Drug Targeting Organ-Specific Strategies

More documents

Recommendations

Info

With the development of more advanced drugs such as therapeutic proteins, antisense molecules and genes, not only controllable release, but also controllable delivery in the target cells becomes desirable. As a consequence, targeting modalities need to be incorporated into the vehicles. Although drugs and drug formulation based on proteins were first considered unfeasible, nowadays practice has proven this not to be the case. Since 1994, on average more than seven FDA approvals per year have been issued for protein-based therapies. It is furthermore believed that the increasing yield of protein molecules produced by recombinant techniques will boost application of protein drugs in the near future [50]. In recent years, various reviews have been published in which the current status of liposome [2] and antibody [6] based drug targeting strategies have been summarized. Similarly, the current status of gene therapy in both pre-clinical and clinical settings have been recently reviewed [51,52].Without trying to be complete, the next sections will give an overview on recently published studies with drug targeting formulations in a clinical setting. 1.4.1 Liposome Based Therapies in the Clinic Several liposomal formulations are either under investigation in phase I/II/III clinical trials or have been approved by the US Food and Drug Administration or cleared for empiric therapy (see also Chapter 8 for FDA approved formulations in cancer therapy). They are in use for the treatment of cancer or fungal infections and, consisting of non-targeted liposomes, aim at slow release of the encapsulated drugs over a prolonged period of time to circumvent dose-limiting (cardiac) toxicity. Recently reported clinical studies with liposome formulations are summarized in Table 1.1. The reader is also referred to references [4] and [53] for a more detailed description of these liposome-based therapeutic strategies. The general outcome of these studies was that the liposomal drugs were well tolerated and exerted a clinical effect, although larger studies need to be carried out to demonstrate the extent of the effects. Furthermore, in the various studies of liposome-incorporated drugs, it was observed that cardiotoxicity was either absent or only limited, in contrast to studies with nonliposomally formulated drugs. 1.4.2 Monoclonal Antibody Therapies in the Clinic 1.4 Drug Targeting Strategies in the Clinic 11 Clinical studies on cancer therapy with antibodies have been elegantly summarized by Farah et al. [6] and more recently by Glennie and Johnson [54]. The majority of antibody-based therapies in the clinic have exploited the activity of the antibody per se. In the therapy of cancer, the highest response rates have been observed in patients with haematological malignancies that are easily accessible to antibodies. In recent years, numerous clinical studies with antibodies directed against the B cell non-Hodgkin lymphoma-associated epitope CD20 (Rituximab, Rituxan) and the breast carcinoma antigen Her-2 (also known as neu or erbB2) have been carried out. The mechanisms of action of these antibodies are believed to consist of complement-mediated lysis, antibody-dependent cellular cytotoxicity by macrophages and natural killer cells, and signal transduction leading to apoptosis or growth arrest [55]. Novel
12 1 Drug Targeting: Basic Concepts and Novel Advances Table 1.1. Overview of some recently reported clinical studies on the application of liposome-based drug formulations. Liposome Drug Disease Clinical Remarks Reference formulation incorporated responsea DaunoXome b Daunorubicin Acute leukaemia 2/23 CR [59] Heptocellular carcinoma 2/12 SD [60] Recurrent progressive 2/14 CR [61] brain tumours in 3/14 PR children 2/14 SD Caelyxc Doxorubicin Hormone refractory 3/15 OR Severe [62] prostate cancer 2/15 SD mucocutaneous toxicities Advanced/metastatic 3/25 PR Highest dose to [63] soft tissue sarcoma 2/25 MR treat not yet 17/25 SD reached Non-small-cell lung 3/15 CR Combination [64] cancer with fractionated Squamous cell head 11/15 CR radio therapy and neck cancer Tumour microvessel density correlated with degree of Caelyx accumulation TLC D-99d Doxorubicin Kaposi’s sarcoma 6/40 PR Dose dependent [65] 26/40 SD response and toxicity Metastatic breast 10/41 OR Combination with [66] cancer cyclophosphamide and fluorouracil AmBisome Amphotericin B Renal Tx recipients 4/4 treated [67] with viscer. Leishm. e successfully Heart surgery with C. 1/1 treated [68] tropicalis endocardititis successfully Bone marrow Tx or Polyprophy- [69] chemotherapy lactic treatment patients with fungal did not reduce infections fungal infections or requirement for systemic therapy TLC C-35 Prostaglandin E1 Acute respiratory 348 patients [70] distress syndrome evaluated: no difference in number of days to discontinuation of ventilation to placebo group; mortality not different to placebo a Number of patients responding/total number of evaluable patients. CR, complete remission/response; PR, partial response; MR, minor response; OR, objective response; SD, stable disease. b Daunorubicin citrate liposome injection formula. c Also known as Doxil; PEG-coated liposome formulation with doxorubicin. d Phosphatidylcholine/cholesterol liposomal formulation with doxorubicin. e Tx, transplantation; visc. Leishm., visceral Leishmaniasis
Page 1 and 2: Drug Targeting Organ-Specific Strat
Page 5 and 6: Preface Drug Targeting Organ-Specif
Page 7 and 8: Foreword Drug Targeting Organ-Speci
Page 9 and 10: X List of Contributors Henderik W.
Page 11 and 12: XII List of Contributors Grietje Mo
Page 13 and 14: Contents Drug Targeting Organ-Speci
Page 15 and 16: Contents XVII 3 Pulmonary Drug Deli
Page 17 and 18: Contents XIX 5.2.1.6 Identification
Page 19 and 20: Contents XXI 7.5 In Vitro Technique
Page 21 and 22: Contents XXIII 9.4 Tumour Vasculatu
Page 23 and 24: Contents XXV 12.8. Tissue Slices fr
Page 27 and 28: Dexa dexamethasone DIVEMA divinyl e
Page 29 and 30: LRP lung resistance related protein
Page 31 and 32: ROS reactive oxygen species RSV res
Page 33 and 34: Index a ADEPT 217, 224, 268, 291 ad
Page 35 and 36: e E. coli expression system 292 eff
Page 37 and 38: polymers, soluble 4, 218 - dendrime
Page 39 and 40: 2 1 Drug Targeting: Basic Concepts
Page 47: 10 1 Drug Targeting: Basic Concepts
Page 61 and 62: 24 2 Brain-Specific Drug Targeting
Page 91 and 92: 54 3 Pulmonary Drug Delivery: Deliv
Page 99 and 100:
62 3 Pulmonary Drug Delivery: Deliv
Page 101 and 102:
Page 103 and 104:
Page 105 and 106:
Page 107 and 108:
Page 109 and 110:
Page 111 and 112:
Page 113 and 114:
Page 115 and 116:
Page 117 and 118:
Page 119 and 120:
Page 121 and 122:
Page 123 and 124:
Page 125 and 126:
4 Cell Specific Delivery of Anti-In
Page 127 and 128:
The sinusoids are lined by the disc
Page 129 and 130:
4.2.2.2 Phagocytosis and Transcytos
Page 131 and 132:
ther inflammatory cells or accessor
Page 133 and 134:
4.3 Hepatic Inflammation and Fibros
Page 135 and 136:
process is not yet available. Sever
Page 137 and 138:
this carrier to the KCs.When the ma
Page 139 and 140:
e taken up rapidly by mannose recep
Page 141 and 142:
y the transcriptional regulatory pr
Page 143 and 144:
4.8 Testing Liver Targeting Prepara
Page 145 and 146:
4.8 Testing Liver Targeting Prepara
Page 147 and 148:
4.9 Targeting of Anti-inflammatory
Page 149 and 150:
4.9 Targeting of Anti-inflammatory
Page 151 and 152:
with monoclonal and bispecific anti
Page 153 and 154:
References 117 [50] Coleman DL, Eur
Page 155 and 156:
References 119 [133] Cronstein BN,
Page 157 and 158:
5 Delivery of Drugs and Antisense O
Page 159 and 160:
5.1 Introduction 123 convoluted tub
Page 161 and 162:
treatment of the targeted cell and
Page 163 and 164:
CL uptake (ml/min/g) centration pro
Page 165 and 166:
5.2.1.4 Specific Binding of Alkylgl
Page 167 and 168:
5.2 Renal Delivery Using Pro-Drugs
Page 169 and 170:
5.2 Renal Delivery Using Pro-Drugs
Page 171 and 172:
5.3 Renal Delivery Using Macromolec
Page 173 and 174:
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
Page 181 and 182:
5.4 Renal Delivary of Antisense Oli
Page 183 and 184:
5.4 Renal Delivery of Antisense Oli
Page 185 and 186:
5.4.8 Benefits and Limitations of A
Page 187 and 188:
via reabsorption from the luminal s
Page 189 and 190:
References 153 [66] Franssen EJF, M
Page 191 and 192:
References 155 [145] Van Zwieten PA
Page 193 and 194:
158 6 A Practical Approach in the D
Page 195 and 196:
Page 197 and 198:
Page 199 and 200:
Page 201 and 202:
Page 203 and 204:
Page 205 and 206:
Page 207 and 208:
172 7 Vascular Endothelium in Infla
Page 209 and 210:
Page 211 and 212:
Page 213 and 214:
Page 215 and 216:
Page 217 and 218:
Page 219 and 220:
Page 221 and 222:
Page 223 and 224:
Page 225 and 226:
Page 227 and 228:
Page 229 and 230:
Page 231 and 232:
Page 233 and 234:
8 Strategies for Specific Drug Targ
Page 235 and 236:
8.2.2 Histogenesis The traditional
Page 237 and 238:
may become obstructed and compresse
Page 239 and 240:
8.5 Strategies to Deliver Drugs to
Page 241 and 242:
8.5 Strategies to Deliver Drugs to
Page 243 and 244:
larly cytotoxic immune effector cel
Page 245 and 246:
contributes to limited tumour penet
Page 247 and 248:
ples onto anti-EGP-2 scFv. Biologic
Page 249 and 250:
In the case of drug-monoclonal anti
Page 251 and 252:
cells, the presence of co-stimulato
Page 253 and 254:
Monomethoxy-polyethylene glycol CH
Page 255 and 256:
e efficiently loaded into the lipos
Page 257 and 258:
8.6 Clinical Studies 223 Table 8.5.
Page 259 and 260:
8.6.3 (Synthetic) (co)Polymers Solu
Page 261 and 262:
8.8 Conclusions and Future Perspect
Page 263 and 264:
References 229 [43] Chaouchi NA, Va
Page 265 and 266:
References 231 [126] Czuczman MS, G
Page 267 and 268:
234 9 Tumour Vasculature Targeting
Page 269 and 270:
Page 271 and 272:
Page 273 and 274:
Page 275 and 276:
Page 277 and 278:
Page 279 and 280:
Page 281 and 282:
Page 283 and 284:
Page 285 and 286:
Page 287 and 288:
Page 289 and 290:
256 10 Phage Display Technology for
Page 291 and 292:
Page 293 and 294:
Page 295 and 296:
Page 297 and 298:
Page 299 and 300:
Page 301 and 302:
Page 303 and 304:
Page 305 and 306:
Page 307 and 308:
11 Development of Proteinaceous Dru
Page 309 and 310:
carrier is an homogenous product. I
Page 311 and 312:
11.3 The Homing Device 11.3 The Hom
Page 313 and 314:
malian cell lines that have acquire
Page 315 and 316:
jugates for the delivery of other a
Page 317 and 318:
11.5 The Linkage Between Drug and C
Page 319 and 320:
actions are directed towards these
Page 321 and 322:
11.5 The Linkage Between Drug and C
Page 323 and 324:
homing potential if the antigen rec
Page 325 and 326:
ly used promoters include T7 RNA po
Page 327 and 328:
the baculovirus expression vector,
Page 329 and 330:
11.8 Recombinant DNA Constructs 297
Page 331 and 332:
11.8 Recombinant DNA Constructs 299
Page 333 and 334:
toxic activity. Anthrax and tetanus
Page 335 and 336:
11.9 Recombinant Domains as Buildin
Page 337 and 338:
References 305 [16] Milstein C, Wal
Page 339 and 340:
References 307 [99] Verma R, Boleti
Page 341 and 342:
12 Use of Human Tissue Slices in Dr
Page 343 and 344:
are also extensively used in a vari
Page 345 and 346:
Meanwhile many incubation systems h
Page 347 and 348:
12.3 Incubation and Culture of Live
Page 349 and 350:
to investigate the effect of differ
Page 351 and 352:
The mechanisms of uptake and excret
Page 353 and 354:
12.6 The Use of Liver Slices in Dru
Page 355 and 356:
12.7 Efficacy Testing of the Drug T
Page 357 and 358:
NO x µM 80 60 40 20 * * 12.7 Effic
Page 359 and 360:
TNFα ng/ml 1.5 1 0.5 0 * Human (n=
Page 361 and 362:
References 329 [33] Ikejima K, Enom
Page 363 and 364:
References 331 [109] Dutt A, Priebe
Page 365 and 366:
334 13 Pharmacokinetic/Pharmacodyna
Page 367 and 368:
Page 369 and 370:
Page 371 and 372:
Page 373 and 374:
Page 375 and 376:
Page 377 and 378:
Page 379 and 380:
Page 381 and 382:
Page 383 and 384:
Page 385 and 386:
Page 387 and 388:
Page 389 and 390:
Page 391 and 392:
Page 393 and 394:
Page 395 and 396:
Page 397 and 398:
Page 399 and 400:
Page 401 and 402:
Page 403 and 404:
372 14 Drug Targeting Strategy: Scr
Page 405 and 406:
374 14 Drug Targeting Strategy: Scr
show all

Drug Targeting Organ-Specific Strategies

Create successful ePaper yourself

Delete template?

Save as template?