Macromolecular Anticancer Therapeutics PDF
Preview Macromolecular Anticancer Therapeutics
CANCER 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 ©SpringerScience+BusinessMedia,LLC2010 Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewritten permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Usein connectionwithanyformofinformationstorageandretrieval,electronicadaptation,computersoftware, orbysimilarordissimilarmethodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyare notidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubject toproprietaryrights. Whiletheadviceandinformationinthisbookarebelievedtobetrueandaccurateatthedateofgoing topress,neithertheauthorsnortheeditorsnorthepublishercanacceptanylegalresponsibilityforany errorsoromissionsthatmaybemade.Thepublishermakesnowarranty,expressorimplied,withrespect tothematerialcontainedherein. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) Dedicatedto Allthosesufferersofthedreadfuldiseasecancer 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 vii 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. ix 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
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