q 2006 by Taylor & Francis Group, LLC - Developers

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selectivity; (3) the ability to carry multiple therapeutic agents, enabling targeted combination therapies; and (4) the ability to bypass physiological and biological barriers. We would all like to hasten the day when chemotherapy—the administration of non-specific, toxic anti-cancer agents—is relegated to medical history. Improvements in diagnostic screening and the development of drugs that target specific biological pathways have begun to turn the tide and contribute to a slow, yet consistent decline in death rates. While confirming that early diagnosis and targeted therapies are pointing us in the right direction, the progress is still incremental. Nanotechnology may be our best hope for overcoming many of the barriers faced by today’s drugs in the battle against cancer. The combined creative forces of engineering, chemistry, physics, and biology will beget new and hopefully transformative options to old, intractable problems. q 2006 by Taylor & Francis Group, LLC Piotr Grodzinski, Ph.D. National Cancer Institute
Preface With parallel breakthroughs occurring in molecular biology and nanoscience/technology, the newly recognized research thrust on “nanomedicine” is expected to have a revolutionary impact on the future of healthcare. To advance nanotechnology research for cancer prevention, diagnosis, and treatment, the United States National Cancer Institute (NCI) established the Alliance for Nanotechnology in Cancer in September 2004 and has pledged $144.3 million in the next five years (for details, visit http://nano.cancer.gov). Among the approaches for exploiting developments in nanotechnology for cancer molecular medicine, nanoparticles offer some unique advantages as sensing, delivery, and image enhancement agents. Several varieties of nanoparticles are available, including polymeric conjugates and nanoparticles, micelles, dendrimers, liposomes, and nanoassemblies. This book focuses specifically on nanoscientific and nanotechnological strategies that are effective and promising for imaging and treatment of cancer. Among the various approaches considered, nanotechnology offers the best promise for targeted delivery of drugs and genes to the tumor site and alleviation of the side effects of chemotherapeutic agents. Multifunctional nanosystems offer tremendous opportunity for combining more than one drug or using drug and imaging agents. The expertise of world-renowned academic and industrial researchers is brought together here to provide a comprehensive treatise on this subject. The book is composed of thirty-eight chapters divided into seven sections that address the specific nanoplatforms used for imaging and delivery of therapeutic molecules. Section 1 focuses on the rationale and fundamental understanding of targeting strategies, including pharmacokinetic considerations for delivery to tumors in vivo, multifunctional nanotherapeutics, boron neutron capture therapy, and the discussion on nanotechnology characterization for cancer therapy, as well as guidance from the U.S. Food and Drug Administration on approval of nanotechnology products. Section 2 focuses on polymeric conjugates used for tumor-targeted imaging and delivery, including special consideration on the use of imaging to evaluate therapeutic efficacy. In Section 3, polymeric nanoparticle systems are discussed with emphasis on biodegradable, long-circulating nanoparticles for passive and active targeting. Section 4 focuses on polymeric micellar assemblies, where sophisticated chemistry is applied for the development of novel nanosystems that can provide efficient delivery to tumors. Many of the micellar delivery systems are undergoing clinical trials in Japan and other countries across the globe. Dendritic nanostructures used for cancer imaging and therapy are discussed in Section 5. Section 6 focuses on the oldest nanotechnology for cancer therapy—liposome-based delivery systems—with emphasis on surface modification to enhance target efficiency and temperature-responsive liposomes. Lastly, Section 7 focuses on other lipid nanosystems used for targeted delivery of cancer therapy, including nanoemulsions that can cross biological barriers, solid-lipid nanoparticles, lipoprotein nanoparticles, and DQAsomes for mitochondria-specific delivery. Words cannot adequately express my admiration and gratitude to all of the contributing authors. Each chapter is written by a world-renowned authority on the subject, and I am deeply grateful for their willingness to participate in this project. I am also extremely grateful to Dr. Piotr Grodzinski for providing the Foreword. Drs. Fredika Robertson and Mauro Ferrari have done a superb job in laying the foundation by providing a chapter entitled “Introduction and Rationale for Nanotechnology in Cancer.” I am grateful to Professor Kinam Park at Purdue University, Professor Robert Langer at MIT, and Professor Vladimir Torchilin at Northeastern University, who have been my mentors and collaborators, as well as many other researchers from academia and industry. Special thanks are due to the postdoctoral associates and graduate students in my laboratory at Northeastern University who have been the “soldiers in the trenches” in our quest to use nanotechnology for the targeted delivery of drugs and genes to solid tumors. Lastly, I am deeply q 2006 by Taylor & Francis Group, LLC
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Page 7: Foreword We are at the threshold of
Page 11: Editor Dr. Mansoor M. Amiji receive
Page 14 and 15: Robert B. Campbell Department of Ph
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38 Nanotechnology for Cancer Therap
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44 4.1 INTRODUCTION The recent deve
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46 (Gly-Phe-Leu-Gly) was developed.
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48 charged generation 5 PAMAM dendr
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50 Using a mannosylated cholesterol
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52 without any changes in the funct
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54 4.4.2.4 Folate Receptor-Mediated
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60 Targeting species Therapeutic 5.
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62 QD+NLS 70kD Dextran Merge QD+MLS
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64 (a) (b) Peptide Peptide Peptide
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66 (e.g., glycans, lipids, oligonuc
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68 layer-by-layer absorption of pol
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70 5.3 CHALLENGES IN INTEGRATING MU
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6 CONTENTS Neutron Capture Therapy
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Neutron Capture Therapy of Cancer 7
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106 7.5.1 Applicability of Standard
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108 consensus as to what measuremen
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110 a nanomaterial. AFM uses a nano
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112 In addition to size, the shape
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114 presence of all these entities
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116 concentration-dependent changes
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118 limits cellular uptake, resulti
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120 Nanotechnology for Cancer Thera
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124 been shown to cause liver injur
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128 7.5.2 IMMUNOGENICITY This issue
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8 CONTENTS Nanotechnology: Regulato
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TABLE 8.1 Nanomedicines: Drugs/Devi
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Regulatory Perspective in Nanotechn
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9 CONTENTS Polymeric Conjugates for
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Polymeric Conjugates for Angiogenes
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10 CONTENTS Poly(L-Glutamic Acid):
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Poly(L-Glutamic Acid): Efficient Ca
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202 development. For example, styre
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204 blood circulation time and pref
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206 11.3.2 MR IMAGING OF A PARAMAGN
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208 FIGURE 11.6 Coronal MR slice im
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210 strong enhancement in the heart
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216 Research in the past decade has
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218 While the majority of work on t
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220 12.4.2.1 Integrins as Targets f
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222 cytotoxicity. Consequently, enc
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224 are lectin-carbohydrate, ligand
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226 H1299 cells was significantly i
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13 CONTENTS Long-Circulating Polyme
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Long-Circulating Polymeric Nanopart
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14 CONTENTS Biodegradable PLGA/PLA
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Biodegradable PLGA/PLA Nanoparticle
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15 CONTENTS Poly(Alkyl Cyanoacrylat
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Poly(Alkyl Cyanoacrylate) Nanoparti
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16 CONTENTS Aptamers and Cancer Nan
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Aptamers and Cancer Nanotechnology
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318 17.5.3.2 Paclitaxel Formulation
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320 TABLE 17.1 Examples of Polymers
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322 are block copolymer vesicles th
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324 17.2.4 PROPERTIES OF MICELLE FO
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328 The amphiphilic or polar nature
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330 of paclitaxel-loaded micelles.
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332 of intracellular drug accumulat
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334 organelles, the non-ionic Pluro
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338 foreign bodies present within t
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340 PEG-b-PDLLA copolymers. Therefo
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342 For in vivo delivery, the LCST
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344 In cases where nuclear targetin
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18 PEO-Modified Poly(L-Amino Acid)
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388 Hydrophilic block Single polyme
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390 concentrations, and organic sol
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392 micelles used for solubilizatio
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394 N O NH2 Nicotinamide Sodium nic
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396 hydrotropic moieties. The main
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TABLE 19.4 Modified Hydrotropic Mon
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402 The loading content of paclitax
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404 concentrations that are clinica
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410 bioavailability, certain clinic
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412 It has been shown that the EPR
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O 2 N O C O O 2 N O C O O O C NO 2
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416 and eventually drug could be cl
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422 the process of chemotherapy. De
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426 were measured. Cell incubation
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428 drug-loaded nanoparticles. It w
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430 DOX Concentration in plasma, μ
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432 Counts 10 0 150 120 90 60 30 0
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434 Tumor volume, mm 3 2500 2000 15
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436 dramatically increased intracel
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438 21.6 CONCLUSIONS In animal mode
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22 CONTENTS Polymeric Micelles Targ
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Polymeric Micelles Targeting Tumor
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23 CONTENTS cRGD-Encoded, MRI-Visib
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MRI-Visible Polymeric Micelles 467
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478 A series of recent developments
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480 O HN O O O O N O H H O H H OH O
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482 Tumor volume (mm 3 ) 2000 1500
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484 24.4 CONCLUSIONS Polymeric gene
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490 25.2 DRUG DELIVERY 25.2.1 INTRO
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494 intracellular DOX concentration
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496 H 2 N H 2 N N H O H N 2 N H NH
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498 incorporated in the PIC micelle
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502 control polymer, Exgen 500. Thi
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504 photocytotoxicity in HeLa cells
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510 H 2N H 2N H N O H N Intermediat
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512 O 2N O HN O O O O OR O HN O O O
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514 making them useful in biologica
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516 x x x x x x x x O O O O O O x O
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518 tumors with little concentratio
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27 CONTENTS PEGylated Dendritic Nan
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PEGylated Dendritic Nanoparticulate
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552 28.2.2.1 Long-Term Toxicity Stu
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558 considerably simplified using h
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562 FIGURE 28.8 PAGE electropherogr
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564 28.1.5.4 Synthesis of Tritium L
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566 10 nm Nanotechnology for Cancer
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568 Rel % 60 50 40 30 20 10 LBCB-6-
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570 25 nm (a) (b) 20.51 nm 27.82 nm
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572 architecture (fenestrated struc
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574 nanoparticle aggregates that sh
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576 harvested, weighed, and process
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578 Biodistribution of 5 nm Positiv
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580 surface Au-composite nanodevice
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582 28.2.2.2 Long-Term Toxicity of
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584 Targeted RadioTherapy (StaRT) i
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586 REFERENCES Nanotechnology for C
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596 range (!200 nm size) and can be
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30 CONTENTS Positively-Charged Lipo
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Positively-Charged Liposomes for Ta
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630 development because of poor pha
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636 FIGURE 31.1 The enhancement of
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32 CONTENTS RGD-Modified Liposomes
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RGD-Modified Liposomes for Tumor Ta
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664 of tissue specificity, and they
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666 OH N H N 2N N N Folic acid NH
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670 FIGURE 33.3 FR-mediated endocyt
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672 FR-b expression seems to be a p
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34 CONTENTS Nanoscale Drug Delivery
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Nanoscale Drug Delivery Vehicles fo
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724 The term macroemulsion is somet
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726 W Oil Water-in oil (W/O emulsio
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728 light scattering), counting (e.
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730 rhizoxin. 31,35 When lecithin w
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732 TABLE 35.3 Area Under the Perce
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734 cholesterol oleate as lipids, e
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736 REFERENCES Nanotechnology for C
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36 CONTENTS Solid Lipid Nanoparticl
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Solid Lipid Nanoparticles for Anti-
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37 CONTENTS Lipoprotein Nanoparticl
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Lipoprotein Nanoparticles as Delive
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788 i.e., the molecular targets of
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790 by apoptosis-triggering drugs.
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794 Paclitaxel / DQA (molar) 0.9 0.
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796 Considering that paclitaxel, ge
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Section 2 Polymer Conjugates q 2006
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Section 4 Polymeric Micelles q 2006
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Section 6 Liposomes q 2006 by Taylo
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