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Faculté de Pharmacie

Ecole Doctorale en Sciences Pharmaceutiques

DEVELOPMENT AND EVALUATION OF CONTROLLED-RELEASE

CISPLATIN DRY POWDERS FOR INHALATION

AGAINST LUNG TUMOURS

Vincent LEVET

Pharmacien

Thèse présentée en vue de l’obtention du grade de Docteur en Sciences

Biomédicales et Pharmaceutiques

Promoteur : Prof. Karim AMIGHI

Co-promoteur : Dr. Nathalie WAUTHOZ

Laboratoire de Pharmacie Galénique et de Biopharmacie, ULB

Composition du jury

Prof. Jean-Michel KAUFFMANN (Président, Faculté de Pharmacie, ULB)

Prof. François DUFRASNE (Secrétaire, Faculté de Pharmacie, ULB)

Prof. Jean-Paul SCULIER (Institut Jules Bordet, ULB)

Dr. Aurélie SCHOUBBEN (Università degli Studi di Perugia)

Dr. Francis VANDERBIST (S.M.B. Galéphar)

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Table of contents Remerciements ... 2 TABLE OF CONTENTS ... 3 ABBREVIATIONS ... 6 SUMMARY ... 8 RESUME ... 12 INTRODUCTION ... 16 1. Lung cancer ... 17

1.1. Epidemiology, historical background and risk factors ... 17

1.2. Symptoms, screening, diagnosis and staging ... 18

1.2.1. Symptoms ... 18

1.2.2. Screening ... 18

1.2.3. Diagnosis ... 19

1.2.4. Staging ... 19

1.3. Primary lung cancer ... 20

1.3.1. Non-small cell lung cancer (NSCLC) ... 20

1.3.2. Small-cell lung cancer (SCLC) ... 27

1.4. Secondary tumours to the lungs ... 29

2. Cisplatin ... 31

2.1. Discovery and current use ... 31

2.2. Structure and chemical properties ... 32

2.3. Solubility and chemical reactivity ... 32

2.4. Cisplatin quantification methods... 33

2.4.1. Generalities... 33

2.4.2. Electrothermal atomic absorption spectrometry (ETAAS) ... 34

2.5. Cell penetration, mechanism of action and cisplatin resistance ... 36

2.5.1. Cisplatin uptake and efflux ... 36

2.5.2. Formation of nuclear DNA adducts ... 36

2.5.3. Other cellular targets ... 37

2.5.4. Cisplatin resistance ... 37

2.6. Challenges in cisplatin administration ... 38

2.6.1. Side-effects ... 38

2.6.2. Routes of administration ... 42

3. Inhaled therapies ... 44

3.1. Structure of the lung ... 44

3.2. Advantages of the pulmonary administration route ... 46

3.3. Inhalational delivery devices ... 46

3.3.1. Nebulizers ... 46

3.3.2. Pressure metered-dose inhalers (pMDIs) ... 48

3.3.3. Dry powder inhalers (DPIs) ... 49

3.4. Fate of deposited drug based particles into the lungs ... 53

3.4.1. Drug particle dissolution and drug release from particles ... 53

3.4.2. Fate of dissolved or released drug ... 55

3.4.3. Fate of undissolved particles ... 55

3.5. Controlled release inhaled therapies ... 56

3.5.1. Micelles ... 58

3.5.2. Dendrimers ... 59

3.5.3. Nano and microparticles ... 60

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3.6. Inhaled chemotherapy (CT) ... 69

3.6.1. Advantages ... 69

3.6.2. Challenges ... 69

3.6.3. Current status of inhaled chemotherapy (CT) ... 73

SCIENTIFIC STRATEGY ... 75

EXPERIMENTAL SECTION ... 79

Part I – Development of cisplatin DPI formulations ... 80

1. Introduction ... 80

2. Preliminary studies ... 82

2.1. Safety procedures ... 82

2.2. Cisplatin characterization ... 82

2.3. Solid-lipid nanoparticles (SLN) ... 82

2.3.1. Materials and Methods ... 82

2.3.2. Results ... 84

2.3.3. Conclusion ... 85

2.4. Solid-lipid microparticles (SLM)... 86

2.4.1. Material and methods ... 86

2.4.2. Results and discussion ... 88

3. Article 1 “Development of controlled-release cisplatin dry powders for inhalation against lung cancers” ... 97

3.1. Abstract ... 97

3.2. Introduction ... 97

3.3. Materials and methods ... 101

3.3.1. Materials ... 101

3.3.2. Methods ... 101

3.4. Results and Discussion ... 108

3.4.1. Formulation processes ... 108

3.4.2. Drug content ... 109

3.4.3. Residual solvent and thermal properties of formulations ... 110

3.4.4. Particle shape and morphology ... 112

3.4.5. Geometric particle size distributions of DPI ... 112

3.4.6. Aerodynamic behavior ... 114

3.4.7. Dissolution properties ... 116

3.5. Conclusion ... 117

3.6. Acknowledgements ... 118

4. Conclusion and perspectives regarding cisplatin dry powder formulations for inhalation ... 119

Part II – Local and Systemic Pharmacokinetic assessment of DPI cisplatin formulations ... 121

1. Introduction ... 123

2. Article 2 “Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and retention properties” ... 123

2.1. Abstract ... 123

2.2. Introduction ... 123

2.3. Materials and methods ... 126

2.3.1. Materials ... 126

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Table of contents

2.3.3. Dry diluent ... 127

2.3.4. Dry powder blends (DPB) ... 129

2.3.5. Animals ... 130

2.3.6. Accurate and reproducible lung delivery of DPBs ... 131

2.3.7. Pharmacokinetic and biodistribution experiment ... 131

2.3.8. Statistical analyses ... 133

2.3.9. Cisplatin quantification using ETAAS ... 133

2.4. Results and discussion ... 133

2.4.1. Dry diluent characterization ... 135

2.4.2. Dry powder blends characterization ... 135

2.4.3. Pharmacokinetic results... 141

2.5. Conclusion ... 148

2.6. Acknowledgments ... 149

3. Conclusion and perspectives regarding platinum pharmacokinetics in mice ... 150

Part III – Tolerance and efficacy assessment of DPI formulations ... 151

1. Introduction ... 151

2. Preliminary evaluations ... 152

2.1. Anti-proliferative assay (MTT) ... 152

2.1.1. Method ... 152

2.1.2. Results and discussion ... 152

2.2. Exploratory survival study ... 153

2.2.1. Method ... 153

2.2.2. Results and discussion ... 153

3. Article 3 “In vivo local and systemic toxicity and antitumour efficacy of cisplatin solid lipid microparticles with controlled-release properties against lung cancers” ... 155

3.1. Introduction ... 155

3.2. Materials and methods ... 157

3.2.1. Materials ... 157

3.2.2. Dry powder inhaler formulation production, characterization and administration ... 158

3.2.3. Maximum tolerated dose of repeated administrations ... 159

3.2.4. Acute local toxicity ... 160

3.2.5. Efficacy evaluation on an orthotopic M109-HiFR tumour model ... 161

3.2.6. Housing conditions and ethics committee approval ... 162

3.2.7. Statistical analyses ... 162

3.3. Results and discussion ... 163

3.3.1. Systemic tolerance following chronic administrations ... 163

3.3.2. Acute pulmonary tolerance of inhaled cisplatin formulations ... 166

3.3.3. Anticancer activity on the orthotopic lung cancer model ... 170

3.4. Conclusion ... 172

GENERAL CONCLUSION AND PERSPECTIVES ... 173

REFERENCES ... 177

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