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Advanced Drug Delivery Reviews (v.63, #1-2)
Prodrug-based intracellular delivery of anticancer agents
by L. Bildstein; C. Dubernet; P. Couvreur (pp. 3-23).
There are numerous anticancer agents based on a prodrug approach. However, no attempt has been made to review the ample available literature with a specific focus on the altered cell uptake pathways enabled by the conjugation and on the intracellular drug-release mechanisms. This article focuses on the cellular interactions of a broad selection of parenterally administered anticancer prodrugs based on synthetic polymers, proteins or lipids. The report also aims to highlight the prodrug design issues, which are key points to obtain an efficient intracellular drug delivery. The chemical basis of these molecular concepts is put into perspective with the uptake and intracellular activation mechanisms, the in vitro and in vivo proofs of concepts and the clinical results. Several active targeting strategies and stimuli-responsive architectures are discussed throughout the article.Display Omitted
Keywords: Abbreviations; 5-FdU; 5-fluoro-2′-deoxyuridine; Ag; Antigen; ApoE; Apolipolipoprotein E; AraC; 1-β-; d; -Arabinofuranosylcytosine (cytarabine); BE; Benzyl elimination; CALI; NAc-gamma calicheamycin; CPP; Cell-penetrating peptide; CPT; Camptothecin; DAUN; Daunorubicin; dFdC; 2′,2′-difluorodeoxycytidine (gemcitabine); DOX; Doxorubicin; DMPC; Dimyristoylphosphatidylcholine; DSC; Differential scanning calorimetry; EPR; Enhanced permeability and retention; FA; Folic acid; FA-R; Folic acid receptor; FITC; Fluorescein isothiocyanate; HA; Hyaluronic acid; HPMA; N; -(2-hydroxyhropyl)methacrylamide; LDL; Low-density lipoprotein; LDL-R; LDL Receptor; LHRH; Luteinizing hormone-releasing hormone; MAb; Monoclonal antibody; MDR; Multidrug resistance; MMAE; Monomethyl auristatine E; MMC; Mitomycin C; MTD; Maximum tolerated dose; MTX; Methotrexate; Mw; Molecular weight; NOAC; N4-octadecyl-AraC; NSCLC; Non-small-cell lung cancer; PAA; poly(aspartic acid); PABC; Para-aminobenzyl carbamate; PAMAM; Poly(amidoamine); PCT; Paclitaxel; PEG; Poly(ethylene glycol); P-gp; P-glycoprotein; PHEG; Poly-[N5-(2-hydroxyethyl)-; l; -glutamine]; PLA; 2; Phospholipase A; 2; RME; Receptor-mediated endocytosis; SMVT; Sodium-dependent multi-vitamin transporter; SQ; Squalene; SST; Somatostatin; TML; Trimethyl lock lactonisationProdrug; Anticancer; Bioconjugate; Immunoconjugate; Immunoliposome; Endocytosis; Passive diffusion; Spacer; Stimuli-responsive; Self-immolative
Superparamagnetic iron oxide nanoparticles (SPIONs): Development, surface modification and applications in chemotherapy
by Morteza Mahmoudi; Shilpa Sant; Ben Wang; Sophie Laurent; Tapas Sen (pp. 24-46).
At present, nanoparticles are used for various biomedical applications where they facilitate laboratory diagnostics and therapeutics. More specifically for drug delivery purposes, the use of nanoparticles is attracting increasing attention due to their unique capabilities and their negligible side effects not only in cancer therapy but also in the treatment of other ailments. Among all types of nanoparticles, biocompatible superparamagnetic iron oxide nanoparticles (SPIONs) with proper surface architecture and conjugated targeting ligands/proteins have attracted a great deal of attention for drug delivery applications.This review covers recent advances in the development of SPIONs together with their possibilities and limitations from fabrication to application in drug delivery. In addition, the state-of-the-art synthetic routes and surface modification of desired SPIONs for drug delivery purposes are described.
Keywords: Abbreviations; SPIONs; superparamagnetic iron oxide nanoparticles; NPs; nanoparticles; MRI; magnetic resonance imaging; PVP; polyvinylpyrrolidone; PLGA; polylactic-co-glycolic acid; PEG; polyethylene glycol; PVA; polyvinyl alcohol; ROS; reactive oxygen species; RES; reticuloendothelial system; DLS; dynamic light scattering; TEM; transmission electron microscope; XRD; X-ray diffractogram; EXAFS; extended X-ray absorption fine structure; HUVECs; Human Umbilical Vein Endothelian Cells; FEM; finite element model; PEGF; poly(ethylene glycol)-co-fumarate; DXM; dexamethasone acetateSuperparamagnetic iron oxide nanoparticles; SPIONs; Coatings; Surfaces; Drug delivery; Toxicity
RNA interference for improving the outcome of islet transplantation
by Feng Li; Ram I. Mahato (pp. 47-68).
Islet transplantation has the potential to cure type 1 diabetes. Despite recent therapeutic success, it is still not common because a large number of transplanted islets get damaged by multiple challenges including instant blood mediated inflammatory reaction, hypoxia/reperfusion injury, inflammatory cytokines, and immune rejection. RNA interference (RNAi) is a novel strategy to selectively degrade target mRNA. The use of RNAi technologies to downregulate the expression of harmful genes has the potential to improve the outcome of islet transplantation. The aim of this review is to gain a thorough understanding of biological obstacles to islet transplantation and discuss how to overcome these barriers using different RNAi technologies. This eventually will help improve islet survival and function post transplantation. Chemically synthesized small interferring RNA (siRNA), vector based short hairpin RNA (shRNA), and their critical design elements (such as sequences, promoters, and backbone) are discussed. The application of combinatorial RNAi in islet transplantation is also discussed. Last but not the least, several delivery strategies for enhanced gene silencing are discussed, including chemical modification of siRNA, complex formation, bioconjugation, and viral vectors.Display Omitted
Keywords: RNA interference; Islet transplantation; siRNA; shRNA
Challenges in inhaled product development and opportunities for open innovation
by Ben Forbes; Bahman Asgharian; Lea Ann Dailey; Douglas Ferguson; Per Gerde; Mark Gumbleton; Lena Gustavsson; Colin Hardy; David Hassall; Rhys Jones; Ruth Lock; Janet Maas; Tim McGovern; Gary R. Pitcairn; Graham Somers; Ron K. Wolff (pp. 69-87).
Dosimetry, safety and the efficacy of drugs in the lungs are critical factors in the development of inhaled medicines. This article considers the challenges in each of these areas with reference to current industry practices for developing inhaled products, and suggests collaborative scientific approaches to address these challenges. The portfolio of molecules requiring delivery by inhalation has expanded rapidly to include novel drugs for lung disease, combination therapies, biopharmaceuticals and candidates for systemic delivery via the lung. For these drugs to be developed as inhaled medicines, a better understanding of their fate in the lungs and how this might be modified is required. Harmonised approaches based on ‘best practice’ are advocated for dosimetry and safety studies; this would provide coherent data to help product developers and regulatory agencies differentiate new inhaled drug products. To date, there are limited reports describing full temporal relationships between pharmacokinetic (PK) and pharmacodynamic (PD) measurements. A better understanding of pulmonary PK and PK/PD relationships would help mitigate the risk of not engaging successfully or persistently with the drug target as well as identifying the potential for drug accumulation in the lung or excessive systemic exposure. Recommendations are made for (i) better industry-academia-regulatory co-operation, (ii) sharing of pre-competitive data, and (iii) open innovation through collaborative research in key topics such as lung deposition, drug solubility and dissolution in lung fluid, adaptive responses in safety studies, biomarker development and validation, the role of transporters in pulmonary drug disposition, target localisation within the lung and the determinants of local efficacy following inhaled drug administration.Display Omitted
Keywords: Aerosol dosimetry; Deposition; Inhalation toxicology; ADME; Isolated perfused lung; Transporter; Pharmacokinetics; Pharmacodynamics
Toward managing chronic rejection after lung transplant: The fate and effects of inhaled cyclosporine in a complex environment
by Ralph W. Niven (pp. 88-109).
The fate and effects of inhaled cyclosporine A (CsA) are considered after deposition on the lung surface. Special emphasis is given to a post-lung transplant environment and to the potential effects of the drug on the various cell types it is expected to encounter. The known stability, metabolism, pharmacokinetics and pharmacodynamics of the drug have been reviewed and discussed in the context of the lung microenvironment. Arguments support the contention that the immuno-inhibitory and anti-inflammatory effects of CsA are not restricted to T-cells. It is likely that pharmacologically effective concentrations of CsA can be sustained in the lungs but due to the complexity of uptake and action, the elucidation of effective posology must ultimately rely on clinical evidence.Display Omitted
Keywords: Abbreviations; AP-1; activator protein-1 transcription factor; API; active pharmaceutical ingredient; BM; basement membrane; BALF; bronchoalveolar lavage fluid; BALT; broncho-associated lymphoid tissue; BCS; biopharmaceutical classification system; BOS; bronchiolitis obliterans syndrome; CLAD; chronic lung allograft dysfunction; CsA; cyclosporine A; DC; dendritic cell; ECM; extracellular matrix; ELT; effector lymphoid tissue; EMT; epithelial to mesenchymal cell transition; LEC; lymphatic endothelial capillary; MAPK; mitogen activated protein kinase; MeBmt; methylated butenyl-methyl-L-threonine; MMAD; mass median aerodynamic diameter; MMF; mycophenolate mofetil; NF-AT; nuclear factor of activated T-cells; NO; nitric oxide; SP; surfactant protein (A through D); OB; obliterative bronchiolitis; PG; propylene glycol; pMDI; propellant metered dose inhaler; RAS; restrictive airway syndrome; RBC; red blood corpuscleAerosol; Cyclosporine A; Chronic rejection; Immunology; Inhalation; Lung transplantation; Pharmacokinetics
Spatial expression and functionality of drug transporters in the intact lung: Objectives for further research
by Mark Gumbleton; Ghaith Al-Jayyoussi; Adam Crandon-Lewis; Danielle Francombe; Katharina Kreitmeyr; Chris J. Morris; Mathew W. Smith (pp. 110-118).
This commentary provides a background appraising evidence in the intact lung on the spatial expression of drug transporters and, where available, evidence in the intact lung of the impact, or otherwise, that such transporters can have upon pulmonary drug absorption and disposition. Ultimately drug discovery and development scientists will wish to identify in a ‘pulmonary’ context the effect of disease upon transporter function, the potential for drug transporters to contribute to drug–drug interactions and to inter-individual variation in drug handling and response.The rate and extent of lung epithelial permeation of drugs involve an interplay between the dose and the deposition site of drug within the lung and physiological variables operational at the epithelial–luminal interface. Amongst the latter variables is the potential impact of active transporter processes which may well display regio-selective characteristics along the epithelial tract. In pulmonary tissues the spatial pattern of drug transporter expression is generally poorly defined and the functional significance of transporters within the intact lung is explored in only a limited manner. Active transporters in the lung epithelium may affect airway residence times of drug, modulate access of drug to intracellular targets and to submucosal lung tissue, and potentially influence airway to systemic drug absorption profiles. Transporters in the lung tissue may also have the capacity to mediate uptake of drug from the systemic circulation resulting in drug accumulation in the lung. Transporters have physiological roles and new drug candidates while not necessarily serving as transport substrates may modulate transporter activity and hence physiology.The commentary highlights a series of recommendations for further work in pulmonary drug transporter research.Display Omitted
Keywords: Transporter; Lung; Pulmonary; Delivery; ATP; P-glycoprotein; MRP; BCRP; OAT; OATP; OCT; OCTN; Pharmacokinetics
Intravital microscopy as a tool to study drug delivery in preclinical studies
by Panomwat Amornphimoltham; Andrius Masedunskas; Roberto Weigert (pp. 119-128).
The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies.Display Omitted
Keywords: Intravital microscopy; Non-linear microscopy; Drug delivery; Cancer
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