Drug Targeting Organ-Specific Strategies

Contents XIX
5.2.1.6 Identification of Target Molecules for Alkylglycosides . . . 131
5.2.1.7 Perspectives of Renal Delivery with Alkylglycoside Vectors 131
5.2.2 The Amino Acid Pro-drug Approach . . . . . . . . . . . . . . . . . . 132
5.2.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
5.2.2.2 The Concept of the Amino Acid Pro-drug . . . . . . . . . . 132
5.2.2.3 Renal Specificity of Amino Acid Pro-drug and their Effects 133
5.2.2.4 Benefits and Limitations of the Amino Acid Pro-drug . . . 133
5.2.2.5 The Soft Drug Concept . . . . . . . . . . . . . . . . . . . . 134
5.2.3 The Folate Pro-drug Approach . . . . . . . . . . . . . . . . . . . . . . 134
5.2.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
5.2.3.2 Potential Renal Selectivity of Folate Constructs . . . . . . . 134
5.2.3.3 Benefits and Limitations of Folate . . . . . . . . . . . . . . 135
5.3 Renal Delivery Using Macromolecular Carriers: The Low-Molecular
Weight Protein Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
5.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
5.3.2 Renal uptake of LMWP Conjugates . . . . . . . . . . . . . . . . . . . 137
5.3.2.1 Renal Uptake of Native LMWPs . . . . . . . . . . . . . . . 137
5.3.2.2 Renal Delivery of Naproxen–Lysozyme . . . . . . . . . . . 137
5.3.2.3 Renal Delivery of Captopril–Lysozyme . . . . . . . . . . . 138
5.3.3 Renal Catabolism of LMWP-conjugates . . . . . . . . . . . . . . . . 139
5.3.3.1 Renal Catabolism of Native LMWPs . . . . . . . . . . . . . 139
5.3.3.2 Renal Catabolism of Naproxen–Lysozyme . . . . . . . . . 141
5.3.3.3 Renal Catabolism of Captopril–Lysozyme . . . . . . . . . . 141
5.3.4 Effects of Targeted Drugs Using an LMWP as Carrier . . . . . . . . 141
5.3.4.1 Renal Effects of Naproxen–Lysozyme . . . . . . . . . . . . 141
5.3.4.2 Renal and Systemic Effects of Captopril–Lysozyme . . . . 142
5.3.5 Renal Disease and LMWP Processing . . . . . . . . . . . . . . . . . 142
5.3.6 Renal Delivery of High Doses of LMWPs . . . . . . . . . . . . . . . 143
5.3.7 Limitations of the LMWP Strategy of Drug Delivery to the Kidney . 144
5.4 Renal Delivery of Antisense Oligodeoxynucleotides . . . . . . . . . . . . . . 144
5.4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
5.4.2 Mechanism of Action of Antisense Oligodeoxynucleotides . . . . . . 145
5.4.3 Stabilization of Antisense Oligodeoxynucleotides . . . . . . . . . . . 145
5.4.4 Pharmacokinetic Aspects of Antisense Oligodeoxynucleotides and
Renal Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.4.5 Cellular Uptake of Antisense Oligodeoxynucleotides . . . . . . . . . 147
5.4.6 Metabolism and Elimination of Antisense Oligodeoxynucleotides . . 147
5.4.7 Effects of Antisense Targeting to the Proximal Tubule . . . . . . . . 148
5.4.8 Benefits and Limitations of Antisense Oligodeoxynucleotides . . . . 149
5.5 Drugs for Renal Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
5.6 In Vitro and In Vivo Models for Renal Targeting . . . . . . . . . . . . . . . . 149
5.6.1 In Vitro Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
5.6.2 In Vivo Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
5.7 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151