Table Of ContentCANCER DRUG DISCOVERY AND DEVELOPMENT
Macromolecular
Anticancer
Therapeutics
Edited by
L. Harivardhan Reddy
Patrick Couvreur
Macromolecular Anticancer Therapeutics
·
L. Harivardhan Reddy Patrick Couvreur
Editors
Macromolecular Anticancer
Therapeutics
Foreword by Rakesh K. Jain
123
Editors
Dr.L.HarivardhanReddy PatrickCouvreur,Ph.D.
Univ.Paris-SudXI Univ.Paris-SudXI
Châtenay-Malabry Châtenay-Malabry
France France
Sanofi-aventis
Vitry-sur-Seine
France
ISBN978-1-4419-0506-2 e-ISBN978-1-4419-0507-9
DOI10.1007/978-1-4419-0507-9
SpringerNewYorkDordrechtHeidelbergLondon
LibraryofCongressControlNumber:2009935754
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Foreword
Currenttreatmentofprimaryandmetastaticsolidtumorsisplaguedbytwomajor
problems – (1) the inability to deliver therapeutics to all regions of a tumor in
therapeutically effective quantities without causing undue toxicity and (2) intrin-
sic or acquired resistance to currently available agents via genetic and epigenetic
mechanisms. Since tumor vessels are leaky to macromolecules and nanoparticles,
andlymphaticswithintumorsarefunctionallyimpaired,this“enhancedpermeabil-
ity and retention (EPR)” effect has propelled the development of macromolecular
anticancer therapeutics. Furthermore, the ability to engineer these molecules and
particles to bind to certain targets in tumors has provided additional rationale for
developingtheseagents.Thisbook–editedbyDrs.L.H.ReddyandP.Couvreur–
represents a timely and comprehensive treatise on advances and challenges in the
developmentofmacromoleculartherapeuticsinoncology.
A primary or metastatic solid tumor is like an aberrant organ – comprised of
cancer cells and host cells embedded in an extra-cellular matrix – nourished by
blood vessels and drained by lymphatic vessels. In its journey from the blood
stream to cancer cells, a therapeutic agent must cross the blood vessel wall and
the extra-cellular matrix that cancer cells are ensconced in. Unfortunately, blood
andlymphaticvesselsaswellasmatrixassociatedwithtumorsareabnormal.Their
structure and function vary from one tumor to the next, from one location within
a tumor to the next, from one moment to the next, from primary tumor to its
metastases, and finally, in response to treatment. This heterogeneity can impede
uniform delivery of drugs and immune cells in tumors, compromise their efficacy
aftertheyaccrueintumors,and,independentofthese,facilitatetumorprogression.
Furthermore the lack of functional lymphatic vessels within tumors coupled with
the leaky nature of tumor vessels contributes to elevated hydrostatic pressure in
thetumormicroenvironment,whichreducesconvectivedeliveryofmacromolecules
in tumors, leads to tumor-associated edema, and facilitates blood and lymphatic
metastases.
Despitethesechallenges,macromoleculartherapeuticsofferseveraladvantages
over conventional low molecular therapeutics. Since the size of “pores” in normal
vessels,ingeneral,issmallerthanthatinmosttumorvessels,toxicityissignificantly
reduced. This permits the use of larger doses of these agents without causing the
sameleveloftoxicity.Ofcourse,someregionsoftumorvesselsalsohaverelatively
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viii Foreword
low permeability – and thus may not permit extravasation of large-sized agents.
Someoftheseproblemshavealreadybeenovercomebyusingmacromoleculesthat
target tumor-associated antigens. For example, trastuzumab – an antibody against
Her2/neuantigen,overexpressedinaboutone-fourthtoone-thirdofbreastcancer–
has led to a significant improvement in both progression free and overall survival
in these patients. However, the patients receiving trastuzumab invariably succumb
to brain metastases, presumably due to the inability of this antibody to cross the
blood–brain barrier. It seems that the patients who receive other macromolecular
therapeuticsarelikelytomeetasimilarfate–makingbrainmetastasesasthenext
frontierofcancertreatment.Inthemeantime,theseagentshaveimprovedsurvival
insomepatientsandprovidedhopeforpreviouslyincurablemalignancies.
Once a molecule has extravasated from tumor vessels, it must cross the inter-
stitialmatrix.Largerthemoleculeslowerisitsdiffusioninthetumorinterstitium.
Several clever approaches have been developed to overcome this limited penetra-
tion.Forexample,onceamacromolecularagentornanoparticlehasextravasated,it
canbedesignedtoreleaseitslowmolecularweightcargo–byexploitinganenzyme
inthetumormicroenvironment.Alternatively,thetumorvasculatureitselfcouldbe
targeted by these agents – so these agents do not have to penetrate into the tumor
interstitium.Thisrationalepropelledthedevelopmentofantibodiesagainstvascu-
larendothelialgrowthfactor(VEGF)andotherangiogenicmolecules.Indeedthese
agentshavechangedthepracticeofoncologyforanumberofmetastaticdiseases,
including colorectal, lung, and breast cancers. Unfortunately, the tumors switch
to other angiogenic pathways not targeted by these agents – limiting the survival
benefitfromtheseverycostlyagentstoweeksandmonths.
As we begin to understand the molecular and cellular mechanisms underlying
these physiological barriers to delivery and drug resistance, we are likely to wit-
nessdevelopmentofnovelstrategiesthatovercomethesebarriersandthusimprove
delivery and efficacy of macromolecular therapeutics. One emerging strategy is to
exploit oligonucleotides, aptamers, or siRNA that interact with specific proteins
on/in cancer or stromal cells in a tumor. The present monograph offers principles
andconcreteexamples–providedbytheleadersinthisfield–onhowtoproceedin
thisnewterritory.
GeneralReferences
1. JainRK(1994)Barrierstodrugdeliveryinsolidtumors.SciAm271:58–65
2. Jain RK, Munn LL, Fukumura D (2002) Dissecting tumor pathophysiology using intravital
microscopy.NatRevCancer2:266–276
3. BrownE,etal.(2003)Dynamicimagingofcollagenanditsmodulationintumorsinvivousing
secondharmonicgeneration.NatMed9:796–801
4. Jain RK (2005) Normalization of the tumor vasculature: an emerging concept in anti-
angiogenictherapyofcancer.Science307:58–62
5. JainRK(2008)Tamingvesselstotreatcancer.SciAm298:56–63
Boston,MA RakeshK.Jain
Preface
Cancertherapyhasbeenamajorchallengesincemostofthemedicinescurrentlyon
themarketdisplaylimitedefficacyand/orsignificanttoxicity.Evenifnewmolecules
arediscoveredtotreatcancerdiseases,theclinicaluseandefficacyofconventional
chemotherapeuticsare,indeed,hamperedbydrugresistanceatthetumorleveldue
tophysiologicalbarriers(noncellular-basedmechanisms),drugresistanceatthecel-
lular level (cellular mechanisms), and by non-specific distribution as well as by
biotransformation and clearance of anticancer drugs in the body. In other words,
conventionalchemotherapeuticsisoftenlimitedtoinadequatedeliveryoftherapeu-
tic concentrations to the tumor target tissue or cells. It is therefore of importance
todevelopnewapproachesforsaferandmoreefficientdeliveryofanticancercom-
poundstotumorsbothatthecellandtissuelevel,therebyimprovingthetherapeutic
indexofthesemedicines.
In this context, “macromolecular therapeutics” represents, behind the conven-
tionalsmallchemicalentities,asecondgenerationofanticancercompoundsholding
enormous promise and making use of smart approaches to fight cancer. Design
anddevelopmentofmacromolecularanticancertherapeuticshaveassembledinter-
disciplinary efforts from scientists belonging to various fields like biochemistry,
immunology, cell biology, chemistry, bioengineering, pharmaceutics, pharmacol-
ogy,andoncology.Macromolecularanticancertherapeuticsrepresentsasignificant
volume of research in the recent years so that a large number of macromolecular
therapeutic substances are already in the market or are currently in clinical trials
orinpre-clinicalstage,demonstratingactivityagainstnumerousexperimentalcan-
cer models. Thus, the therapeutic index of various anticancer substances may be
increasedbylinkagewithmacromoleculesofdifferentnature(i.e.,proteins,lipids)
in order to improve pharmacokinetic and biodistribution. Other anticancer macro-
moleculesareactiveperse:bymimickingMotherNature,theyareabletorecognize
cancer targets in a highly specific manner (i.e., antibodies or oligonucleotides). It
isoutofquestionthatmacromolecularanticancertherapeuticspossessesimproved
specificity toward cancer tissues whereas in certain circumstances they also can
overcome resistance which, as stated before, is an important drawback associated
with many of the conventional currently available anticancer substances. Thus,
macromolecularanticancertherapeuticsopensnewprospectsinthecurrenttherapy
ofcancer.
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x Preface
This book will describe in great detail the possible ways to improve cancer
treatmentbyusingthesemacromolecular-basedtherapieswhichare
(1) by the selective delivery of small molecule drugs to tumors; this is the major
challenge in efficient and safe cancer therapy. The capability of macromolec-
ular substances such as polymers and lipids to alter the fate of conjugated
small molecule drugs in the biological environment has prompted the devel-
opment of macromolecular prodrugs. Thus, a variety of such macromolecular
entitieshavesuccessfullyimprovedthebiologicalfateoftheconjugatedsmall
molecules and positively contributed toward improvement of efficacy in the
treatmentofdrug-sensitiveanddrug-resistanttumors,simultaneouslylowering
theassociatedtoxicity;
(2) by the employment of tumor-specific antibodies, tumors can be targeted with
highmolecularrecognitionandefficienttherapycanbeassured;
(3) byusingsyntheticfragmentsofDNAorRNA(i.e.,antisenseoligonucleotides,
aptamers,orsmallinterferingRNA),itispossibletoinhibitoncogeneexpres-
sion.
Practicallyandinordertodiscussthesevarioustherapeuticstrategies,thisbook
containing17chaptersisdividedinto6parts.
InPartI,theanticancerdrugshavebeenclassified,andthevarioussignaltrans-
duction pathways involved in the cancer growth and resistance to therapy are
discussed. Different classes of anticancer therapeutics either in preclinical or in
clinicalphaseshavealsobeenelaborated.
Parts II and III describe the different categories of macromolecular therapeu-
ticsofpolymerandlipidorigin,respectively,designedtoimprovetheaccumulation
of anticancer agents into tumors by virtue of their physicochemical and pharma-
cokineticproperties.Designanddevelopment,opportunitiesandchallenges,current
status, and preclinical and clinical progress of these macromolecular prodrugs are
detailed.
Part IV discusses the antibody-mediated drug targeting to cancer employ-
ingantibody–drugconjugates,radioimmunoconjugates,toxin–antibodyconjugates,
antibody-mediated enzyme prodrug therapeutics, and using also antibodies them-
selvestointerferewithspecificmoleculartargetsresponsiblefortumorgrowthand
progression. This part principally deals with the design, the development, the pre-
clinicalandclinicalstatus,aswellasthechallengesinvolvedincancertherapyusing
variouscategoriesofantibody-basedtherapeutics.
PartVreferstoavarietyoftherapeuticanticanceroligonucleotidesdesignedand
developed for specific inhibition of oncogenes. Their efficacy is discussed both at
thepre-clinicalandclinicalstate.
Part VI primarily deals with the molecular therapeutic interventions in breast
cancertreatment.
On the whole, this book assembles all the major areas related to the use of
macromolecular strategies for cancer therapy and it discusses the “past, present,
and future” of these pharmacological approaches. This book is expected to serve
Preface xi
asanessentialreferencetoabroadscientificcommunityincludingchemists,biolo-
gists,biomedicalscientists,pharmacologistsandpharmaceuticaltechnologists,and
oncologists.
Wewouldliketothankfirstofall,allthecontributorstothisbookfortheircom-
prehensive contributions, and Prof. Rakesh K. Jain at Harvard Medical School &
Massachusetts General Hospital for the contribution of foreword for this book.
L. Harivardhan Reddy is grateful to his parents Sri. L. Sudhakar Reddy and Smt
L. Hampamma for their moral support, and thankful to his wife (Haritha) for her
constantencouragementforsuccessfulcompletionofthisbook.PatrickCouvreuris
thankfultohiswife(Cecile)andhischildrenCatherine,Marie,andNicolasfortheir
loveandaffectionandmoralsupport.
Finally, we would like to extend our special thanks to the team at Springer
Sciencewhoprovidedanopportunity,help,andsupportformakingtheideaofthis
bookintoreality.
Châtenay-Malabry,France;Vitry-sur-Seine,France L.HarivardhanReddy
Châtenay-Malabry,France PatrickCouvreur
