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Advanced Drug Delivery Reviews (v.60, #12)
Renal uptake and metabolism of radiopharmaceuticals derived from peptides and proteins
by Hiromichi Akizawa; Tomoya Uehara; Yasushi Arano (pp. 1319-1328).
Radiolabeled anti-CD20 antibodies have demonstrated impressive efficacy in the treatment of relapsed non-Hodgkin lymphoma. This encourages the treatment of solid tumor with radiolabeled antibody fragments and peptides. However, both preclinical and clinical studies revealed that persistent localization of radioactivity in the kidney constitutes a major obstacle that compromises therapeutic efficacy. Recent extensive studies show that long residence times of radiolabeled end products from lysosomes are responsible for the renal radioactivity levels. Recent studies have also elucidated the involvement of megalin-cubilin in renal tubular reabsorption of radiolabeled antibody fragments and peptides. In light of these findings, efforts are being made to block tubular reabsorption of radiolabeled antibody fragments and peptides by competitive inhibitors, charge modification, and PEGylation. An interposition of an enzyme-cleavable linkage between antibody fragments and radiolabels would constitute an alternative approach to reduce renal radioactivity levels. Recent findings of these studies will be described.
Keywords: Antibody fragments; Peptides; Proteins; Radiotherapy; Diagnostic imaging; Kidney; Reabsorption; Metabolism; Metabolizable linkage; Radiometabolite
Radionuclides delivery systems for nuclear imaging and radiotherapy of cancer
by Misara Hamoudeh; Muhammad Anas Kamleh; Roudayna Diab; Hatem Fessi (pp. 1329-1346).
The recent developments of nuclear medicine in oncology have involved numerous investigations of novel specific tumor-targeting radiopharmaceuticals as a major area of interest for both cancer imaging and therapy. The current progress in pharmaceutical nanotechnology field has been exploited in the design of tumor-targeting nanoscale and microscale carriers being able to deliver radionuclides in a selective manner to improve the outcome of cancer diagnosis and treatment. These carriers include chiefly, among others, liposomes, microparticles, nanoparticles, micelles, dendrimers and hydrogels. Furthermore, combining the more recent nuclear imaging multimodalities which provide high sensitivity and anatomical resolution such as PET/CT (positron emission tomography/computed tomography) and SPECT/CT (combined single photon emission computed tomography/computed tomography system) with the use of these specific tumor-targeting carriers constitutes a promising rally which will, hopefully in the near future, allow for earlier tumor detection, better treatment planning and more powerful therapy. In this review, we highlight the use, limitations, advantages and possible improvements of different nano- and microcarriers as potential vehicles for radionuclides delivery in cancer nuclear imaging and radiotherapy.
Keywords: Abbreviations; BNCT; boron neutron capture therapy; DTPA; diethylene triamine penta acetic acid; 18; FDG; [2-; 18; F]-2-fluoro-2-deoxyglucose; FR; folates receptor; Gd-NCT; gadolinium neutron capture therapy; GF; grouth factor; HMPAO; hexa methyl propylene amine oxime; HAS; human serum albumin; LET; linear energy transfer; MAA; macroaggregated albumin; MR; magnetic resonance; MRI; magnetic resonance imaging; NP; nanoparticles; NTA; nitrilotriacetic acid; PAP; polychelating amphiphilic polymer; PEG; poly(ethylene glycol; PET; positron emission tomography; PET/CT; positron emission tomography-computed tomography; PLLA; poly (; l; -lactic acid; RES; reticuloendothelial system; SPECT; single photon emission computed tomography; SPECT/CT; combined single photon emission computed tomography/computed tomography system; SUV; small unilamellar vesicleRadionuclides; Delivery; Imaging; Radiotherapy; Tumor; Labelling; Carrier
Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides
by Shuang Liu (pp. 1347-1370).
Receptor-based radiopharmaceuticals are of great current interest in molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals.
Keywords: List of Abbreviations for Common Chelators; BCNOTA; 2,2′-(2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)ethylazanediyl)diacetic acid; CB-TE2A; 2,2′-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl)diacetic acid; DADS; N; 2; S; 2; diamidedithiols; DO3A; 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate; DOTA; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DOTA-AA; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(; p; -aminoanilide); DOTA-D-PheNH; 2; 1,4,7,10-tetraazacyclododecane-4,7,10-tricarboxymethyl-1-yl-acetyl-; d; -Phenylalanine-amide; DTPA; diethylenetriaminepentaacetic acid; HEDTA; N; -hydroxyethylethylenediamine-; N; ,; N; ,′; N; ′-triacetic acid; HYNIC; 6-hydrazinonicotinamide; MAMA; monoamidemonoaminedithiols; map; 2,3-bis(mercaptoacetamido)propanoate; mapt; 4,5-bis(thioacetamido)pentanoate; NOTA; 1,4,7-triazacyclononane-1,4,7-triacetic acid; NODAGA; 1,4,7-triazacyclononane-; N; -glutamic acid-; N; ′,; N; ″-diacetic acid; NODASA; 1,4,7-triazacyclononane-; N; -succinic acid-; N; ′,; N; ″-diacetic acid; SarAr; N1-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine; TETA; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acidRadiopharmaceuticals; Radionuclides; Target-specific delivery; Diagnosis; Radiotherapy
Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications
by Matthias Miederer; David A. Scheinberg; Michael R. McDevitt (pp. 1371-1382).
Alpha particle-emitting isotopes have been proposed as novel cytotoxic agents for augmenting targeted therapy. Properties of alpha particle radiation such as their limited range in tissue of a few cell diameters and their high linear energy transfer leading to dense radiation damage along each alpha track are promising in the treatment of cancer, especially when single cells or clusters of tumor cells are targeted. Actinium-225 (225Ac) is an alpha particle-emitting radionuclide that generates 4 net alpha particle isotopes in a short decay chain to stable209Bi, and as such can be described as an alpha particle nanogenerator. This article reviews the literature pertaining to the research, development, and utilization of targeted225Ac to potently and specifically affect cancer.
Keywords: Actinium-225; 225; Ac; Alpha particle-emitter; Nano-device; Targeted therapy; Monoclonal antibody; DOTA; Radioimmunotherapy
The chemistry of irreversible capture
by Claude F. Meares (pp. 1383-1388).
The specific recognition and binding of biological molecules by antibodies is fundamentally important. Natural antibodies are multivalent, having at least two identical ligand-binding sites; this permits them to bind tightly at cell surfaces, which present multiple copies of their target ligands. Antibodies that bind to soluble monovalent ligands, such as most small molecules, do not share this multivalent advantage. Nor do engineered fragments of antibodies, such as single-chain Fv proteins or Fab fragments, which generally possess only a single ligand-binding site. Engineered monovalent antibody/ligand pairs that retain the binding specificity of the antibody, but do not dissociate, are promising components of new delivery systems. These are based on a combination of genetic manipulation of the protein and chemical synthesis of appropriate ligands, examples of which are reviewed here.
Keywords: Antibody; Receptor; Protein engineering; Bifunctional chelating agent; Macrocycle; DOTA; Affinity label; Mutagenesis
Pharmacokinetics and dosimetry of188Re-pharmaceuticals
by Guillermina Ferro-Flores; Consuelo Arteaga de Murphy (pp. 1389-1401).
The main objective of this review is to apportion current and new insight into the biodistribution, radiopharmacokinetics, dosimetry and cell targeting of rhenium-188 labeled radiopharmaceuticals used as therapeutic drugs. The emphasis lies on the generator obtained rhenium-188, its physical, therapeutic, dosimetric and coordinated compounds. Its use in radioimmunotherapy for lymphoma and other hematological diseases with monoclonal antibodies is discussed. Radiolabeled peptides to target cell receptors are an important field in nuclear medicine and in some research facilities are already being used, especially, somatostatin, bombesin and other peptides. Small molecules labeled with188Re are promising as therapeutic drugs. A review about some of the non-specific targeting molecules with therapeutic or pain palliation effect such as phosphonates, lipiodol, microparticles and other interesting molecules is included. Research on the labeling of biomolecules with the versatile rhenium-188 has contributed to the development of therapeutics with favorable pharmacokinetic and dosimetric properties for cancer treatment.
Keywords: Rhenium-188; Cancer therapy; Lymphoma; Beta emitters in cancer; Radiopeptides; Specific targeting; Radioimmunotherapy; Peptide receptors radionuclide therapy
Alpha-particles for targeted therapy
by George Sgouros (pp. 1402-1406).
Alpha-particles are helium nuclei that deposit DNA damaging energy along their track that is 100 to 1000 times greater than that of conventionally used beta-particle emitting radionuclides for targeted therapy; the damage caused by alpha-particles is predominately double-stranded DNA breaks severe enough so as to be almost completely irreparable. This means that a small number of tracks through a cell nucleus can sterilize a cell and that, because the damage is largely irreparable, alpha-particle radiation is not susceptible to resistance as seen with external radiotherapy (e.g., in hypoxic tissue). The ability of a single track to influence biological outcome and the stochastic nature of alpha-particle decay require statistical or microdosimetric techniques to properly reflect likely biological outcome when the biologically relevant target is small or when a low number of radionuclide decays have occurred. In therapeutic implementations, microdosimetry is typically not required and the average absorbed dose over a target volume is typically calculated. Animal and cell culture studies have shown that, per unit absorbed dose, the acute biological effects of alpha-particles are 3 to 7 times greater than the damage caused by external beam or beta-particle radiation. Over the past ten to 15 years, alpha-particle emitting radionuclides have been investigated as a possible new class of radionuclides for targeted therapy. Results from the small number of clinical trials reported to date have shown efficacy without significant toxicity.
Keywords: Alpha-particle; Targeted therapy; Dosimetry
Use of antibodies and immunoconjugates for the therapy of more accessible cancers
by Robert M. Sharkey; David M. Goldenberg (pp. 1407-1420).
There are currently 6 unconjugated antibodies and 3 immunoconjugates approved for use in the United States in a variety of cancers, with a considerable number of new agents in clinical testing and preclinical development. Unconjugated antibodies alone can be effective, but more often, antibodies need to be combined with chemotherapy, which enhances the efficacy of the standard treatment. Immunoconjugates tend to be more effective than their unconjugated counterparts, but their increased toxicity often restricts when and how they are used. In order to improve efficacy, a number of immunoconjugates are being examined in settings where the disease is more easily accessible, such as leukemias, or within compartments that allow easier and more direct access to the tumor, such as in the peritoneal cavity or brain, or both locally and systemically, in adjuvant situations, where the disease burden has been reduced by some other means, and with the main goal of these treatments being to kill residual disease.
Keywords: Antibody–drug conjugates; Antibody–toxin conjugates; Immunotherapy; Pretargeting; Radioimmunotherapy
Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance
by Greg M. Thurber; Michael M. Schmidt; K. Dane Wittrup (pp. 1421-1434).
Antibodies have proven to be effective agents in cancer imaging and therapy. One of the major challenges still facing the field is the heterogeneous distribution of these agents in tumors when administered systemically. Large regions of untargeted cells can therefore escape therapy and potentially select for more resistant cells. We present here a summary of theoretical and experimental approaches to analyze and improve antibody penetration in tumor tissue.
Keywords: Tumor targeting; Antibodies; Binding site barrier; Cellular trafficking; Drug distribution; Pharmacokinetics; Mathematical modeling; Affinity; Immunotherapy
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