and its

The Scientific World Journal 3

(i)-(ii)

Shell cross-linkednanoparticles (SCKs)

amphiphilic diblock copolymer

(iii)

Folate functionalized SCKs

(v)

TETA labeled folatefunctionalized SCKs

(iv)

FTSC labeled folatefunctionalized SCKs

OH

OH

OH

OH

OH

OHOH

HOHO

HO

HO

HO

HO

HO

O O

O

O O

NN

N N

NN

N N

N

O

O

O

O

O

O

O

OH

OH

OHOH

HO

HO

HO

HO

HO

OO

OO

O

O

O

O

O

O

O

O

O

O

O

O

OH

OH

OHOH

HO

HO

HO

HO

O

O

O

O

O

O

OO

O

OO

OO

O

O

OH

OH

OHOH

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

O

H

NH

HN

HN

HN

HN

HN

NH

NH2

PAA93-b-PMA164

n n

OH

HO

NN

N N

N

O

OO

O

O

H

HN

HN

NH

NH2

n

m

p

34

OH

HO

NN

N N

N

O

OO

OO

O

H

N

S

H

HN

HN

NH

NH2

34

34

CO2H

Figure 1 Polymeric micelle prepared from PMA-b-PAA This research was originally published in JNM R Rossin D P J Pan K Qi JL Turner X K Sun K L Wooley and M J Welch ldquoCu-64-labeled folate-conjugated shell cross-linked nanoparticles for tumor imagingand radiotherapy Synthesis radiolabeling and biologic evaluationrdquo J Nucl Med 2005 46 1210-1218 The Society of Nuclear Medicine andMolecular Imaging Inc copy


ON

OO

OO

OO

OO

O SO

S

OOOOOO

N

O

O O

MASI MMA PEGMA O

OS

S

AIBN O SHO OOHN

OOO

O

HN

N

N N

N

HO

O

OHOO

OH

O

n

x y z

n

x y z

PEG 11 kDa20 kDa50kDa

Figure 2 Scheme for poly(methyl methacrylate-co-methacryloxysuccinimide-graft-poly(ethylene glycol))

undesired uptake at liver and spleen was high Howeverowing to the combined effects of FR-mediated cell uptake andEPR effect the micelle was accumulated at the tumor regionwith 21plusmn03 32plusmn07 60plusmn19 and 56plusmn09 IDg at 10min1 h 4 h and 24 h from the administration respectively

212 Poly(methyl methacrylate-co-methacryloxysuccinimide-graft-poly(ethylene glycol)) To suppress undesired micelleuptake by RES comb copolymers with branching vari-ous lengths of poly(ethylene glycol) (PEG) chains (11ndash50 kDa) were synthesized by standard reversible addition-fragmentation chain-transfer (RAFT) polymerization con-ditions [29] and to the polymer terminal end 14710-tetra-azacyclododecanetetra-acetic acid (DOTA) ligand wasintroduced as a chelator for radionuclides (Figure 2) Thechelation with 64Cu was carried out after preparation ofpolymeric micelles Diameters of the micelles prepared fromcopolymers with PEG of 11 20 and 50 kDa were 97 plusmn 1117 plusmn 2 and 20 plusmn 3 nm respectively

Three types of 64Cu labeled micelles were injected intorats from the tail vein and their biodistribution was deter-mined by organ harvesting method so as to evaluate theeffect of PEG chain length on the micelle biodistributionAdditionally the imaging studieswere carried out using smallanimal PET system The 50 kDa PEG micelle underwent aslow blood clearance and 31 plusmn 2 of the dose was still inblood at 48 h after injection which was almost ten times andtwice higher than that of 11 kDa and 20 kDa PEG micellesrespectively Biodistribution trend in the liver was oppositeto that observed in the blood Liver uptake of 11 20 and50 kDaPEGmicelles at 24 h from the injectionwas decreasedin this order and to be ca 40 28 and 12 IDg respectivelyThese results indicated that surface modification with PEGis important to control in vivo dynamics of the micelle andprolongation of blood circulation time and low accumulationin excretory organs can be achieved by increased thickness ofPEG shell

213 Poly(lauryl methacrylate)-b-poly(N-(2-hydroxypropyl)methacrylamide) Amphiphilic copolymer consisted of

hydrophobic poly(lauryl methacrylate) (poly(LMA)) and hy-drophilic poly(N-(2-hydroxypropyl)methacrylamide) (poly(HPMA)) blocks that was synthesized via RAFT poly-merization and PEG

2000

was incorporated into the sidechain of the hydrophilic block with 0ndash11 modificationratio [30] Further the amphiphile was covalently labeledby radionuclides of 18F Polymeric micelle was preparedfrom the amphiphile and the effects of the PEGylationon micelle size biodistribution and cell uptake behaviorwere evaluated In animal experiments using rats polymericmicelle with diameter of 381 plusmn 21 nm which was preparedfrom amphiphilic block copolymer with 7 PEGylationexhibited the most favorable organ distribution patternshowing highest blood circulation behavior as well as lowestundesired uptake at spleen and liver Tumor cells of Walker256 mammary carcinomas were clearly visualized by animalPET system after 2 h from the micelle dosage

The group also synthesized random copolymers as wellas block copolymers Polymeric micelles were prepared fromthese copolymers and their cellular uptake and biodistri-bution were evaluated using two different types of tumormodels (AT1 prostate carcinoma and Walker-256 mammarycarcinoma) They concluded that not only PEGylation butalso other numerous factors including molecular weight ofthe copolymers polymer structure size of the micelle andcharacteristics of tumor affected the intratumor accumula-tion level of the micelle [31] Therefore preclinical screeningto analyze polymer uptake for each individual patient isconsidered to be essential for each chemo- and radiotherapyusing polymer-based DDS

22 Core-Cross-Linked Type Polymeric Micelle (CCPM) forEnhanced Thermodynamic Stability Compared with lipo-some polymeric micelle is thermodynamically stable Thisis because relatively long hydrophobic polymer chains canstabilize themolecular assembliesmore than the hydrophobicinteraction among alkyl chains of phospholipids Aiming atfurther improvement of polymeric micelle stability inter-molecular cross-linking of copolymers via covalent bonds hasbeen examined


N

O

NHO

Si OO O

N

3-(Triethoxysilyl)propyl-Cy7

BrOO OO

OSiO

OO

OO

OO

Br

CuBrN N

OO

OO

OSiO

OO

ESPMA PEGMA

N NHOOCHOOC

NHOOC COOH

COOH

CCPM

DTPA-Bz-NCSSHNHN

x y

nn

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2NH2NH2

H2N

H2NH2N

H2N

NH2

NH2

NH2NH2NH2

CF3COO

CF3COO

H3N

H3N

ClO4

Figure 3 Preparation of core-cross-linked polymeric micelle (CCPM)

221 Poly(triethoxysilyl propylmethacrylate)-b-poly(PEG-methacrylate) Poly(triethoxysilyl propylmethacrylate)-b-poly(PEG-methacrylate) (PESPMA-b-PPEGPMA) was syn-thesized by atom transfer radical polymerization (ATRP)From the mixture of the polymer and 3-(trimethox-ysilyl)propyl-Cy7 polymeric micelle was prepared by sol-gelprocess upon addition of acetic acid The acid caused rapidhydrolysis of ethoxy silane precursors and subsequentcross-link of the PESPMA core with the Cy7 derivative viaSindashO bonds Targeting the amino group which is located atterminal end of hydrophilic block DTPA was inserted on thesurface of the core-cross-linked polymeric micelle (CCPM)and used for chelate formation with 111In (Figure 3) To thebreast tumor cells of MDA-MB468 transplanted mice 111In-DTPA-CCPM with diameter of 24 plusmn 89 nm was injected and120574-scintigraphy and NIRF optical imaging were performed[32] CCPM showed prolonged blood circulation behavior(11990512120572

= 125 h 11990512120573

= 4618 h) and passively accumulated atthe tumor region (55 IDg at 48 h after injection) At 120 hfrom the dosage tumorblood and tumormuscle signalratios reached 444 and 280 respectively

Characteristic point of CCPM is location of amino groupon the surface and therefore it is possible to attach target-ing ability to CCPM by ligand conjugation For exampleEphB4-binding peptide and synthetic somatostatin analogueof octreotide-conjugated CCPMs were prepared to detectEphB4-positive PC-3M prostate and somatostatin receptoroverexpressed glioblastoma U87 cells respectively [33 34]When a cell undergoes apoptosis phosphatidylserine isexposed on the cell surface Then annexin A5-conjugatedCCPM which binds strongly with phosphatidylserine wasalso prepared [35] Utilizing these 111In labeled CCPMs dual

SPECT and NIRF imaging of the targeted region was accom-plished Further time for accumulation of these ligand-conjugated CCPMs to the targeted region could be shortenedby specific bindings with corresponding receptors and signalintensity ratio against background was also improved

222 Poly(7-(2-methacryloyloxyethoxy)4-methylcoumarin)-b-poly(hydroxyethylmethacrylate)-b-poly(ethylene glycol)Copolymer consisting of one hydrophobic 7-(2-methacryl-oyloxyethoxy)-4-methylcoumarin (CMA) and two hydro-philic hydroxyethylmethacrylate (HEMA) and PEG blockswas also synthesized by Jensen et al [36] To hydroxyl groupsof the HEMA block DOTA or CB-TE2A was conjugatedas a chelator for radioactive metal of 64Cu After micelleformation by using self-assembling mechanism the micelledispersion was irradiated by UV light so as to cross-link4-methylcoumarin moieties in the hydrophobic core Thecross-linkedmicelle showed higher stability in blood andwasaccumulated at transplanted tumor region (U87MG) ofmiceAfter 22 and 46 h from the dosage of 64Cu labeled micellestumor can be visualized

23 Micelle Formation from Biodegradable andBiocompatible Amphiphilic Polymers

231 Poly(120576-caprolactone)-b-poly(ethylene glycol) Polymericmicelle can be prepared from various amphiphilic polymersFrom the view point that polymer nanoparticles are appliedas carrier for DDS utilization of biodegradable and bio-compatible amphiphilic polymers should take priority Thenpoly(120576-caprolactone) which is representative biodegradable


OOH

O

O

OO

O H

O

Amino group can be used for chemical modification of

the amphiphilic polymer

Caprolactone

H2NH2Nn m n

Figure 4 Amphiphilic poly(120576-caprolactone)-b-poly(ethylene glycol) for micelle preparation

polymer connecting through ester linkages was selected ashydrophobic block of the amphiphilic polymer (Figure 4)[37] For the chelate formation with 111In terminal end ofthe amphiphilic polymer is modified by diethylene triaminepenta-acetic acid (DTPA) which is a well-known chelator toform stable complexes with metals From DTPA modifiedpoly(120576-caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG)polymer micelle was prepared and then radionuclide 111Inwas chelated to DTPA [38] To the tumor-bearing mice the111In labeled micelle with diameter of ca 60 nmwas injectedand its biodistribution and pharmacokinetics were evaluatedby the organ harvesting method and SPECTCT in vivoimaging systemThemicelle was passively accumulated at thetumor region (9plusmn2 IDg) and transplanted tumor could beimaged by SPECT

On a cell surface of various types of epithelial cancersincluding lung and breast epidermal growth factor receptor(EGFR) is known to be overexpressed The micelle surfacewas functionalized by conjugating EGF to terminal aminogroup of the amphiphile so as to improve the 111In labeledmicelle delivering efficiency to the targeted tumor region[39] Compared with the accumulation of the nontargetingmicelle (EGFminus) in vivo cell uptake and cell membranebinding of the EGF modified micelle (EGF+) to tumorsoverexpressing EGFRwere significantly enhanced (119875 lt 005)111In can be also utilized as therapeutic nucleotide as

emitter of auger electrons [40] Using the EGF modified mi-celle effect of auger electron therapy against EGFR-positivebreast cancer cells was performed [41] In this research threetypes of human breast cancer cell cultures of MDA-MB-468(1 times 106 EGFRcell) MDA-MB-231 (2 times 105 EGFRcell) andMCF-7 (1 times 104 EGFRcell) were used Correlated with thedensity of EGFR expression level on these cancer cells EGFR-mediated uptake of the micelle (EGF+) was increased Inin vitro cell survival assay cell number of MDA-MB-468was significantly decreased after 21 h from the treatment by1MBq of 111In-DTPA modified micelle (EGF+) However

the micelle showed no cytotoxicity against MCF-7 with lowEGFR expression level

On the cell surface of breast cancer it is known to expressdifferent levels of HER2 Then 111In labeled micelle whosesurface is modified by HER2 specific antibody (trastuzumabfab) instead of the EGF sequence was prepared and its ther-apeutic performance was also evaluated [42 43] Targetingthe gastric cancer diagnosis glucose-regulated protein 78(GRP78) binding peptide modified micelle was attached tothe 111In labeled micelle surface and in vivo SPECT imagingwas accomplished [44] In short polymeric micelle can bearranged in accordance with the intended uses

Preparation of multifunctional micelles for photothermaltherapy (PTT) is also conducted [45] To the hydrophobiccore of the micelle prepared from DTPA modified PCL-b-PEG near-infrared (NIR) dye of IR-780 iodide was encapsu-lated as signal agent forNIRF imaging and photosensitizer forPTT Further 188Re was chelated to DTPA as a signal sourcefor SPECT imaging The micelle was designed so that in vivodynamics after dosage can be traced by SPECT system Basedon the real time monitoring of the micelle integration to thetargeted tumor region NIR light irradiation could be carriedout

Characters of molecular assemblies can be controlledby changing polymer architecture and its hydrophilic-hydrophobic balance For example thermosensitive hydrogelcontaining a therapeutic radionuclide (188Re-Tin colloid)and a chemotherapeutic drug (liposomal doxorubicin) wasprepared from PCL-b-PEG-b-PCL triblock copolymer [46]The thermosensitive gel was intratumorally administratedto the hepatocellular carcinoma and the therapeutic effectwas evaluated At the tumor region liposomal doxorubicinand 188Re-Tin colloid were released slowly and steadily Thetherapeutic effect was greater than the cases in which eithercomponent was individually used and the synergetic effectagainst tumor growth was confirmed


PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane

Self-assembly Polymerization

Nonpolymerized micelles Polymerized micelles(NPM micelles) (PM micelles)

Figure 5 Schematic illustration of 10B-enriched micelle preparation from acetal-PEG-b-PLA-MA and polymerizable VB-carboraneReprinted fromBiomaterials 2012 33 3568-3577 S SumitaniMOishi T Yaguchi HMurotani YHoriguchiM Suzuki K OnoH Yanagieand Y Nagasaki ldquoPharmacokinetics of core-polymerized boron-conjugated micelles designed for boron neutron capture therapy for cancerrdquoCopyright (2012) with permission from Elsevier

232 Poly(ethylene glycol)-b-poly(lactic acid) Poly(lacticacid) (PLA) is representative biodegradable polymer con-necting through ester linkage Polymeric micelle preparedfrom PEG-b-PLA is also evaluated and used as nanoorderedcarriers for DDS by various research groups [47]

Nonradioactive 10B is known to produce 120572 particlesand 7Li nuclei with ca 23MeV of energy by the capturereaction of thermal neutrons and therefore utilization 10Bon boron neutron capture therapy (BNCT) is investigatedBNCT could make it possible to irradiate directly targetedtumor region with suppressing nonspecific exposure How-ever restricted neutron source for the treatment is one of themajor problems for practical usages Sumitani et al evaluatedutilization of PEG-b-PLA micelle to improve deliveringefficiency of boron derivatives to the targeted tumor region[48 49] In this study polymeric micelle was prepared fromamphiphilic PEG-b-PLA polymer derivative of acetal-PEG-b-PLA-MA whose PEG and PLA terminal ends are modifiedby acetal and methacryloyl groups respectively To themicelle 1-(4-vinylbenzyl)-closo-carborane (VB-carborane)and azobisisobutyronitrile (AIBN) mixtures were encapsu-lated and core cross-polymerized and boron-conjugatedmicelles were prepared by the free radical polymerizationmethod (Figure 5) To the tumor transplanted mice the 10B-enriched micelle was administrated and neutron irradiationwas performed after 24 h from the dosage The 10B-enrichedmicelle was accumulated at the tumor region and showedsignificant therapeutic effects after the neutron irradiation

233 Poly(sarcosine)-b-poly(l-lactic acid) Amphiphilic pol-ydepsipeptide of (sarcosine)

70

-b-(l-lactic acid)30

is knownto form polymeric micelle with diameter of ca 35 nm andthe polymeric micelle was named as ldquoLactosomerdquo [18 50]Sarcosine (Sar) N-methyl glycine in other words is naturalamino acid and its homopolymer shows high solubilityagainst aqueous solution like PEG Therefore polymericmicelle whose surface is covered with poly(Sar) was alsoexpected to show aprolonged blood circulation behaviorwithlow undesired accumulation by reticuloendothelial system(RES)

As a radionuclide for PET imaging hydrophobized 18Fby attaching PLLA chain ([18F]SFB labeled poly(l-lactic acid)

of 30mer) was encapsulated into the core region of thepolymeric micelle by using hydrophobic interactions [51]The 18F labeled Lactosome was administrated from the tailvein to the tumor transplanted mice and PET images weretaken after 6 h from the dosage Lactosome showed a goodblood circulation behavior owing to the surface modifi-cation with hydrophilic poly(sarcosine) chains Thereforesignal intensity at organs with high blood flows was highHowever the accumulated signal in the transplanted tumorregion could be detected Since Lactosome surface was notspecifically modified by ligands Lactosome is considered tobe passively accumulated to the tumor region by the EPReffect

As a therapeutic radionuclide [131I]SIB labeled PLLAwas encapsulated into the Lactosome as 120573minus ray emitter bythe same approach with the previous 18F compound forPET imaging To the tumor transplanted mice which werepreliminary treatedwith preethanol injection therapy (PEIT)131I labeled Lactosome of 200MBqkg was injected and timecourses of tumor growth were observed [52] As a result 131Ilabeled Lactosome could be delivered to the tumor regionand the tumor growth was significantly suppressed

24 Accelerated Blood Clearance (ABC) Phenomenon of Lac-tosome Lactosome is a candidate nanoordered carrier fordrug andor imaging agent delivery On medicinal usagesnanocarriers are expected to show unaltered dispositionon multiple administrations However production of anti-Lactosome antibody occurred after 3 days from the firstLactosome administration and the antibody production kepthigh level for 6 months [53] Lactosome on second dosagewas opsonized by the anti-Lactosome antibody soon after theadministration and entrapped by reticuloendothelial system(RES) This phenomenon is named as accelerated bloodclearance (ABC) phenomenon of Lactosome and resembledphenomenon is sometimes observed on PEGylated materials[54 55]

The production amounts of the anti-Lactosome IgMwere revealed to be inversely correlated with that of thefirst Lactosome dosage When first Lactosome dosageis over 150mgkg the Lactosome ABC phenomenon


0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time

Lactosome ICG-Lactosome NIRF imaging

(a) (b)

ndash7 days

(0ndash350mgkg) (5mgkg)

1st administration 2nd administration

15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)

Figure 6 Effect of the first Lactosome dose on the Lactosome ABC phenomenon NIRF images of mice at (a) 15min (view from A inFigure 6(d)) and (b) 24 h (view fromC in Figure 6(d)) after ICG-Lactosome of 2nd dose Lactosomes (5 25 and 50mgkg100 120583L and 150 250and 350mgkg200 120583L) were injected into the mice 7 days before the ICG-Lactosome administration SUIT-2pEFluc cells were transplantedat the right femoral region ofmice in which tumor sites are indicated bywhite arrowsThe fluorescein signal ranges were set to be the same forall the images frommax count 5000 tomin count 1000 (c) Time schedule for the NIRF imaging Black and green arrows indicate the injectiontime points of Lactosome and ICG-Lactosome respectively NIRF imaging was performed at red arrows (d) NIRF images were taken usingShimadzu Clairvivo OPT which can take five images from different directions (AndashE) with one time shot The white circles indicate positionsof ROI (L liver B background) Reprinted from Biochemica et Biophysica Acta (BBA)-General Subjects 2013 1830 4046ndash4052 E HaraA Makino K Kurihara M Sugai A Shimizu I Hara E Ozeki and S Kimura ldquoEvasion from accelerated blood clearance of nanocarriernamed as ldquoLactosomerdquo induced by excessive administration of Lactosomerdquo Copyright (2013) with permission from Elsevier BV

could be suppressed by induced immunological tolerance(Figure 6) Further even if anti-Lactosome IgM is onceproduced the Lactosome ABC phenomenon can be evadedby dosing Lactosome over 50mgkg Importantly acutetoxicity was not observed at the Lactosome dosage amount[56]

Recently the production of anti-Lactosome IgM has beenfound to be suppressed by increasing the local densityof poly(sarcosine) chains on the micelle surface Higherlocal density of the surrounding hydrophilic polymer chainsshould be related with prevention of the interaction betweenmicelles and B cell receptors [57]


N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt

Folate-NHS esterFolate

OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I

Figure 7 Representation of multifunctional hollow nanoparticles and their TEM image Reprinted from Biomaterials 2011 32 2213-2221P L Lu Y C Chen T W Ou H H Chen H C Tsai C J Wen C L Lo S P Wey K J Lin T C Yen and G H Hsiue ldquoMultifunctionalhollow nanoparticles based on graft-diblock copolymers for doxorubicin deliveryrdquo Copyright (2011) with permission from Elsevier

Further it is still unclear whether the ABC phenomenonis a general phenomenon for nanoparticles However todevelop repeatedly injectable nanoordered carriers is essen-tial for its general usages

3 Vesicular Assemblies

The number of examples using vesicular assemblies as acarrier forDDS in nuclearmedicinal field is relatively limitedIt may be because of more difficult preparation of vesicularassemblies than polymeric micelles

Lu et al prepared multifunctional hollow nanoparticlefrom a mixture of doxorubicin hydrochloride (DOX-HCl)mPEG

5000

-b-poly(dl-lactic acid)1510

(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200

phenolic ester-PEG5000

-b-PLA650

and poly(N-vinylimidazole-co-N-vinylpyrrolidone)

9600

-g-PLA4900

(Figure 7) [58] The hollow nanoparticle is designedto show sensitivity against intracellular pH changes byusing pH sensitive character of N-vinylimidazole (NVI)(pKa values of NVI are around 60) Depending on thepH changes of the dispersion its diameter was reversiblychanged between 90 nm (pH 74) and 80 nm (pH 50) andrate of encapsulated DOX-HCl release could be acceleratedunder weak acidic conditions Extracellular matrix of thetumor region is known to be in a weakly acidic conditionand therefore the DOX-HCl is expected to be releasedselectively at the tumor region Folate-PEG

5000

-b-PLA1200

provided the nanoparticle with a tumor-targeting ability andphenolic ester-PEG

5000

-b-PLA650

was used for modificationof the nanoparticle with 123I by the iodogen method

To the tumor transplanted mice the multifunctionalhollow nanoparticle was administrated and the time courseof tumor growth was observed Dynamics of the nanopar-ticle at 05ndash6 h from the administration were noninvasively

visualized by SPECT Shortly after the administration thenanoparticlewas accumulated at the tumor regionwith a highlevel due to the folate-binding protein effect Compared withthe case of free DOX-HCl the tumor growth was effectivelysuppressed with a minimum body weight loss

4 Conclusion

In particular in these ten years application of polymericnanoparticles as a carrier for tumor-targeted drug deliverysystem (DDS) is expanded to nuclear medicinal fields It isa tremendous advantage to apply polymeric nanoparticlesfor DDS because in vivo pharmacokinetics can be wellcontrolled by suitable selections about their size shapeand surface characters and can be free from the loadingimaging or therapeutic compounds Therefore when thesame nanoparticle is used as a carrier for imaging and ther-apeutic purposes diagnostic outcomes can directly predictthe treatment efficiency of the loading therapeutic agent onthe nanoparticle Further imaging results before and afterchemotherapy can be used for prediction and evaluationof the therapeutic effect respectively In order to improvepersonal medical treatment it is essential to dose the ther-apeutic agent properly to each patient Polymeric micellesand vesicles endowed with two functions for diagnosis andtherapy are expected to be potential materials for futurepersonalizedmedicine and these research areas are especiallynamed as ldquonanotheranosticsrdquo

However there are many research problems to be dis-solved For example almost all types of nanoparticles aredesigned to evade from undesired capture by reticuloen-dothelial system (RES) and to show a prolonged bloodcirculation behavior Radioactivity is decreased with distincthalf-life of each radionuclide and time period which can


be effectively used is limited Therefore radionuclides withrelatively long half-life period such as 64Cu for PET and 111Infor SPECT are mainly selected for radiolabeling of polymernanoparticles Further how to control radiation exposureis also extremely important in nuclear medicinal fields Forthese reasons purpose of polymer nanoparticle DDS ismainly diagnosis which can be performed by relatively lowradioactivity and research trials on inner radiotherapy aresmall in number To accomplish practical usages of polymernanoparticles as carriers for inner radiotherapy (1) furtherimprovement of drug delivery efficiency and (2) reductionof radiation exposure at radiosensitive organs such as bonemarrow are essential by controlling the nanoparticles invivo dynamics It has already been revealed that to createsynergetic therapeutic effect is possible by combined usagesof therapeutic nanoparticle with conventional therapies andtherefore therapeutic nanoparticles are now in an early phaseof development

Another problem for the view point of commercializationis how to ensure the quality of the nanoparticle The numberof examples utilizing polymeric nanoparticles as carriers forDDS in human clinical practice is limitedTherefore to makerules for polymer nanoparticle production and their clinicalstudies is also considered to be important and started ingovernment regulatory agencies [59]

There are many problems to be dissolved howeverapplication and commercialization researches on theranosticnanoparticles are expected surely to make future progressesin nuclear medicinal fields

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

This study was partially supported by Coordination Supportand Training Program for Translational Research by MEXTJapan

References

[1] R Hao R J Xing Z C Xu Y L Hou S Goo and S H SunldquoSynthesis functionalization and biomedical applications ofmultifunctional magnetic nanoparticlesrdquo Advanced Materialsvol 22 no 25 pp 2729ndash2742 2010

[2] P Horcajada R Gref T Baati et al ldquoMetal-organic frameworksin biomedicinerdquoChemical Reviews vol 112 no 2 pp 1232ndash12682012

[3] D Peer J M Karp S Hong O C Farokhzad R Margalit andR Langer ldquoNanocarriers as an emerging platform for cancertherapyrdquo Nature Nanotechnology vol 2 no 12 pp 751ndash7602007

[4] M Ferrari ldquoCancer nanotechnology opportunities and chal-lengesrdquo Nature Reviews Cancer vol 5 no 3 pp 161ndash171 2005

[5] R K Jain and T Stylianopoulos ldquoDelivering nanomedicine tosolid tumorsrdquo Nature Reviews Clinical Oncology vol 7 no 11pp 653ndash664 2010

[6] Z Jiao X Wang and Z Chen ldquoAdvance of amphiphilicblock copolymeric micelles as drug deliveryrdquo Asian Journal ofChemistry vol 25 no 4 pp 1765ndash1769 2013

[7] M Elsabahy and K L Wooley ldquoDesign of polymeric nanopar-ticles for biomedical delivery applicationsrdquo Chemical SocietyReviews vol 41 no 7 pp 2545ndash2561 2012

[8] Z Ge and S Liu ldquoFunctional block copolymer assembliesresponsive to tumor and intracellular microenvironments forsite-specific drug delivery and enhanced imaging performancerdquoChemical Society Reviews vol 42 no 17 pp 7289ndash7325 2013

[9] S Ganta H Devalapally A Shahiwala andM Amiji ldquoA reviewof stimuli-responsive nanocarriers for drug and gene deliveryrdquoJournal of Controlled Release vol 126 no 3 pp 187ndash204 2008

[10] J H Park S Lee J-H Kim K Park K Kim and I CKwon ldquoPolymeric nanomedicine for cancer therapyrdquo Progressin Polymer Science vol 33 no 1 pp 113ndash137 2008

[11] J Fang H Nakamura and H Maeda ldquoThe EPR effect uniquefeatures of tumor blood vessels for drug delivery factorsinvolved and limitations and augmentation of the effectrdquoAdvancedDrugDelivery Reviews vol 63 no 3 pp 136ndash151 2011

[12] A K Iyer G Khaled J Fang and H Maeda ldquoExploitingthe enhanced permeability and retention effect for tumortargetingrdquo Drug Discovery Today vol 11 no 17-18 pp 812ndash8182006

[13] H Maeda J Wu T Sawa Y Matsumura and K Hori ldquoTumorvascular permeability and the EPR effect in macromoleculartherapeutics a reviewrdquo Journal of Controlled Release vol 65 no1-2 pp 271ndash284 2000

[14] L Brannon-Peppas and J O Blanchette ldquoNanoparticle andtargeted systems for cancer therapyrdquo Advanced Drug DeliveryReviews vol 64 pp 206ndash212 2012

[15] S P Egusquiaguirre M Igartua R M Hernandez and JL Pedraz ldquoNanoparticle delivery systems for cancer therapyadvances in clinical and preclinical researchrdquo Clinical andTranslational Oncology vol 14 no 2 pp 83ndash93 2012

[16] H Tanisaka S Kizaka-Kondoh A Makino S Tanaka MHiraoka and S Kimura ldquoNear-infrared fluorescent labeledpeptosome for application to cancer imagingrdquo BioconjugateChemistry vol 19 no 1 pp 109ndash117 2008

[17] Y Chen and X Li ldquoNear-infrared fluorescent nanocapsuleswith reversible response to thermalPH modulation for opticalimagingrdquo Biomacromolecules vol 12 no 12 pp 4367ndash43722011

[18] A Makino S Kizaka-Kondoh R Yamahara et al ldquoNear-infrared fluorescence tumor imaging using nanocarrier com-posed of poly(l-lactic acid)-block-poly(sarcosine) amphiphilicpolydepsipeptiderdquo Biomaterials vol 30 no 28 pp 5156ndash51602009

[19] R Weissleder ldquoA clearer vision for in vivo imagingrdquo NatureBiotechnology vol 19 no 4 pp 316ndash317 2001

[20] D L Bailey and K P Willowson ldquoQuantitative SPECTCTSPECT joins PET as a quantitative imagingmodalityrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 41 no1 pp 17ndash25 2013

[21] Y Li S M A Rizvi J M Blair et al ldquoAntigenic expression ofhumanmetastatic prostate cancer cell lines for in vitromultiple-targeted120572-therapywith 213Bi-conjugatesrdquo International Journalof Radiation Oncology Biology Physics vol 60 no 3 pp 896ndash908 2004

[22] B Cornelissen S Darbar R Hernandez et al ldquoErbB-2 blockadeand prenyltransferase inhibition alter epidermal growth factor


and epidermal growth factor receptor trafficking and enhance111In-DTPA-hEGF auger electron radiation therapyrdquo Journal ofNuclear Medicine vol 52 no 5 pp 776ndash783 2011

[23] D L Costantini C Chan Z L Cai K A Vallis and RM Reilly ldquo 111In-labeled trastuzumab (Herceptin) modifiedwith nuclear localization sequences (NLS) an auger electron-emitting radiotherapeutic agent for HER2neu-amplified breastcancerrdquoThe Journal of NuclearMedicine vol 48 no 8 pp 1357ndash1368 2007

[24] B Cambien P R Franken A Lamit et al ldquo(TcO4-)-Tc-99m-auger-mediated thyroid stunning dosimetric requirements andassociatedmolecular eventsrdquo PLoS ONE vol 9 no 3 Article IDe92729 2014

[25] W D Bloomer and S J Adelstein ldquo5-125I-iododeoxyuridineas prototype for radionuclide therapy with Auger emittersrdquoNature vol 265 no 5595 pp 620ndash621 1977

[26] R Rossin D P J Pan K Qi et al ldquo64Cu-labeled folate-conjugated shell cross-linked nanoparticles for tumor imagingand radiotherapy synthesis radiolabeling and biologic evalu-ationrdquo Journal of Nuclear Medicine vol 46 no 7 pp 1210ndash12182005

[27] K Qi Q Ma E E Remsen C G Clark Jr and K L WooleyldquoDetermination of the bioavailability of biotin conjugated ontoshell cross-linked (SCK) nanoparticlesrdquo Journal of the AmericanChemical Society vol 126 no 21 pp 6599ndash6607 2004

[28] J Sudimack and R J Lee ldquoTargeted drug delivery via the folatereceptorrdquo Advanced Drug Delivery Reviews vol 41 no 2 pp147ndash162 2000

[29] E D Pressly R Rossin A Hagooly et al ldquoStructural effects onthe biodistribution and positron emission tomograpgy (PET)imaging of well-defined 64Cu-labeled nanoparticles comprisedof amphiphilic block graft copolymersrdquo Biomacromolecules vol8 no 10 pp 3126ndash3134 2007

[30] M Allmeroth D Moderegger D Gundel et al ldquoPEGylation ofHPMA-based block copolymers enhances tumor accumulationin vivo a quantitative study using radiolabeling and positronemission tomographyrdquo Journal of Controlled Release vol 172no 1 pp 77ndash85 2013

[31] M Allmeroth D Moderegger D Gundel et al ldquoHPMA-LMAcopolymer drug carriers in oncology an in vivo PET studyto assess the tumor line-specific polymer uptake and bodydistributionrdquo Biomacromolecules vol 14 no 9 pp 3091ndash31012013

[32] Z Yang S Zheng W J Harrison et al ldquoLong-circulating near-infrared fluorescence core-cross-linked polymeric micellessynthesis characterization and dual nuclearoptical imagingrdquoBiomacromolecules vol 8 no 11 pp 3422ndash3428 2007

[33] R Zhang C Xiong M Huang et al ldquoPeptide-conjugatedpolymeric micellar nanoparticles for Dual SPECT and opticalimaging of EphB4 receptors in prostate cancer xenograftsrdquoBiomaterials vol 32 no 25 pp 5872ndash5879 2011

[34] Y Hong H Zhu J Hu et al ldquoSynthesis and radiolabeling of111In-core-cross linked polymeric micelle-octreotide for near-infrared fluoroscopy and single photon emission computedtomography imagingrdquo Bioorganic and Medicinal ChemistryLetters vol 24 no 12 pp 2781ndash2785 2014

[35] R Zhang W Lu X Wen et al ldquoAnnexin A5-conjugatedpolymeric micelles for dual SPECT and optical detection ofapoptosisrdquo Journal of Nuclear Medicine vol 52 no 6 pp 958ndash964 2011

[36] A I Jensen T Binderup P Kumar EkAKjaeligr PH Rasmussenand T L Andresen ldquoPositron emission tomography based anal-ysis of long-circulating cross-linked triblock polymericmicellesin a U87MGmouse xenograftmodel and comparison of DOTAand CB-TE2A as chelators of copper-64rdquo Biomacromoleculesvol 15 no 5 pp 1625ndash1633 2014

[37] M Okada ldquoChemical syntheses of biodegradable polymersrdquoProgress in Polymer Science vol 27 no 1 pp 87ndash133 2002

[38] BHoangH Lee RM Reilly andC Allen ldquoNoninvasivemon-itoring of the fate of111in-labeled block copolymer micelles byhigh resolution and high sensitivity microSPECTCT imagingrdquoMolecular Pharmaceutics vol 6 no 2 pp 581ndash592 2009

[39] H Lee B Hoang H Fonge R M Reilly and C Allen ldquoInvivo distribution of polymeric nanoparticles at the whole-bodytumor and cellular levelsrdquo Pharmaceutical Research vol 27 no11 pp 2343ndash2355 2010

[40] R M Reilly R Kiarash R G Cameron et al ldquo111In-labeledEGF is selectively radiotoxic to human breast cancer cellsoverexpressing EGFRrdquo Journal of Nuclear Medicine vol 41 no3 pp 429ndash438 2000

[41] H Fonge H Lee R M Reilly and C Allen ldquoMultifunctionalblock copolymer micelles for the delivery of 111in to EGFR-positive breast cancer cells for targeted Auger electron radio-therapyrdquo Molecular Pharmaceutics vol 7 no 1 pp 177ndash1862010

[42] B Hoang RM Reilly and C Allen ldquoBlock copolymermicellestarget auger electron radiotherapy to the nucleus of HER2-positive breast cancer cellsrdquo Biomacromolecules vol 13 no 2pp 455ndash465 2012

[43] B Hoang S N Ekdawi R M Reilly and C Allen ldquoActivetargeting of block copolymer micelles with trastuzumab fabfragments and nuclear localization signal leads to increasedtumor uptake and nuclear localization in HER2-overexpressingxenograftsrdquo Molecular Pharmaceutics vol 10 no 11 pp 4229ndash4241 2013

[44] C-C Cheng C-F Huang A-S Ho et al ldquoNovel targetednuclear imaging agent for gastric cancer diagnosis glucose-regulated protein 78 binding peptide-guided 111In-labeled poly-meric micellesrdquo International Journal of Nanomedicine vol 8pp 1385ndash1391 2013

[45] C-L Peng Y-H Shih P-C Lee T M-H Hsieh T-Y Luo andM-J Shieh ldquoMultimodal image-guided photothermal therapymediated by188Re-labeled micelles containing a cyanine-typephotosensitizerrdquo ACS Nano vol 5 no 7 pp 5594ndash5607 2011

[46] C-L Peng Y-H Shih K-S Liang et al ldquoDevelopment of in situforming thermosensitive hydrogel for radiotherapy combinedwith chemotherapy in a mouse model of hepatocellular carci-nomardquo Molecular Pharmaceutics vol 10 no 5 pp 1854ndash18642013

[47] D H Yu Q Lu J Xie C Fang and H Z Chen ldquoPeptide-conjugated biodegradable nanoparticles as a carrier to targetpaclitaxel to tumor neovasculaturerdquo Biomaterials vol 31 no 8pp 2278ndash2292 2010

[48] S Sumitani M Oishi T Yaguchi et al ldquoPharmacokineticsof core-polymerized boron-conjugated micelles designed forboron neutron capture therapy for cancerrdquo Biomaterials vol 33no 13 pp 3568ndash3577 2012

[49] S Sumitani and Y Nagasaki ldquoBoron neutron capture therapyassisted by boron-conjugated nanoparticlesrdquo Polymer Journalvol 44 no 6 pp 522ndash530 2012

[50] A Makino E Hara I Hara et al ldquoControl of in vivo bloodclearance time of polymeric micelle by stereochemistry of


amphiphilic polydepsipeptidesrdquo Journal of Controlled Releasevol 161 no 3 pp 821ndash825 2012

[51] F Yamamoto R Yamahara A Makino et al ldquoRadiosynthesisand initial evaluation of 18F labeled nanocarrier composed ofpoly(L-lactic acid)-block-poly(sarcosine) amphiphilic polydep-sipeptiderdquoNuclear Medicine and Biology vol 40 no 3 pp 387ndash394 2013

[52] E Hara A Makino K Kurihara et al ldquoRadionuclide therapyusing nanoparticle of131I-Lactosome in combination with per-cutaneous ethanol injection therapyrdquo Journal of NanoparticleResearch vol 15 Article ID 2131 2013

[53] E Hara A Makino K Kurihara F Yamamoto E Ozeki andS Kimura ldquoPharmacokinetic change of nanoparticulate formu-lation ldquoLactosomerdquo on multiple administrationsrdquo InternationalImmunopharmacology vol 14 no 3 pp 261ndash266 2012

[54] T Ishida and H Kiwada ldquoAccelerated blood clearance (ABC)phenomenon upon repeated injection of PEGylated liposomesrdquoInternational Journal of Pharmaceutics vol 354 no 1-2 pp 56ndash62 2008

[55] A S Abu Lila H Kiwada and T Ishida ldquoThe acceleratedblood clearance (ABC) phenomenon clinical challenge andapproaches to managerdquo Journal of Controlled Release vol 172no 1 pp 38ndash47 2013

[56] E Hara A Makino K Kurihara et al ldquoEvasion from accel-erated blood clearance of nanocarrier named as ldquolactosomerdquoinduced by excessive administration of Lactosomerdquo Biochimicaet Biophysica ActamdashGeneral Subjects vol 1830 no 8 pp 4046ndash4052 2013

[57] E Hara M Ueda A Makino I Hara E Ozeki and S KimuraldquoFactors influences in vivo disposition of polymeric micelleson multiple administrationsrdquo ACSMedicinal Chemistry Lettersvol 5 no 8 pp 873ndash877 2014

[58] P-L Lu Y-C Chen T-W Ou et al ldquoMultifunctional hollownanoparticles based on graft-diblock copolymers for doxoru-bicin deliveryrdquo Biomaterials vol 32 no 8 pp 2213ndash2221 2011

[59] MGWacker ldquoNanotherapeuticsmdashproduct development alongthe nanomaterial discussionrdquo Journal of Pharmaceutical Sci-ences vol 103 no 3 pp 777ndash784 2014

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Representative radionuclides used for imaging and radiotherapy

Radionuclide Emission type Half-life Usage111C 120573+ (998) 120574 (02) 2039min I13N 120573+ (998) 120574 (02) 9965min I15O 120573+ (999) 120574 (01) 2037min I18F 120573+ (967) 120574 (33) 1098min I32P 120573minus (100) 1424 day T64Cu 120573+ (174) 120574 (436) 1270 h TI

120573minus (390)89Sr 120573minus (100) 5053 day T90Y 120573minus (100) 6400 h T99mTc 120574 (gt999) 6015 h TI111In 120574 (100) 2805 day TI123I 120574 (100) 1322 h I125I 120574 (100) 5940 day TI131I 120573minus 8021 day TI186Re 120573minus 120574 3718 day TI188Re 120573minus 120574 1700 h T211At 120572 7214 h T213Bi 120572 214min T225Ac 120572 100 day T1Radionuclide usage for imaging and therapy are abbreviated as ldquoIrdquo and ldquoTrdquo respectively

near-infrared light in tissue is limited to a few centimeters[19] Therefore the NIRF imaging system is suitable for invivo experiments using small animals but its applicative areain human clinical uses is limited to near the surface wherefluorescent signal can be detectable On the other handin general sensitivity of nuclear imaging is high Furtherquantitative analyses are available by using PET imagesWhen it comes to the quantitative performance SPECT isless competitive than PET but has been improved by recentmechanical developments [20] Positron emitters such as 11C13N 15O 18F and 64Cu are used for PET imaging as signalsources and 120574-ray emitters such as 99mTc 111In and 123I arefor SPECT imaging (Table 1) For preparation of nanoparticletype probes for nuclear imaging techniques strategies onhow to encapsulate these radioisotopes into nanoparticlesare important There are considerable approaches for theencapsulation which can be classified into three categories(1) hydrophobized radionuclides are encapsulated into thehydrophobic core region of polymeric micelle (2) radionu-clide solution is encapsulated into the inner cavity of vesicularassemblies and (3) metal radionuclides such as 64Cu and99mTc can be attached to the nanoparticles as chelates bymod-ifying constituent amphiphilic polymers with appropriatechelators About the inner radiation therapy 120573minus ray emitterssuch as 90Y and 131I are generally used In addition attemptsto utilize radionuclides emitting120572-ray (211At 213Bi) and augerelectron (99mTc 111In and 125I) are also performed (Table 1)[21ndash25] Any radionuclides labeled nanoparticle can be pre-pared by selecting appropriate methods for encapsulation aswritten above

In this review recent research developments on solidtumor-targeting DDS using polymer nanoparticle carriers innuclear medicinal fields are summarized

2 Polymeric Micelles

21 Importance of Surface Modification withPoly(ethylene glycol) (PEG)

211 Poly(methyl acrylate)-b-poly(acrylic acid) One of theinitial trials to utilize polymeric micelle as a carrier for PETtracer agent was performed in 2005 by Rossin et al [26]Polymeric micelle was prepared from amphiphilic poly(methyl acrylate)-b-poly(acrylic acid) (PMA

164

-b-PAA93

)which was synthesized via sequential atom transfer radicalpolymerization (ATRP) [27] As illustrated in Figure 1PMA-b-PAA in the micelle was cross-linked between thecarboxyl acid group of PAA and the amine functionalitiesof 221015840-(ethylenedioxy)diethylamine poly(acrylic acid) toform shell cross-linked (SCK) nanoparticles Folate receptor(FR) is well-known molecular target for tumor therapies[28] and therefore folate-poly(ethylene glycol)-amine wasconjugated to the surface of the micelle Further 14811-tetra-azacyclotetradecane-1198731015840 11987310158401015840 119873101584010158401015840 1198731015840101584010158401015840-tetra-aceticacid (TETA) was also modified to the micelle surface for64Cu chelate formation

Using tumor transplanted mice biodistribution of themicelle was examined by organ harvesting method Themicelle was recognized by reticuloendothelial system (RES)which is self-defense system of living organisms and its


(i)-(ii)



(iii)


(v)


(iv)


OH

OH

OH

OH

OH

OHOH

HOHO

HO

HO

HO

HO

HO

O O

O

O O

NN

N N

NN

N N

N

O

O

O

O

O

O

O

OH

OH

OHOH

HO

HO

HO

HO

HO

OO

OO

O

O

O

O

O

O

O

O

O

O

O

O

OH

OH

OHOH

HO

HO

HO

HO

O

O

O

O

O

O

OO

O

OO

OO

O

O

OH

OH

OHOH

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

O

H

NH

HN

HN

HN

HN

HN

NH

NH2

PAA93-b-PMA164

n n

OH

HO

NN

N N

N

O

OO

O

O

H

HN

HN

NH

NH2

n

m

p

34

OH

HO

NN

N N

N

O

OO

OO

O

H

N

S

H

HN

HN

NH

NH2

34

34

CO2H



ON

OO

OO

OO

OO

O SO

S

OOOOOO

N

O

O O

MASI MMA PEGMA O

OS

S

AIBN O SHO OOHN

OOO

O

HN

N

N N

N

HO

O

OHOO

OH

O

n

x y z

n

x y z








2000





N

O

NHO

Si OO O

N


BrOO OO

OSiO

OO

OO

OO

Br

CuBrN N

OO

OO

OSiO

OO

ESPMA PEGMA

N NHOOCHOOC

NHOOC COOH

COOH

CCPM

DTPA-Bz-NCSSHNHN

x y

nn

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2NH2NH2

H2N

H2NH2N

H2N

NH2

NH2

NH2NH2NH2

CF3COO

CF3COO

H3N

H3N

ClO4



= 125 h 11990512120573








OOH

O

O

OO

O H

O



Caprolactone

H2NH2Nn m n










PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane







70









0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(i)-(ii)



(iii)


(v)


(iv)


OH

OH

OH

OH

OH

OHOH

HOHO

HO

HO

HO

HO

HO

O O

O

O O

NN

N N

NN

N N

N

O

O

O

O

O

O

O

OH

OH

OHOH

HO

HO

HO

HO

HO

OO

OO

O

O

O

O

O

O

O

O

O

O

O

O

OH

OH

OHOH

HO

HO

HO

HO

O

O

O

O

O

O

OO

O

OO

OO

O

O

OH

OH

OHOH

HO

HO

HO

HO

HO

O

O

O

O

O

O

O

O

H

NH

HN

HN

HN

HN

HN

NH

NH2

PAA93-b-PMA164

n n

OH

HO

NN

N N

N

O

OO

O

O

H

HN

HN

NH

NH2

n

m

p

34

OH

HO

NN

N N

N

O

OO

OO

O

H

N

S

H

HN

HN

NH

NH2

34

34

CO2H



ON

OO

OO

OO

OO

O SO

S

OOOOOO

N

O

O O

MASI MMA PEGMA O

OS

S

AIBN O SHO OOHN

OOO

O

HN

N

N N

N

HO

O

OHOO

OH

O

n

x y z

n

x y z








2000





N

O

NHO

Si OO O

N


BrOO OO

OSiO

OO

OO

OO

Br

CuBrN N

OO

OO

OSiO

OO

ESPMA PEGMA

N NHOOCHOOC

NHOOC COOH

COOH

CCPM

DTPA-Bz-NCSSHNHN

x y

nn

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2NH2NH2

H2N

H2NH2N

H2N

NH2

NH2

NH2NH2NH2

CF3COO

CF3COO

H3N

H3N

ClO4



= 125 h 11990512120573








OOH

O

O

OO

O H

O



Caprolactone

H2NH2Nn m n










PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane







70









0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ON

OO

OO

OO

OO

O SO

S

OOOOOO

N

O

O O

MASI MMA PEGMA O

OS

S

AIBN O SHO OOHN

OOO

O

HN

N

N N

N

HO

O

OHOO

OH

O

n

x y z

n

x y z








2000





N

O

NHO

Si OO O

N


BrOO OO

OSiO

OO

OO

OO

Br

CuBrN N

OO

OO

OSiO

OO

ESPMA PEGMA

N NHOOCHOOC

NHOOC COOH

COOH

CCPM

DTPA-Bz-NCSSHNHN

x y

nn

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2NH2NH2

H2N

H2NH2N

H2N

NH2

NH2

NH2NH2NH2

CF3COO

CF3COO

H3N

H3N

ClO4



= 125 h 11990512120573








OOH

O

O

OO

O H

O



Caprolactone

H2NH2Nn m n










PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane







70









0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

O

NHO

Si OO O

N


BrOO OO

OSiO

OO

OO

OO

Br

CuBrN N

OO

OO

OSiO

OO

ESPMA PEGMA

N NHOOCHOOC

NHOOC COOH

COOH

CCPM

DTPA-Bz-NCSSHNHN

x y

nn

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2NH2NH2

H2N

H2NH2N

H2N

NH2

NH2

NH2NH2NH2

CF3COO

CF3COO

H3N

H3N

ClO4



= 125 h 11990512120573








OOH

O

O

OO

O H

O



Caprolactone

H2NH2Nn m n










PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane







70









0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















OOH

O

O

OO

O H

O



Caprolactone

H2NH2Nn m n










PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane







70









0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















PLA

PEG

Acetalgroup

groupMethacrylic

VB-carborane







70









0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0

5

5 25 50 150 250 350

555 5 5 5

(mgkg)

(mgkg)

5000

1000

(cou

nts)

15min

1st dose

2nd dose

(a)

5000

1000

(cou

nts)

24h

(b)

0

Time


(a) (b)

ndash7 days



15min 24h

(c)

A

B

C

D

E

Tumor

A B C D E

L

B

(d)





N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

N NOO

O

OH

O

(1)N

NO O

O

OH

O

(2) O HO

O

O

O

12n

AIBNAcetone

TolueneO

O O H

O

(3)NH

O HO

O

O

O

12n NH

O O O H

OBOC

Alcoholrt

Alcoholrt


OHHN

BOC

OO

O

O

12n Toluene

Toluene

O OHO

HNBOC

HOOC O COOH

DCC DPTSDCM(4)

O OO

HNBOC

O

OCOOH

DCC DPTS DCM

HO OHO

OO

HNBOC

O

O O

O OH

(5)

(7)(6) Dialysis

DOX

Folate

n n

x y z

x n

x n

n x

n xn x

70∘C 24h

Sn(Oct)2

Sn(Oct)2

Sn(Oct)2

130∘C

130∘C

130∘C

PdC H2

+ +

+

+

+

rt 24 h

rt 24 h

CH2CH2O CH2CH2O

H3COH3CO xminus1

xminus1

123I






5000


(mPEG5000

-b-PLA1510

)folate-PEG

5000

-b-PLA1200


-b-PLA650


9600

-g-PLA4900


5000

-b-PLA1200


5000

-b-PLA650




4 Conclusion









Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















Acknowledgment


References





































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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