Nanoparticles and Brain Tumor Treatment

7/30/2019 Nanoparticles and Brain Tumor Treatment

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Gerardo Caruso

Maria CaffoGiuseppe RaudinoFrancesco Tomasello

Nanoparticlesand Brain Tumor

Treatment

Biomedical & NaNomedical TechNologies

coNcise moNograph series


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Contents

1. I 12. G bgy 42.1 Invasion and angiogenesis 4

3. B-b b 93.1 Blood-brain barrier physiology 93.2 Blood-brain barrier transport systems 11

4. N hgy 144.1 Nanoparticle drug delivery 19

4.1.1 Nanoparticle distribution 20

4.1.2 Nanoparticle unctionalization 214.1.3 Nanoparticle targeting 234.2 Nanomedicine and cancer 254.3 Nanomedicine and toxicity 30

5. N hg 335.1 Polymeric and polymer-drug conjugate nanoparticles 335.2 Micelle nanoparticles 355.3 Liposomes 375.4 Gold and silver nanoparticles 39

5.5 Metal oxide 415.6 Magnetic nanoparticles 425.7 Carbon nanotubes 435.8 Fullerenes 445.9 Peptides nanoparticles 455.10 Silica nanoparticles 465.11 Quantum dots 485.12 Dendrimers 49

6. N b 51

6.1 Brain tumor drug targeting 556.1.1 Systemic approaches 556.1.2 Physiological approaches 56

6.1.2.1 Receptor-mediated transcytosis 576.1.2.2 Adsorptive-mediated transcytosis 586.1.2.3 Eux pump inhibition 606.1.2.4 Cell-mediated drug transport 61

6.1.3 Direct CNS approaches 616.1.3.1 Intracerebral routes 65

6.1.4 Drug modications and prodrugs 667. Ex 698. C 77Rf 81


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Ab

Despite progresses in surgery, radiotherapy, and in chemotherapy, an eec-tive curative treatment o gliomas does not yet exist. Mortality is still closeto 100% and the average survival o patients with GBM is less than 1 year.Te efcacy o current anti-cancer strategies in brain tumors is limited bythe lack o specic therapies against malignant cells. Besides, the deliveryo the drugs to brain tumors is limited by the presence o the blood brainbarrier. Te oncogenesis o gliomas is characterized by several biologicalprocesses and genetic alterations, involved in the neoplastic transormation.Te modulation o gene expression to more levels, such as DNA, mRNA,

proteins and transduction signal pathways, may be the most eective mo-dality to down-regulate or silence some specic gene unctions. Gliomas arecharacterized by extensive microvascular prolieration and a higher degreeo vasculature. In malignant gliomas targeted therapies efcacy is low. Inthis complex eld, it seems to be very important to improve specic selectivedrugs delivery systems. Drugs, antisense oligonucleotides, small intererenceRNAs, engineered monoclonal antibodies and other therapeutic moleculesmay diuse into CNS overcoming the BBB. Nanotechnology could be usedboth to improve the treatment efcacy and to reduce the adverse side eects.

Nanotechnology-based approaches to targeted delivery o drugs across theBBB may potentially be engineered to carry out specic unctions as needed.Moreover, nanoparticles show tumor-specic targeting and long blood cir-culation time, with consequent low-short-term toxicity. Nanotechnologydeals with structures and devices that are emerging as a new eld o re-search at the interace o science, engineering and medicine. Nanomedicine,the application o nanotechnology to healthcare, holds great promise orrevolutionizing medical treatments, imaging, aster diagnosis, drug deliveryand tissue regeneration. Tis technology has enabled the development o

nanoscale device that can be conjugated with several unctional moleculesincluding tumor-specic ligands, antibodies, anticancer drugs, and imag-ing probes. Nanoparticle systems are, also emerging as potential vectors orbrain delivery, able to overcome the difculties o the classical strategies. Byusing nanotechnology it is possible to deliver the drug to the targeted tis-sue across the BBB, release the drug at the controlled rate, and avoid romdegradation processes. At the same time, it is also necessary to retain thedrug stability and ensure that early degradation o drugs rom the nano-carriers does not take place. Large amounts o small molecules, such as

contrast agents or drugs, can be loaded into NPs via a variety o chemicalmethods including encapsulation, adsorption, and covalent linkage. Mosttargeting molecules can be added to the surace o NPs to improve targetingthrough a concept dened as surace-mediated multivalent afnity eects.


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v Nanoparticles and Brain Tumor Treatment

Te uture challenges may be the possibility to modiy the cell genome andinduce it to a reversion to the wild-type conditions and the enhancing o im-mune system anti-tumor capacity. Recent advances in molecular, biologicaland genetic diagnostic techniques have begun to explore cerebral glioma-associated biomarkers and their implications or gliomas development andprogression. Realization o targeted therapies depends on expression o thetargeted molecules, which can also provide as specic biomarkers. Te de-velopment o multiunctional NPs may contribute to the achievement otargeted therapy in glioma treatment.


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1. I

Gliomas are the most common primary brain tumors in adults, with aworldwide incidence o approximately 7 out o 100,000 individuals per year.Although brain tumors constitute only a small proportion o overall humanmalignancies, they carry high rates o morbidity and mortality. Mortalityis still close to 100% and the average survival o patients with glioblastomamultiorme (GBM) is less than 1 year when classical treatment is used.Recent progress in multimodal treatment o this disease has led to only aslight increase in average survival up to 1518 months. Te eectiveness othe actual chemotherapeutic approach and multimodal targeted therapiesremains modest in gliomas.

Gliomas are brain tumors with histological, immunohistochemical andultra structural eatures o glial dierentiation. Approximately 50% o pri-mary brain tumors are gliomas, arising rom astrocytes, oligodendrocytes,or their precursors and ependymal cells. Gliomas are classied rom I toIV according to the World Health Association (WHO) malignancy scale.Grade I gliomas are benign with a slow prolieration rate and include py-locitic astrocytoma most common in pediatric age. Grade II gliomas arecharacterized by a high degree o cellular dierentiation and grow diuselyinto the normal brain parenchyma and are prone to malignant progression.Tey include astrocytoma, oligodendroglioma and oligoastrocytoma. GradeIII lesions include anaplastic astrocytoma, anaplastic oligoastrocytoma andanaplastic oligodendroglioma. Tese tumors show a higher cellular densityand a notable presence o atypia and mitotic cells. Grade IV tumors are themost malignant and also the most requent gliomas and include glioblas-toma and gliosarcoma. Tese tumors presented microvascular prolierationsand pseudopalisading necrosis.

Conventional brain tumor treatments include surgery, radiation therapyand chemotherapy. Surgical treatment is invasive but represents the rstapproach or the vast majority o brain tumors due to diculties arisingin early stage detection. However, ater surgical resection, the residual poolo invasive cells rises to recurrent tumor which, in 96% o cases arise ad-

jacent to the resection margins [1]. Aggressive treatment modalities haveextended the median survival rom 4 months to 1 year, but the survival isoten associated with signicant impairment in the quality o lie. Radiationtherapy and chemotherapy are non-invasive options oten used as adjuvanttherapy, but may also be eective or curing early-stage tumors. In patientswith recurrent GBM, the 6-months progression-ree survival is only 21%ater treatment with temozolomide [2]. Adjuvant radiotherapy gives limitedbenets and causes debilitation side eects which reduce its ecacy [3]. Teeectiveness o systemic chemotherapy is limited by toxic eects on healthycells, generally resulting in morbidity or mortality o the patient. Moreover,the presence o the BBB limits the passage o a wide variety o anticancer


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2 Nanoparticles and Brain Tumor Treatment

agents. Te high incidence o recurrence and poor prognosis o malignantgliomas compel the development o more powerul anti-cancer treatments.Te compromise o the quality o remaining lie as well as the limited suc-cess o current treatment options in shrinking tumors, raise increasingconcerns about the adverse eects o cancer treatment on brain unction.Deterioration in neurological unction is accompanied by signicant deteri-oration in the global quality o lie in patients aected by malignant gliomas.Te advent o molecular studies allows evaluation o the possibility o re-examination o the biology o gliomas with, a level o precision that prom-ises interesting advances toward the development o specic and eectivetherapies. It is now generally understood that tumor genesis occurs either,by over-expression o oncogenes, or inactivation o tumor suppressor genes.Te modulation o gene expression at more levels, such as DNA, mRNA,proteins and transduction signal pathways, may be the most eective mo-dality to down-regulate or silence some specic gene unctions.

Cerebral gliomas represent an important challenge in modern oncology,and only in the last years has the development o new multimodal thera-peutic strategies given the beginning to a new research eld o neuroon-cology: nanotechnology and nanomedicine. With the advancement in BBBstructure and pathophysiology knowledge, brain delivery and targetingskills, and brain tumor biology, these new interesting possibilities couldlead to new perspectives in brain tumor treatment. Nanotechnology is anemerging eld that deals with interactions between molecules, cells andengineered substances such as molecular ragments, atoms and molecules.Te impact o nanotechnology in medicine can mainly be seen in diagnosticmethods, drug-release techniques and regenerative medicine. In the recentpast, nanotechnology has garnered much attention due to its potential ap-plication in cancer, and the National Cancer Institute has constituted anAlliance o Nanotechnology in Cancer with ocus on the development onovel nanoplatorm-based diagnostics, therapeutics and preventive agents.Nanomedicine could lead to new possibilities to overcome important prob-lems in malignant brain tumors, such as the non specicity o cancer cellsdrug-delivering and targeting, as well as the non complete passage o drugsthrough the BBB and into cancer cells avoiding side eects in normal braintissue. Nanoparticles are colloidal particles typically synthesized in eitheraqueous or organic phases. Due to their small size, nanoparticles can easilyfow through blood capillaries and enter the target cancer cells. Reductiono toxicity to peripheral organs can also be achieved with these systems[4]. Nanoparticle-based drug-delivery systems, an antisense approach tomodiy gene expression in cancer cell genome, and molecular-based cancercell targeting all represent important possibilities in cerebral gliomas treat-ment. Nanosystems with dierent compositions and biological propertieshave been extensively investigated or drug and gene delivery applications[45]. Te type and the number o linkers within and on the surace o


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Introduction 3

nanoparticles and the size o the nanoparticle itsel can be modulated tocontrol the loading/releasing o the encapsulated or covalently linked drugcomponents or to add surace coating. Moreover, they can improve the e-cacy o existing imaging and treatment regimens. Te ability to deliver con-trast or therapeutic agents selectively to tumors at eective concentrationsis a key actor or the ecacy o cancer detection and therapy. Additionally,encapsulation o drugs within nanoplatorms can provide a signicant ad-vantage when employing poorly soluble, poorly absorbed or labile agents byincorporating them in the matrix o the nanoparticle during the ormula-tion/synthetic process.

Tis study presents a review o the recent studies o nanoparticle systemsin cerebral gliomas treatment with a particular emphasis on the develop-ment o nanocarrier drug delivery systems or brain cancer therapy appli-cations. Tese technologies include polymeric and polymer-drug conjugatenanoparticles, micelle nanoparticles, liposomes, metallic and magneticnanoparticles, metal oxide, carbon derivates, peptide nanoparticles, inor-ganic nanopaerticles, quantum dots, and dendrimers.


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2. G b

Genomic DNA aberrations are key genetic events in gliomagenesis.Recurrent genomic regions o alteration, including net gains and losses,have been ound in gliomas. Whereas some o these regions containknown oncogenes and tumor suppressor genes, the biologically relevantgenes within other regions remain to be identied. Te phenotypic andgenotypic heterogeneity indicate that no isolated genetic event accountsor gliomagenesis, but rather the cumulative efects o a number o alter-ations that operate in a concerted manner. In this pathological processare included various biological events, such as activation o growth actorreceptor signaling pathways, down-regulation o many apoptotic mecha-nisms, and imbalance o pro- and anti-angiogenic actors. Several growthactor receptors, such epidermal growth actor receptor (EGFR), platelet-derived growth actor receptor (PDRGF), C-Kit, vascular endothelialgrowth actor receptor (VEGFR) are over-expressed, amplied and/ormutated in gliomas (Figure 2-1). In able 2-1 are summarized the mostcommon glioma genetic alterations requently ound. In the light o thisnovel inormation, the modulation o gene expression at more levels, suchas DNA, mRNA, proteins and transduction signal pathways, may repre-sent the most efective modality to down-regulate or silence some specicgenic unctions or introduce genes, down-regulated or deleted selectively,into neoplastic cells.

2.1 Iv

Glioma cell invasion consists o an active translocation o glioma cellsthrough host cellular and extracellular matrix barriers [67]. Cerebralgliomas show a unique pattern o invasion and with rare exceptions do notmetastasize outside o the brain. How invasive glioma cells survive in thesetting o invasion, evading immune detection, and deerring commitment

to prolieration, remains unknown. Invading glioma cells normally migrateto distinct anatomical structures. Tese structures include the basementmembrane (BM) o blood vessels, the subependymal space, the glial limi-tans externa, and parallel and intersecting nerve bre tracts in the whitematter. Glioma cells adhesion to proteins o the surrounding extracellularmatrix (ECM), degradation o ECM components by proteases secretionby neoplastic cells and migration o glioma cells are undamental phases inthis process. ECM is composed o proteoglycans, glycoproteins, and colla-gens and also contains bronectin, laminin, tenascin, hyaluronic acid, and

vitronectin. Critical actors in glioma invasion include the synthesis anddeposition o ECM components by glioma and mesenchymal cells, the re-lease o ECM-degrading activities or remodeling interstitial spaces, thepresence o adhesion molecules and the efects o cell-matrix interactionson the behavior o glioma cells. ECM modication aids the loss o contact


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Glioma Biology 5

inhibition, allowing tumor cells to reely migrate and invade the surround-ing tissues. Te proteolytic degradation o the BM is mediated by pro-teases, such as the matrix metalloproteases (MMPs), secreted by tumorand stromal cells [8]. MMPs play an important role in human brain tumorinvasion, probably due to an imbalance between the production o MMPsand tissue inhibitor o metalloproteases-1 (IMP-1) by the tumor cells[8]. MMP-1 is able to initiate breakdown o the interstitial collagens and to

F 2-1 Growth actors signaling pathways in cerebralgliomas (K-kinase, EGF-epidermal growth actor, PDGF-plateled derived growth actor, mOR-mammalian target o

rapamycin, PEN-tumor suppressor phosphatise and tensinhomolog, PKC-protein kinase C, PI3K phosphatidylinositol-3-kinase, PLC-phospholipase, Akt-, MEK-1/2-mitogen-activatedprotein kinase and extracellular signal-regulated protein kinase-1/2, kinase, MAPK/ERK-1/2-mitogen-activated protein kinase/extracellular signal-regulated protein kinase-1/2).


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Table2-1Main

geneticalterationsincerebralgliomas.

Gene

Chromosome

Molecular

alteration

Molecularalteration

efects

Histotypeand

(WHOGrade)

TP53

Cr17p13.1

M

utation

Cellcyclecontrolloss,

prolieration

Astrocytomaandoligodendroglioma

(W

HOGradeII).Precociousmu

tationin

secondaryGBM

PDGFR-a

PDGF-A

Cr4q11-q12

A

mplication/

o

ver-expression

Prolier

ation/invasion


(W

HOGradeIIIII)

Unknowntumo

r

suppressorgene

s

1p,19q,4q,9p

and11ploss

L

osso

h

eterozygosity

Prolier

ation,invasiveness,

angioge

nesis


(W

HOGradeIIIII)

Unknowntumo

r

suppressorgene

s

Cr22q

D

eletion

Prolier

ation


(W

HOGradeII)

Rb1

Cr13q14.2

M

utations/

d

eletion

Cellcyc

lecontrolloss,

prolieration


(W

HOGradeIIIII)

P16

Cr9p

C

DKN2/p16

d

eletion

Cellcyclecontrolloss,

prolieration


(W

HOGradeIIIII)

PTEN

Cr10q23

L

OH

RegulationAkt/PKBsignal-

ingpathwayloss;proli-

eration

andtumorgrowth;

invasive

ness,angiogenesis


(W

HOGradeIIIIV)

BAX

Cr19q24

L

OH

Pro-apoptoticactionloss,

prolieration


(W

HOGradeIIIII)

EGFR(c-erb-2)

Cr7p11-p12

A

mplication/

o

ver-expression

Celltransormationand

prolieration

De

novoGBM

MDM2

Cr12q14.3-q15

O

ver-expression

Cellcyclecontrollossand

prolieration

De

novoGBM


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Glioma Biology 7

activate the other MMPs which allow glioma cell inltration. Cell adhesionis the binding o the cells to each other and to the ECM through cell adhe-sion molecules such as integrins, selectins, cadherins, the immunoglobulinsuperamily and lymphocyte homing receptors. Te extracellular ligandsthat anchor these adhesions include laminin, bronectin, vitronectin, andvarious collagens. Integrins are heterodimers oa- and b-subunits that reg-ulate many aspects o the cell behavior including survival, prolieration, mi-gration and diferentiation. Integrins are expressed on diferent cell types,including neurons, glial cells, meningeal and endothelial cells. b2 integrinsare specically expressed by leukocytes and they are ound on microgliaand on inltrating leukocytes within the CNS. Down-regulated b1 inte-grin protein levels in vivo probably afect interactions o glioma cells withECM components, leading to reduced migration along vascular basementmembranes [9]. Tese data can be interpreted as contributing to the locallyinvasive behavior o astrocytic tumors, avoring the regulation o proteasesactivation.

Cerebral gliomas are characterized by extensive microvascular proliera-tion and a higher degree o vasculature. Angiogenesis, the ormation o newblood vessels rom existing microvessels, is a histological indicator o thedegree o malignancy and prognosis. Angiogenesis also includes vessel pen-etration into avascular regions o the tissue, and is critically dependent onthe correct interactions among endothelial cells, pericytes and surroundingcells and their association with the ECM and the vascular BM. Cafo et al.[10] demonstrated that, the presence o endothelial glomeruloid-like pro-lieration in neoplastic vessels, was predictive o active tumor invasiveness(Figure 2-2). Endothelial cells are guided into avascular areas via macro-molecules such as VEGF-A, a pro-angiogenic actor and endothelial cellmitogen. VEGF-A activation causes endothelial cell diferentiation and aVEGF-A gradient induces stalk cell prolieration along an opening in theBM in the ormation o a new vessel sprout. VEGF also induces expression

F 2-2 Presence o marked endothelial glomeruloid-likeprolierations in neoplastic vessels. Tis eature is indicative oactive tumor progression and invasiveness, and o neoplasticcellular migration.


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o the delta-like ligand, DLL-4, in tip cells that bind to its receptors, as wellas Notch 1 and Notch 4, on adjacent stalk endothelial cells. DLL-4-Notchsignaling unctions act as a dampening mechanism in preventing excess an-giogenesis and promoting orderly development o new vessels. Membranetype 1-matrix metalloproteinase M1-MMP on the endothelial cell sur-ace, are also required or the subsequent step in the angiogenesis cascadeo tube ormation, by playing a role in endothelial intracellular vacuole andlumen ormation. Te BM is built up o scafolding laminins and essentialcomponents such as collagen IV and collagen XVIII [11]. Part o the nalstage o angiogenesis is the recruitment o pericytes as their association withendothelial and vascular smooth muscle cells, is essential or the maturationo endothelial tubes into blood vessels.


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Scope

This nis monograph series focuses on the

implementation of various engineering principles

in the conception, design, development, analysisand operation of biomedical, biotechnological and

nanotechnology systems and applications. Authors are

encouraged to submit their work in the following core

topics, but authors should contact the commissioning

editor before submitting a proposal:

BIoMeDIcAL DeVIceS & MATeRIALS

Trauma AnalysisVibration and Acoustics in Biomedical Applications

Innovations in Processing, Characterization and

Applications of Bioengineered Materials

Viscoelasticity of Biological Tissues and Ultrasound

Applications

Dynamics, and Control in Biomechanical Systems

Clinical Applications of Bioengineering

Transport Phenomena In Biomedical Applications

Computational Modeling and Device Design

Safety and Risk Analysis of Biomedical Engineering

Modeling and Processing of Bioinspired Materials

and Biomaterials

NANoMeDIcAL DeVIceS & MATeRIALS

Bio Nano Materials

Nano Medical SciencesMaterials for Drug & Gene Delivery

Nanotechnology for Central Nervous System

Nanomaterials & Living Systems Interactions

Biosensing, Diagnostics & Imaging

Cancer Nanotechnology

Micro & Nano Fluidics

Environmental Health & Safety

Soft Nanotechnology & Colloids

Biomedical & NaNomedical TechNologies

coNcise moNograph series

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Nanoparticles and Brain Tumor Treatment