摘要:

AbstractThe advent of monoclonal antibodies has revitalised the concept of magic bullets and various agents (eg. drugs, toxins and isotopes) have been conjugated to monoclonal antibodies for selective delivery to tumours. Preclinical studies in mouse tumour models have been impressive and have lead to several clinical trials. These phase I trials have been less impressive. However, keeping in mind the aim of Phase I trials, the safety of using these conjugates in humans have been established. Several, major problems still remain to be overcome before these agents may be useful for the treatment of cancer. These problems stem from the nature of tumour vasculature, cytotoxic activity of the moiety linked to antibody and the targeted tumour antigen expressed on the cell surface. This review will deal with these various aspects described above and possible approaches to overcome these obstacles with a definite bias towards drug-monoclonal antibody conjugates. However, these concepts are equally applicable for improved targeting of other agents.

ISSN:1061-186X    

DOI:10.3109/10611869408996804

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractA novel∞-amino acid based oligopeptide system has been designed, which combines structural features of lipids with those of amino acids and peptides. Because of their bifunctional nature, the fatty amino acids and peptides have the capacity to be chemically conjugated to drugs and peptides with a wide variety of functional groups. The linkage between drug and lipidic unit may either be biologically stable (ie. a new drug is formed) or exhibit biological or chemical instability (ie. the conjugate is a pro-drug). In either case, the resulting conjugates would be expected to possess a high degree of membrane-like character, which may be sufficient to facilitate their passage across membranes. The long alkyl side chains may also have the additional effect of protecting a labile parent drug from enzymatic attack. The lipidic system has been conjugated to a wide variety of different compounds, including (i) alkaloids (ii)β-lactam antibiotics, (iii) anticancer compounds (iv) CNS drugs and (v) peptides. The biological examination of the conjugates showed that an increase in lipophilicity caused an increase in thein vitrocellular andin vivooral uptake, as well as passage through the blood-brain-barrier, suggesting that conjugation to lipidic amino acids and peptides is a useful approach to improve the absorption of poorly-absorbed drugs. Lipidic conjugates of peptides (TRH, LHRH) resulted in higher enzymatic stability of the conjugates, proving that the long alkyl side chains also have the additional effect of protecting a labile parent drug or peptide in a biological environment. A novel Lipid-Core-Peptide (LCP) system has also been synthesised by incorporating lipidic amino acids to a lysine based polyamino acid system to enhance lipophilicity and membrane binding effects and the metabolic stability of the compound. The LCP system as a combined adjuvant-carrier-vaccine greatly increased the immunogenicity of synthetic peptides.

ISSN:1061-186X    

DOI:10.3109/10611869408996805

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractThe oral delivery of drugs to the colon has applications in a variety of therapeutic areas. This review is concerned with the approaches taken to achieve a universal system for delivery. The design of such a system requires the identification and exploitation of a unique feature of the colonic environment. The use of transit times, pH and bacterial enzymes are critically assessed. In addition, the system must provide protection for the drug during transit to the colon. Upper gastro-intestinal physiology and the transit of pharmaceuticals through these regions are reviewed with reference to their relevance in achieving site specificity.

ISSN:1061-186X    

DOI:10.3109/10611869408996806

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractIn order to avoid reticuloendothelial system (RES) uptake and prolong systemic circulation of cisplatin (CDDP)-encapsulating thermosensitive liposomes, stearylpolyoxyethylene (POE) derivatives [SnC, stearyl-O-(CH2CH22O)n-CH2COONa] were incorporated as membrane modifiers into lipid bilayers composed of dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC).The incorporation of S2C, S5C, S10C or S15C [lipid/SnC=10/2 (w/w)] greatly reduced liposomal aggregation without impairing liposomal stability. After being intravenously administered to rats, the liposomes remained longer in the systemic circulation and showed lower RES levels than the control liposomes. When incorporated into liposomes [DPPC/DSPC=7/3 (w/w)], S10C provided the greatest increase in systemic circulation time and the RES-avoiding activity among the modifiers tested. The systemic elimination rate (the ratio of the percent of the dose systemically eliminated to the AUC of the liposome level) for this type of liposome was 0.24/hr, about one fourth the rate for the control liposomes, and the RES uptake rate (the ratio of the percent of the dose taken up by the RES to the AUC) was 0.04/hr, one seventh the rate for the control liposomes. The RES uptake rate for S10C 7/3-liposomes was similar to the rate reported for GM1liposomes, although the systemic elimination rate was double that for the GM1liposomes.The obtained RES avoidance activity can be attributed to decreased liposomal aggregation and increased surface hydrophilicity. This type of thermosensitive liposome should be more useful in hyperthermia-mediated targeted tumor drug delivery systems than the thermosensitive liposomes without the modifiers to avoid RES uptake.

ISSN:1061-186X    

DOI:10.3109/10611869408996807

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor