David L.Andrews、Zeev Valentine Vardeny、Duncan H.Gregory、Thomas Nann
目錄：
2.01 纳米颗粒用于光动力学治疗
2.01.1 Introduction
2.01.1.1 Photodynamic Therapy
2.01.1.2 History of PDT
2.01.1.3 Mechanisms of Photodetection and Photodynamic Action
2.01.1.4 PDT Effect In Vitro
2.01.1.5 PDT Effect on Tumor Ablation
2.01.1.6 Molecular Photosensitizers for PDT
2.01.1.7 Challenges in PDT
2.01.1.8 NP Delivery Platforms Developed for PDT
2.01.1.9 Photodetection and Diagnosis of Diseases
2.01.2 Targeting NPs for PDT
2.01.2.1 Passive Targeting:EPR Effect
2.01.2.2 Active Targeting
2.01.3 NPs for PDT Treatment
2.01.3.1 Polymer-Based NPs
2.01.3.1.1 Polymeric NPs
2.01.3.1.2 Polymer-photosensitizer conjugates
2.01.3.2 Polymeric Micelles
2.01.3.3 Liposomes
2.01.3.4 Dendrimers
2.01.3.5 Ceramic NPs
2.01.3.6 Gold NPs
2.01.3.7 Quantum Dots
2.01.3.8 Magnetic NPs
2.01.3.9 Other Types of NPs in Use for PDT
2.01.4 Pharmacokinetics and the Issue of NP Safety in PDT
2.01.5 Light Sources for PDT
2.01.6 Summary
References
2.02 光合成捕光复合物中的能量转移:从光谱学到定量研究模型
2.02.1 Introduction
2.02.2 Structure and Exciton Spectra of LH1LH2 Bacterial Antenna
2.02.3 Equilibration Dynamics in LH1 and B850-LH2
2.02.3.1 Exciton Relaxation Dynamics
2.02.3.2 Interplay of Excitonic and Vibrational Coherences
2.02.4 Variety of Excitation Dynamics in B850-LH2 Revealed by Single-Molecule Spectra
2.02.4.1 Conformational Disorder and Spectral Fluctuations
2.02.4.2 Conformational Disorder and Excitation Dynamics
2.02.4.3 Multistate Model for Conformational Switching
2.02.5 Competition of Intraband B800-B800 and Interband B800-B850 Energy Transfer in LH2
2.02.5.1 Excitation-Wavelength-Dependent Decay of B800 Band
2.02.5.2 B800-B800 and B800-B850 Transfers:Modeling of Polarized TA
2.02.5.3 B800-B800 and B800-B820850 Transfers:2D PE Studies
2.02.6 How Energy Flows in the Major Light-Harvesting Complex II of Higher Plants:Connecting Spectroscopy with the 2.72? Crystal Structure
2.02.6.1 The Origin of the Steady-State and TA Spectra
2.02.6.2 Energy Transfer within Monomeric Subunit
2.02.6.3 Intra-and Intermonomeric Transfers:Comparing the Redfield and the F? rster Approaches
2.02.6.4 Energy Equilibration between Monomeric Subunits
2.02.6.5 Comparing the Exciton Model and Single-Molecule Spectra
2.02.6.6 Nonphotochemical Quenching of Excitations
2.02.7 Summary and Outlook
References
2.03 光子纳米颗粒用于细胞和组织标记
2.03.1 Introduction
2.03.2 Background
2.03.2.1 Surface Functionalization
2.03.2.2 Enhanced Optical Properties
2.03.3 Fluorescent Semiconductor QDs
2.03.3.1 Background
2.03.3.2 Surface Functionalization
2.03.3.3 In Vitro Assays
2.03.3.4 In Vivo Assays
2.03.3.5 Toxicity
2.03.3.5.1 In vitro toxicity
2.03.3.5.2 In vivo toxicity
2.03.4 Plasmonic Noble Metal NPs
2.03.4.1 Introduction
2.03.4.2 Surface Plasmons
2.03.4.3 Tuning Metal NP Surface Plasmon Properties
2.03.4.4 Surface-Enhanced Raman Spectroscopy
2.03.4.4.1 Potential advantages of SERS as an imaging modality
2.03.4.5 Surface Modification and Functionalization
2.03.4.6 In Vitro Studies
2.03.4.6.1 Dark-field microscopy
2.03.4.6.2 Sers
2.03.4.7 In Vivo Studies
2.03.4.7.1 Optical coherence tomography
2.03.4.7.2 In vivo SERS
2.03.4.7.3 Photoacoustic imaging
2.03.4.8 Toxicity
2.03.4.8.1 In vitro study
2.03.4.8.2 In vivo study
2.03.5 Conclusions and Future Perspectives
References
2.04 DNA偶联的纳米颗粒在生物分析中的应用
2.04.1 Introduction
2.04.2 Nanomaterials
2.04.3 Nucleic Acid Probes
2.04.4 Silica NPs
2.04.4.1 Synthesis of Fluorescent Silica NPs
2.04.4.2 Surface Functionalization of Silica NPs
2.04.4.3 DNA-Conjugated Silica NPs for Bioanalysis Applications
2.04.4.3.1 Dye-doped silica NPs for nucleic acid analysis
2.04.4.3.2 Dye-doped silica NPs for DNA microarray detection
2.04.4.3.3 Silica NP-aptamer conjugates for signal amplification in cancer cell detection
2.04.5 Magnetic Nanoparticles
2.04.5.1 Preparation of MNPs
2.04.5.2 DNA Surface Functionalization of MNPs
2.04.5.3 MNPs for Bioanalysis Applications
2.04.5.3.1 Magnetic nanocapturers for trace amount mRNA collection
2.04.5.3.2 Aptamer-conjugated MNPs and fluorescent silica NPs for selective collection and detection of cancer cells
2.04.6 Gold NPs
2.04.6.1 Preparation of Gold NPs
2.04.6.2 Functionalization of Gold NPs with Thiol-Modifier DNA
2.04.6.3 Bioapplications of Gold NPs
2.04.6.3.1 Gold NP-based colorimetric assay for direct detection of cancerous cells
2.04.6.3.2 DNA-conjugated nanodevice for reliable genotyping
2.04.6.3.3 Gold-DNA nanoconjugates for gel electrophoresis
2.04.6.3.4 Summary
2.04.7 Nanorods
2.04.7.1 Synthesis of Au NR Seeds
2.04.7.2 Synthesis of Au-Ag NRs
2.04.7.3 Gold NRs of Varying Aspect Ratios
2.04.7.4 Functionalization of Au-Ag NRs
2.04.7.5 Cancer Cell Targeting Using Multiple Aptamers Conjugated on NRs
2.04.7.6 Selective Photothermal Therapy for Mixed Cancer Cells Using Aptamer-Conjugated NRs
2.04.8 Carbon Nanotubes
2.04.8.1 Carbon Nanotube-Quenched Fluorescent Oligonucleotide:Probes That Fluoresce upon Hybridization
2.04.8.2 Regulation of Singlet-Oxygen Generation Using SWNTs
2.04.8.3 Carbon Nanotubes Protect DNA Strands during Cellular Delivery
2.04.9 Conclusion and Future Perspective
References
2.05 福斯特共振能量转移
2.05.1 Introduction
2.05.2 Basic Concepts in Fluorescence and FRET
2.05.2.1 Basic Concepts in Fluorescence
2.05.2.2 F?rster Theory and Experimental Tests-An Overview
2.05.2.3 Photophysical Determinants of FRET
2.05.3 Selected FRET Applications and Variants
2.05.3.1 FRET as a Tool for Studying Biological Folding
2.05.3.2 Multidistance FRET for Structure Determination of Multicomponent Complexes
2.05.3.3 FRET Applications in Synthetic Nanotechnology
2.05.3.4 FRET and VariationsTwo-Photon,Bioluminescence Resonance Energy Transferin Studies of Cells or Whole Organisms
2.05.4 Single-Molecule FRET
2.05.4.1 SmFRET Introduction
2.05.4.2 Early smFRET Observations
2.05.4.3 SmFRET to Probe Conformational Dynamics for Immobilized Molecules
2.05.4.4 SmFRET of Diffusing Molecules-Subpopulations,Distance Distributions,and Conformational Dynamics
2.05.4.5 Particle Tracking and smFRET in Cells
2.05.4.6 Advanced Techniques
2.05.4.6.1 Multiparameter fluorescence,advanced analysis,and multiplexed excitation
2.05.4.6.2 Combination of smFRET with other techniques
2.05.4.6.3 FRET and fluorescence nanoscopy
2.05.4.7 Concluding Remarks
References
2.06 蛋白质纳米颗粒化学及材料研究
2.06.1 Introduction
2.06.2 Structure and Properties
2.06.2.1 Virus
2.06.2.1.1 Rod-like virus
2.06.2.1.2 Spherical virus
2.06.2.2 Ferritin
2.06.2.3 Heat Shock Protein
2.06.2.4 Enzyme Complexes and Other Protein Nanoparticles
2.06.3 Modification
2.06.3.1 Genetic Modification
2.06.3.2 Chemical Modification
2.06.4 Template Synthesis of Composite Materials
2.06.5 Self-Assembly of Protein Nanoparticles
2.06.5.1 Interfacial Self-Assembly
2.06.5.2 TMV Head-to-Tail Assembly
2.06.5.3 Layer-by-Layer Assembly
2.06.5.4 Convective Alignment
2.06.5.5 Other Assembly Techniques
2.06.6 Outlook
References
2.07 组织工程
2.07.1 Introduction
2.07.2 Tissue Engineering
2.07.2.1 Basic Principles
2.07.2.2 Cells
2.07.2.2.1 Autologous,allogeneic,and xenogeneic cells
2.07.2.2.2 Tissue-specific and progenitor cells
2.07.2.2.3 Stem cells
2.07.2.2.4 Primary cells versus cell lines
2.07.2.3 Scaffolds
2.07.2.3.1 Physical properties
2.07.2.3.2 Biological properties
2.07.2.3.3 Fibrous scaffolds,porous scaffolds,and hydrogels
2.07.2.3.4 Chemical composition of scaffolds:Natural and synthetic
2.07.2.3.5 Scaffold fabrication
2.07.2.4 Bioreactors
2.07.2.4.1 Static bioreactor
2.07.2.4.2 Rotary bioreactor
2.07.2.4.3 Perfusion bioreactor
2.07.2.4.4 Electrical-stimuli bioreactor
2.07.2.4.5 Mechanical-stimuli bioreactor
2.07.2.5 Examples of In Vitro Tissue Engineering
2.07.2.5.1 Example 1:The standard tissue-engineering paradigm used for muscle tissue
2.07.2.5.2 Example 2:The importance of functional tissue engineering for tendon tissue
2.07.2.5.3 Example 3:Importance of growth factors and cell-free tissue engineering for bone tissue
2.07.2.5.4 Example 4:Scaffold-free tissue engineering and ectopic implantation for hepatic tissue
2.07.2.5.5 Example 5:In vitro substitutes for in vivo microenvironment for follicle tissue
2.07.2.5.6 Example 6:Appreciating the complexity of the body in neural tissue
2.07.3 Successful Clinical Applications of Tissue Engineering
2.07.3.1 Trachea
2.07.3.2 Bladder
2.07.3.3 Cartilage
2.07.3.4 Blood Vessel
2.07.3.5 Heart Valve
2.07.3.6 Skin
2.07.4 Case Study:Cardiac-Tissue Engineering
2.07.4.1 The Tissue-Engineering Paradigm:Cell,Scaffold,and Bioreactor Approach
2.07.4.2 Hydrogel Encapsulation and Mechanical Stimulation
2.07.4.3 Matrix-Free Approaches
2.07.4.4 Repair of Infarcted Myocardium Using Engineered Cardiac Tissue
2.07.4.5 Challenges and Future Studies
2.07.5 Summary
References
2.08 水凝胶生物仿生膜
2.08.1 Overview
2.08.2 Artificial Lipid Bilayer Membranes
2.08.2.1 Phospholipids for Engineered Biomimetic Membranes
2.08.2.2 Lipid Bilayer Formation by PaintingMueller-Rudin Method
2.08.2.3 Monolayer Folding MethodMontal-Mueller Method
2.08.2.4 Shortcomings of Artificial Bilayer Technologies
2.08.3 Engineering Biomimetic Membranes with Hydrogels
2.08.3.1 Early Work with Hydrogels
2.08.3.2 In Situ Hydrogel Encapsulation of Lipid Bilayers
2.08.3.3 Hydrogel-Conjugated Membranes
2.08.3.4 Other Biomimetic Membranes Using Hydrogels
2.08.3.5 Applications Using Hydrogel-Supported Membranes
2.08.4 Outlook
References
2.09 蛋白质纳米力学
2.09.1 Introduction
2.09.2 Mechanical UnfoldingFolding of Proteins
2.09.3 Pioneering Work in Single-Molecule Force Spectroscopy on Proteins
2.09.4 Polyprotein Engineering Techniques
2.09.4.1 Necessity and Advantages of the Polyprotein Approach
2.09.4.2 Methodologies for the Construction of Polyproteins
2.09.4.3 Special Considerations
2.09.5 Operation Modes of Single-Molecule Force Spectroscopy
2.09.5.1 Constant Velocity Single-Molecule Force Spectroscopy
2.09.5.2 Force-Clamp Single-Molecule AFM
2.09.6 Folding Studies via Single-Molecule AFM
2.09.7 Mechanical Stability of Proteins
2.09.7.1 Mechanical Stability versus Thermodynamic Stability and Kinetic Stability
2.09.7.2 Pulling Directions Affect the Mechanical Stability of Proteins:Mechanical Stability is an Anisotropic Property
2.09.8 Toolbox of Elastomeric Proteins:From Naturally Occurring Elastomeric Proteins to Nonmechanical Protein-Based Artificial Elastomeric Proteins
2.09.9 Case Studies
2.09.9.1 Mechanical Protein I27:A Paradigm in Single-Protein Mechanics
2.09.9.2 Nonmechanical Protein GB1:An Ideal Candidate for Constructing Artificial Elastomeric Proteins
2.09.9.3 Mechanical Protein I27 and Nonmechanical Protein GB1:A Comparison
2.09.10 Molecular Determinants of Mechanical Stability of Proteins
2.09.10.1 Topology Plays Important Roles in Determining the Mechanical Stability of a Given Protein
2.09.10.2 Mutations in the Key Regions of Proteins Can Alter the Mechanical Stability
2.09.10.3 Ligand Binding Can Influence the Mechanical Stability of Proteins
2.09.10.4 Environmental Factors Can Affect the Mechanical Stability of Proteins
2.09.11 From Single Protein to Protein Complexes and Tissues:Bridging the Gap between Single-Protein Mechanics and Tissue Mechanics
2.09.12 Conclusion
References
2.10 扫描近场光学显微镜在生物成像中的应用
2.10.1 Introduction
2.10.2 Methodology
2.10.3 Biological Imaging
2.10.3.1 Fluorescence-Based NSOMApertured Approach
2.10.3.1.1 Lipids and lipid rafts
2.10.3.1.2 Cell-surface receptors
2.10.3.1.3 Amyloid fibrils
2.10.3.2 Apertureless Near-Field Imaging
2.10.3.2.1 Signal derivation
2.10.3.2.2 Amyloid fibrils
2.10.3.2.3 DNA
2.10.3.2.4 Viruses
2.10.3.2.5 Proteins at cell surface
2.10.3.2.6 Neurons
2.10.3.2.7 Cell-Biomaterial interface
2.10.3.2.8 Photothermal NSOM
2.10.4 Artifact-Free Near-Field Signal
2.10.5 Conclusions
References
2.11 单分子和纳米技术在生物信号中的应用
2.11.1 Proteins and Cells from a Nanomaterials Perspective
2.11.1.1 Proteins as Nanomaterials
2.11.1.2 Robustness of Proteins against Mutation
2.11.1.3 Cells as Nanostructured Materials
2.11.1.4 Biological Signal Transduction
2.11.2 Single-Molecule Studies of Conformational Dynamics and Protein-Protein Interactions in Signaling
2.11.2.1 Introduction to Single-Molecule Force Spectroscopy
2.11.2.2 Single-Molecule Force Spectroscopy of Photoactive Yellow Protein:Anisotropy and Functional Conformational Changes
2.11.2.2.1 Introduction to PYP
2.11.2.2.2 Force spectroscopy of conformational changes during PYP signaling
2.11.2.2.3 Force spectroscopy of anisotropy in the structural stability of PYP
2.11.2.3 Single-Molecule Force Spectroscopy of the Transmembrane Signaling Complex of Sensory Rhodopsin II
2.11.2.3.1 Introduction to SR
2.11.2.3.2 Force spectroscopy of a transmembrane signaling complex
2.11.2.3.3 Conclusions and general implications for the use of single-molecule force spectroscopy in studying the structural and functional properties of proteins
2.11.3 Fluorescence Resonance Energy Transfer and Fluorescence Correlation Spectroscopy Approaches of In Vivo Signaling
2.11.3.1 Introduction to FRET and FCS
2.11.3.2 Using FRET to Probe Protein-Protein Interactions in Chemotactic E. coli Cells
2.11.3.2.1 Introduction to chemotaxis signaling in E. coli
2.11.3.2.2 Probing in vivo chemotactic signaling in E. coli by FRET
2.11.3.3 FCS Approaches to Biological Signaling
2.11.3.3.1 Using FCS to measure the concentration of signaling proteins in a single cell
2.11.3.3.2 Correlating signaling protein concentration and responses of a single cell
2.11.3.3.3 Conclusions and general implications for signal transduction
2.11.3.4 Consequences of Thermal Noise for Biological Signaling
2.11.3.4.1 Robustness of cellular behavior against thermal noise
2.11.3.4.2 Molecular noise as a key element in chemotactic signaling
2.11.3.4.3 Exploiting thermal noise for biological signaling:Competence in Bacillus subtilis
2.11.3.4.4 Conclusions and general implications on the role of noise in biological signaling
2.11.4 Subcellular Nanoscale Protein Clusters in Biological Signaling
2.11.4.1 The Cytoplasm and Cytoskeleton of Bacteria
2.11.4.2 Nanoclusters for Signaling in Bacterial Chemotaxis
2.11.4.2.1 Nanoscale protein clusters in E. coli chemotaxis
2.11.4.2.2 Introduction to chemotaxis in Rb. sphaeroides
2.11.4.2.3 Nanoscale complexes of signaling proteins in Rb. sphaeroides
2.11.4.3 Conclusions and Implications of Nanoscale Protein Clusters for Biological Signaling
References
2.12 太阳能转换:从自然到人工
2.12.1 Nature''s Way
2.12.1.1 Construction of Light-Harvesting and Energy-Converting Pigment Systems of Photosynthesis
2.12.1.2 Need for a Light-Harvesting Antenna
2.12.1.3 Spectral Coverage
2.12.1.4 Efficient Energy Flow through the Light-Harvesting Antenna Systems
2.12.1.5 Intracomplex Energy Transfer
2.12.1.6 Delocalized Excitons in Photosynthetic Light Harvesting
2.12.1.7 Efficient Antenna-RC Coupling:Long-Distance Energy Transfer versus Short-Distance Charge Transfer
2.12.1.8 Carotenoid Molecules in Photosynthesis-Their Spectroscopy
2.12.1.9 Light Harvesting by Carotenoid Molecules
2.12.1.10 Protection of the Photosynthetic Machinery-Quenching of Chlorophyll Excited States by Carotenoids
2.12.1.11 Storing the Energy of Light-Photosynthetic Charge Separation
2.12.2 The Artificial Way
2.12.2.1 Nanostructured Materials for Solar Electricity
2.12.2.2 Nanostructured Dye-Sensitized Metal Oxides of Gr?tzel Solar Cells
2.12.2.3 Electron Injection from Sensitizer to Semiconductor in DSCs
2.12.2.4 Charge Recombination and Transport in Dye-Sensitized Semiconductor Materials
2.12.2.5 Dye-Semiconductor Binding from Recombination Dynamics in Dye-Sensitized Materials
2.12.2.6 Recombination and DSC Performance
2.12.2.7 Charge Transport in Dye-Sensitized Nanostructured Semiconductor Films
2.12.2.8 Plastic Solar Cells Based on the BHJ Concept
2.12.2.8.1 Charge generation and recombination
2.12.2.8.2 Relation of BHJ photophysics to solar cell function
References
內容試閱：
2.01 Nanoparticles for Photodynamic Therapy
Y Cheng and C Burda, Case Western Reserve University, Cleveland, OH, USA a 2011 Elsevier B.V. All rights reserved.
2.01.1Introduction12.01.1.1PhotodynamicTherapy12.01.1.2HistoryofPDT12.01.1.3MechanismsofPhotodetectionandPhotodynamicAction22.01.1.4PDTEffectInVitro32.01.1.5PDTEffectonTumorAblation42.01.1.6MolecularPhotosensitizersforPDT42.01.1.7ChallengesinPDT62.01.1.8NPDeliveryPlatformsDevelopedforPDT62.01.1.9PhotodetectionandDiagnosisofDiseases72.01.2TargetingNPsforPDT72.01.2.1PassiveTargeting:EPREffect72.01.2.2ActiveTargeting72.01.3NPsforPDTTreatment72.01.3.1Polymer-BasedNPs92.01.3.1.1PolymericNPs92.01.3.1.2Polymer?photosensitizerconjugates102.01.3.2PolymericMicelles112.01.3.3Liposomes122.01.3.4Dendrimers142.01.3.5CeramicNPs142.01.3.6GoldNPs162.01.3.7QuantumDots172.01.3.8MagneticNPs182.01.3.9OtherTypesofNPsinUseforPDT192.01.4PharmacokineticsandtheIssueofNPSafetyinPDT212.01.5LightSourcesforPDT222.01.6Summary23References23
2.01.1 Introduction
2.01.1.1 Photodynamic Therapy
PhotodynamictherapyPDTisahighlyselectivetreatmentmodalitywherebyonlythelight-irradiatedareascontainingaphotosensitizerandsufficientamountsofoxygencanbeaffected,andthephotosen-sitizerideallyisnontoxicintheabsenceoflight[1,2].Asaminimallyinvasivetherapy,PDThasbeencon-sideredasanoveltreatmentforavarietyofcancersincludingprostate,brain,pancreatic,breast,andskincancer[2].Moreover,thistreatmenthasbeenexpandedtononcancerousdiseases,suchasage-relatedmaculardegenerationAMD,periodontaldiseases,coronaryheartdisease,andmicrobialinfections[3?6].
2.01.1.2 History of PDT
Theoriginsofphotoactivatedtherapycanbetracedbackfromantiquitytothemodernday[7].LightwasemployedinthetreatmentofdiseasesbytheearlyGreeks,Egyptians,andIndians,butthispracticedis-appearedforcenturiesandwasonlyrediscoveredagainbyWesternculturesattheturnofthetwentiethcentury[8,9].TheworkoftheDanishphysicianNielsFinsen,whousedlightforthetreatmentofvariousmedicalconditions,resultedinfurtheringthedevelopmentofphototherapyinmoderntimes[10].In1903,hewasawardedtheNobelprizefollowinghisworkonthedevelopmentofcarbonarcphototherapyforthetreatmentofcutaneous
2 Nanoparticles for Photodynamic Therapy
tuberculosis.TheuseoflightincombinationwithchemicalstoinducecelldeathwasfirstreportedbyOscarRaabin1900,whileconductinghismedicalresearchunderthedirectionofProf.HermanvonTappeinerinMunich,Germany[11].DuringthecourseofRaab’sstudyontheeffectsofacridineonmalaria-causingprotozoa,hediscoveredthelethaleffectofthecombinationoflightandacridineredonthedisease-causingparamecium.Raabdiscoveredthatitwasnotthelightbutrathersomeproductofthefluorescencethatinducedtheobservedinvitrotoxicity.Hepostulatedthatthiseffectwascausedbythetransferofenergyfromthelighttothereagent.Shortlyafterthisdiscovery,vonTappeinerdemon-stratedthefirstmedicalapplicationoftheinteractionbetweenafluorescentcompoundandlight[12].Usingthecombinationoftopicaleosinandwhitelight,theywereabletodemonstratethetreatmentofskintumorsusingthistherapeuticmethod.Followingthiswork,vonTappeinertogetherwithJodlbauerwentontodemonstratetherequirementofoxygeninthephotosensitizationreactions[13],and,in1907,theyintroducedtheterm‘photodynamicaction’[14]thatgavebirthtothemodern-daytherapeuticmethodofPDT.
Sinceitsdiscovery,PDThasdevelopedintoanemergingcancertreatmentthathasgrownintoaFoodandDrugAdministrationFDA-approvedtherapyfordifferentmalignancies[1,15?19]andhasdemonstratedpotentialinthetreatmentofotherail-mentsanddiseasessuchascoronaryheartdisease,acquiredimmunodeficiencysyndromeAIDS,andpsoriasis[20,21].Thegrowingpopularityofthistherapeuticmethodcanbeattributedtoitshighlyselectivenatureoferadicatingdiseasedtissues,whichisbasedonthelocalizedgenerationofcytotoxicsingletoxygen,followingtheactivationofanontoxicphotosensitizerwithlight[22].Overthepastyears,muchefforthasbeendevotedtowardthedevelop-mentofPDTagents,whichhavespecificlightabsorptionandtissuedistributionproperties.Afirst-generationphotosensitizerthathasbeenacceptedforclinicaluseisthehematoporphyrinderivative,Photofrin[23].TheclinicalsuccessofPhotofrinhasinspiredthedevelopmentofnewPDTphotosensiti-zers,whichcouldofferimprovementinopticalandchemicalproperties.Amongthemorepromisingsecond-generationphotosensitizersthatarecurrentlybeingevaluatedforPDTapplicationsarethephtha-locyaninesPc’s[19,24].Pcderivativeshavefavorablephotophysicalandchemicalproperties,whichincludestrongabsorbanceatlongwavelengthsandchemicaltunabilitythroughsubstituentadditionontheperipheryofthemacrocycleorontheaxialligands[19,22].However,likemostphotosensitizingagentsandcancerdrugsingeneral,Pc’shavelowsolubilityinwaterandtendtoaggregateinaqueoussolutions,whichcanresultinthelossofphotoche-micalactivityandaffecttheircell-targetingproperties[22,25].Inordertoresolvesuchissues,nanoparticleNPconjugatesarecurrentlybeingexploredaspotentialthird-generationPDTphoto-sensitizers,ordirectlyasPDTagents.OnenovelalternativeistoconjugategoldnanoparticlesAuNPstoPcphotosensitizerstofacilitatethedevelop-mentofanamphiphilicPDTsystem,whichhasshownhighefficiency[26,27].Similarly,silica-basedNPswererecentlydevelopedtoentrapwater-insolublephotosensitizingagentsandwereshowntobeeffectivePDTdrugcarriersinaqueousmedia[28].ThesedevelopmentsillustratethepotentialofNP-basedPDTfortherapyapplications.
NP-basedPDThassincebeendevelopingexplo-sivelyasaresearchfield,andmanyresearcherscurrentlycontributetodaytoitsfastadvancement.Whileweattempttosummarizethecurrentstateoftheart,weapologizetoeveryonewhohascontrib-utedtothefieldandisnotmentionedinthistext.
2.01.1.3 MechanismsofPhotodetectionandPhotodynamicAction
ThefirstcomponentofPDTisvisible-to?near-infra-redvis?NIRlight,whichbyitselfcanbeconsideredanontoxicreagent.Therangeoflightbetween620and850nm,thatis,theso-called‘phototherapeuticwindow’,hasmaximumtissuepermeabilityandcanpenetratetissuemorethan1cmindepth[29,30].Inthisrange,lightisminimallyabsorbedbyendogen-ousbiomoleculessuchasproteins,melanin,deoxygenatedhemoglobinHb,andoxygenatedhemoglobinHbO2Figure1[31].
Furthermore,PDTinvolvesaphotosensitizerthatinthedarkisineffective;however,whenirradiatedwithvis?NIRlight,thephotosensitizerisactivatedandcanbeusedtotreatdiseasessuchascancers.Theactivatedphotosensitizerscanundergoseveralphotophysicaltransitions.Apartoftheexcitationenergycanbereleasedintheformofphotonsfluor-escence.Theemissionwavelengthislongerthantheexcitationwavelength,whichmakesphotodetectionandmonitoringofthephotosensitizerdeliverypos-sible.TheS1excitedstatecanconverttoitstripletstateT1byintersystemcrossing.Sincethe
Nanoparticles for Photodynamic Therapy 3
Absorption coefficient, μa cm?1
106 105 104 103 102 101 100
0.1 0.3 1 3 10 Wavelength, λ μm
Figure1Opticalabsorptioncoefficientsofprincipaltissuechromophoresinthe0.1?12mmspectralregion.ReprintedfromVogelAandVenugopalanV2003Mechanismsofpulsedlaserablationofbiologicaltissues.ChemicalReviews103:577?644.
relaxationfromT1totheenergeticgroundstateS0isspin-forbidden,T1hasalongerlifetimeandcandirectlyreactwithsubstratesinproximitythroughdiffusionaldynamics.Ingeneral,twotypesofreac-tionscantakeplaceatthisstateandproducehighlyreactiveoxygenspeciesROStodamagethesub-strates[32].ThetypeIreactioninvolvesanelectronorahydrogenatomtransfertocreatefreeradicals.TheseradicalscanrapidlyinteractwithmolecularoxygentogenerateROSsuchassuperoxideanionradicalsandsuperoxideions.ThetypeIIreaction,whichisregardedasthepredominantprocessoccur-ringinPDT,involvesthedirectenergytransfertooxygen 1O2Figure2.BothtypeIandtypeIIreactionsmayoccursimultaneously.Thetypeofreactiondependsonmanyfactorssuchastheproper-tiesandlocalizationofphotosensitizers,theoxygenconcentration,substrates,lightexposuredoses,andwavelengths.
molecular oxygen to produce cytotoxic singlet
7
S1
4
T1 9
1 2 3 5 6
S0
2.01.1.4 PDT Effect In Vitro
ROSssuchas1O2canreadilyreactwithalargevarietyofbiologicalmolecules,includingunsaturatedlipids,aminoacidresiduesinproteins,andnucleicacidbasesinDNARNA[32?35].Therefore,thecellmembranesconsistingoflipids,cholesterol,and
1Σg 1Δg
3Σg
Figure2PhotoinducedphysicalandchemicalprocessesinvolvedinphotodynamictherapyPDT.Steps1?10:
1 absorption,2fluorescence,3internalconversion,4intersystemcrossing,5phosphorescence,6nonradiativeT1relaxation,7chemicalstepsbasedonelectronorhydrogentransfer,8chemicalreactionstypeI,and9energytransfer,and10chemicalreactionstypeII.ReprintedfromSzacilowskiK,MacykW,Drzewiecka-MatuszekA,BrindellM,andStochelG2005Bioinorganicphotochemistry:Frontiersandmechanisms.ChemicalReviews105:2647?2694.
4 Nanoparticles for Photodynamic Therapy
proteinsarethepotentialtargetstobedamagedbyPDT.Inaddition,thehalf-lifetimeof1O2islessthan
0.04 msandthereforehasareactionradiusoflessthan20nminbiologicalsystems[36].Theshortreactionradiusensuresthatonlythetargetedtumorcellsexposedtolightarekilledwithoutdestroyingthehealthyandunradiatedtissuenearby.Mostofthephotosensitizerslocalizeoutsideofthenuclei,whichmakethemlessphotodamagingtoDNA[37].Theapolarphotosensitizerstendtolocateinhydrophobiclocisuchasthemembranesofmitochondria,lyso-somes,endosomes,Golgiapparatus,endoplasmicreticulumER,andplasmamembranesandcausephototoxicityincells[1].
Inthepresenceofphotosensitizersandoxygen,thelight-treatedcellscanbedestroyedmainlythroughapoptosis,necrosis,orthecombinationofboth[2,32].Apoptosisisaformofprogrammedcellsuicide,whichresultsinDNAandcellularfragmen-tation.Thefragmentscanbeengulfedbyneighboringcellsormacrophages.Incontrast,necro-sisisanuncontrolledcelldeathwithplasmamembranebreakageandinflammatoryresponse.Thecelldeathpathwayisdeterminedbytheintra-cellularlocalizationofthephotosensitizers,lightdoses,andmanyotherconditions.Thedifferentsub-cellularbindingsitesofphotosensitizerscancausedifferentPDTresults[38].Forinstance,mitochon-driaareoneofthemostimportanttargetsofPDT[32].Theyplayacentralroleintheapoptosispath-waybyreleasingcytochromecintothecytoplasm,whichactivatesapoptoticcaspases.Photosensitizerslocalizinginmitochondriacauserapidapoptoticcelldeathandshowthemostphototoxicitycomparedtothoseinothercellularloci[39].DamageoftheERcanalsopromotetheapoptosispathwayduetotheincreaseoffreecalciumconcentrationincells[40].Photosensitizersinplasmamembranesorlysosomescaninhibitordelaytheapoptosisprocessandstillleadtothecelldeathinotherwayse.g.,necrosis[32].Thecell-deathpathwayisalsolight-dosedependent.Atlowdosesoflight,apoptosisbecomesthepredominantpathofcelldamage,whilehighlight-dosescausenecrosis[41].OtherfactorssuchasthephotosensitizerdoseandcelltypescanaffecttheoutcomeofPDTaswell.
2.01.1.5 PDT Effect on Tumor Ablation
ThemechanismofPDTinvivoismorecomplicatedthanthatinvitro.Ingeneral,therearethreeinter-dependentmechanismsinvolvedinPDTthataffecttumors[42].First,theROSgeneratedbytheexcitedphotosensitizerscandirectlydestroythetumorcellsbyapoptosisandornecrosis[32].Itrequiresthedeliveryofphotosensitizerstothetumorsandthentheuptakebythetumorcells.Photosensitizerscanalsoefficientlytargetthetumorvasculature[1].Sincethetumorcellssurvivebyconsumingoxygenandnutrientssuppliedbytumorvessels,photodam-ageorshutdownofthevasculatureprovidesanalternativemechanismfortumordestruction[43,44].AstheendothelialcellsandthevascularbasementmembraneinthevasculatureofthetumoraredamagedbyROS,thesupplyofoxygenandnutrientsisdisturbed[45].Tumorgrowthscanthere-forebesuppressed.Athirdmechanismtokilltumorcellsistheactivatedanti-tumorimmuneresponse[42,46].Duringthecellapoptosisandornecrosis,theimmunesystemcanbestimulatedandcauseacuteinflammation.Leukocytesandlymphocytescantheninfiltratethetumorsiteagainstthetumors[42].Thesethreemechanismsinteractwitheachotherandtogetherdestroytumors.Factorssuchasthelocalizationofthephotosensitizer,PDTdrugdose,drugadministrationroute,lightdose,andthetimeintervalbetweentheadministrationandlighttreatmentcanaffectPDTefficacyinvivo[1,2].
2.01.1.6 MolecularPhotosensitizersforPDT
InPDT,photosensitizersneedtohavetheabsorptioninthevisibleorNIRregionforenergytransferandbetterpenetration[47].InordertotransfertheenergyfromthetripletstateT1totissueoxygen,theenergyofT1hastobegreaterthantheenergytoexcitethegroundstateofoxygentosingletoxygen94kJmol1[48].Varioustypesofstructureshavebeenusedforphotosensitizers.PorphyrinsthatexistinbiologicalsystemsarethemostextensivelystudiedcompoundsforPDT.Theporphyrinstructurecontainsfourpyrroleringsinterconnectedbytheir-carbonatomsviamethinebridgesTCH.Photofrin,apartiallypurifiedhematoporphyrinderivativeFigure3,wasthefirstapprovedPDTdruginclinicaluse[1].
Asafirst-generationPDTagent,ithasbeenapprovedtotreatlung,esophageal,endobronchial,cervical,gastric,andpapillarybladdercancersworld-wide[2,32,49].Thereare,however,severallimitationstothedrugthathamperitsfurtherappli-cation,suchasthepurity,weakabsorptionattheactivationwavelength630nm,poorselectivity,andprolongedskinphotosensitivity[1,49].In
Nanoparticles for Photodynamic Therapy 5
Figure 3 The structure of hematoporphyrin.
addition,theactivationlightat630nmpenetrateslessintotissuesthandoesNIRlight,whichmakesitlesssuitablefordeep-seatedtumors.
Second-generationPDTdrugswithhighpuritieshavebeendevelopedtoovercometheshortcomingsofthefirst-generationPDTdrugs.Newphotosensitizersbasedonporphyrinsandporphyrin-relatedmacro-cyclicstructurese.g.,chlorins,phythalocyanineshavebeendeveloped,suchasphotoporhyrinIXFigure4,meta-tetrahydroxyphenylchlorinm-THPCorFoscanFigure5,andsiliconphthalo-cyanine4Pc4Figure6[49].
PhotoporphyrinIXPpIX,anintermediatetohemebiosynthesis,isanendogenousphotosen-sitizerforPDT[50].Theformationofthisphotosensitizerisenhancedbyitsbiosyntheticpre-cursor,5-aminolevulinicacid5-ALA[51].5-ALAand5-ALAderivativesareapprovedforPDTtreat-mentanddiagnosisoftumors[50,52].FoscanFigure7isachlorine-basedphotosensitizerthat
Figure5Thestructureofmeta-tetrahydroxyphenylchlorin.
N
OSi
N
NN
NSi
N
NN
N
HO
Figure6Thestructureofsiliconphthalocyanine4Pc4.
H3C2N
NCH32
S
Cl
Figure 7 The structure of methylene blue MB.
isapprovedforclinicalPDTtotreatheadandneck,prostate,andpancreaticcancers.Verylowdrug0.10?0.15mgkg1 bodyweightandlightdosesaretheadvantagesofusingFoscanforPDT[53,54].Duetoitshydrophobicity,thedrugneedstobedissolvedinacombinationsolutionofpolyethyleneglycolPEGethanolwaterforclinicaluse[53,55].Inaddition,Foscanshowslong-termskinphotosensiti-zationofuptoseveralweeks[49].
Amongthesecond-generationphotosensitizers,PcderivativeshavegreatadvantagesforPDT[22].Pc’saretetraazatetrabenzoporphyrins,whichhavealargemacrocyclicelectronsystem.Comparedto
Figure 4 The structure of photoporphyrin IX.
6 Nanoparticles for Photodynamic Therapy
porphyrins,Pc’shavelongerabsorptionandahighermolarextinctioncoefficient105 M1cm 1intheNIR.Moreover,thelongerexcitationwavelengthallowsbettertissuepenetrationandcanbeusedfordeep-seatedtumors.Awell-knownexampleofthiskindofPDTagentisPc4,whichhasbeenapprovedforuseinphaseIhumanclinicaltrialsincludingcancerpatients[22,56].Similartomostphotosensiti-zers,Pc4isinsolubleinwater[22].
Afewnonporphyrin-basedphotosensitizershavealsobeeninvestigatedforPDT,forexample,methy-leneblueMB.MBiswatersolubleandhasastrongabsorptionat668nm[47].Ithasshownhighsingletoxygengenerationyieldandgoodphototoxicityinvitro.However,invivothephotosensitizercanbereducedtothecolorlessmethlyeneblue,whichdecreasesitsPDTactivity[57].
2.01.1.7 Challenges in PDT
ThereareseveralchallengesinPDT.First,mostorganicphotosensitizersarehydrophobic[25].Ononehand,thehydrophobiccharacteristicallowsthephotosensitizerstopenetratethecellmembraneandlocateinphotosensitivecellularcompartmentse.g.,membranesoftheorganelles[25,32].Ontheotherhand,thepoorwatersolubilityofthephotosensiti-zersmakesthemincompatibleforsystemicadministration.Photosensitizersarephotoactivewhentheyareinmonomericunits.However,inaqueoussolutions,especiallyunderphysiologicalconditions,thehydrophobicphotosensitizerstendtoformaggregates,whichaffectthephotophysicalpropertiese.g.,1O2generationandthephotodam-ageactivity[58].
Second,duringthejourneytotransportphotosen-sitizers,physiologicalbarriersandnonspecificuptakecanaffecttheiraccesstothetargets[59,60].Forexample,unlikemostnormaltissue,thephysiologicalpropertiesoftheinterstitiuminsolidtumorse.g.,highinterstitialfluidpressurecanresultinreduceddrugaccess[61].Photosensitizershavetoovercometheoutwardconvectionintheinterstitialspacetodiffuseintothetumorcells[61,62].
Furthermore,lowselectivityofphotosensitizerstotheirdesiredtargetsisstillamajorchallengeinPDT[63,64].AlthoughtargetingofPDTtreatmentcanbeachievedbyspecificdeliveryoflighttothetargets,thenonselectivebiodistributionofphotosen-sitizerscanaffectthePDToutcome.Thelowerthedruguptakeratioofthetumor-to-normaltissues,thehigherthedoseofphotosensitizersneedstobeescalatedinvivoinordertoobtainthedesirablePDTeffect.Moreover,thelackofselectivityofthephotosensitizerscancausesideeffectsinthehealthytissuee.g.,prolongedskinphotosensitivity.
Theselimitationscanbeovercomebyeitherexploringnewphotosensitizersorutilizingmulti-functionaldrugdeliverysystems.
2.01.1.8 NP Delivery Platforms Developed for PDT
NPswithuniquepropertiesholdgreatpromiseasphotosensitizerdeliverysystemsaswellasthecom-plementarycomponentsforPDT[58,63?66].Theycanovercomemostoftheshortcomingsofconven-tionalphotosensitizersandexpandtheapplicationofPDTaswell[66,67].AremarkablepropertyofNPsisthemodifiablesurface.Smallmolecules,peptides,orantibodiescanbeattachedtothesurfacetoachievetargetingdeliveryandincreasedspecificity.Inaddi-tion,thesizeofNPscanbeengineeredinarangefrom1to1000nm.Itiswellknownthatthenanosizedparticlescanselectivelytargettumorvasculatureviathe‘enhancedpermeabilityandretention’EPReffect[68,69].Dependingonthematerials,theshapeoftheNPscanbecontrolledfromlinearstructurestospheres.Highdrug-loadingamountscanbeobtainedbyreasonabledesignofthesizeandstructureofNPs.Photosensitizerscanbedeliveredthroughcovalentattachment,noncovalententrapment,oradsorption.Thereleaseofthephoto-sensitizerscanbeaccomplishedbydiffusion,pH,light,heat,orothermethods.PDTcanalsobeachievedwithoutreleaseofthephotosensitizersfromtheNPs.Inaddition,light-harvestingNPse.g.,two-photonabsorptionNPs[70]andupcon-vertingNPs[71]expandtheapplicableexcitationwavelengthsforPDT.SomeNPshavedualfunctionsforPDTdrugdeliverybesidesasphotosensitizers.[72,73].Forexample,quantumdotQD-basedNPswithtunableabsorptionandsizeholdpotentialasnewphotosensitizers[74].Theycantransferenergytoactivatethephotosensitizersordirectlytooxygenandgeneratesingletoxygen[75,76].
VariousPDTdrugdeliveryplatformsbasedondifferentmaterialspolymers,inorganicoxides,semi-conductors,silica,andmetalshavebeenexploredtodeliverphotosensitizerswithdifferentphysicalprop-erties[62,66,67].HydrophilicpolymersandsmallligandswithchargesareoftenusedtomaketheNPsstableinaqueoussolutionandbiocompatible.Biodegradableandnonbiodegradablepolymer-based
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