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Biomedical subjects

M V Pimm

Publications and source records attributed to M V Pimm.

At least 19 recordsLinked to original sources
PubMed1996

Biodistribution in tumour-bearing mice of polycationic, amphoteric and polyanionic branched polypeptides with a poly(L-lysine) backbone labelled with 125I and 111In: tumour accumulation less than that of labelled serum proteins.

The biodistribution has been studied in mice with subcutaneously transplanted solid tumours (mammary carcinoma and melanoma) of synthetic branched-chain polypeptides based on poly(L-lysine). The polypeptides were a poly(L-lysine) backbone with side-chains of three DL-alanine residues (AK, which is polycationic), AK with additional glutamic acid residues at the end of the side-chains (EAK, which is amphoteric) and EAK in which the terminal glutamic acid amino groups had been acetylated (AcEAK, which is polyanionic) or succinylated (SucEAK, which is highly polyanionic). Polypeptides were labelled with 125I by reaction with Bolton and Hunter reagent, or with 111In by chelation to diethylenetriaminepentaacetic acid previously conjugated to them. As controls, natural plasma proteins (immunoglobulin G, albumin and transferrin) were similarly labelled. Over a study period of up to 7 days, even with the polypeptides showing most prolonged blood survival (EAK and AcEAK) there was no particular uptake or retention in tumour tissue, over and above what was seen with control plasma proteins and/or in normal tissues. Overall these findings suggest that any enhanced permeability and retention in tumour tissue, reported by other workers with other synthetic macromolecules, operates poorly with the present polypeptides and/or tumours. Specific tumour targeting, for example with monoclonal antibodies, would seem a better option than non-specific accumulation of macromolecules.

Animals↗
PubMed1996

Gamma scintigraphy of the biodistribution of 123I-labelled N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates in mice with transplanted melanoma and mammary carcinoma.

An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin conjugate is currently under clinical evaluation as a new antitumour agent. It has been shown previously that such conjugates exhibit selective tumour accumulation. In this study HPMA copolymer doxorubicin conjugates of low (LMW) or high (HMW) molecular weight were synthesised (which had a weight average molecular weight (Mw) of 25,000 and 94,000 respectively) and additionally contained a small amount (1 mol%) of the comonomer methacryloyltyrosinamide to permit labelling with [123I or 125I]iodide. Gamma camera imaging using the 123I-labelled probes was used to follow time-dependent biodistribution after intraperitoneal (i.p.) or intravenous (i.v.) administration to mice bearing subcutaneously either B16F10 melanoma or a mammary carcinoma. Imaging showed more rapid clearance of LMW conjugate from the peritoneal cavity than HMW conjugate. The images of mice given the LMW conjugate revealed rapid urinary excretion of radioactivity after both i.p. and i.v. injection with an early high concentration of tracer in the bladder, and subsequently a very high concentration in the kidneys, which came to dominate the views. Dissection analysis 2 days after administration of the LMW conjugate revealed a kidney level of radioactivity corresponding to 25-40% dose/g tissue in mice bearing the two tumour models. Following administration of the HMW conjugate kidney accumulation at 2 days was less due to retention of the higher molecular weight polymer molecules in the circulation, and spleen and liver displayed the highest concentrations of radioactivity. The tumour accumulation of LMW and HMW conjugates was; mammary carcinoma 3.18 and 5.29% dose/g respectively; B16F10 melanoma 3.23 and 8.82 %dose/g although these levels of tracer enabled visualisation in the images of the mammary carcinoma with HMW conjugate at later time points. The smaller size of the B16F10 tumour masses did not permit clear visualisation.

Animals↗
PubMed1996

Gamma scintigraphy of a 123I-labelled N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugate containing galactosamine following intravenous administration to nude mice bearing hepatic human colon carcinoma.

Polymer drug conjugates composed of N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer covalently bound doxorubicin, and containing additionally galactosamine to facilitate hepatocyte-specific targeting (HPMA copolymer-dox-gal), were synthesised to contain a small amount (approximately 1 mol%) of the monomer methacryloyltyrosinamide to permit radioiodination with [123I]iodide. After intravenous administration to both normal mice and nude mice bearing hepatic human colon carcinoma, the biodistribution of the conjugate was monitored using the gamma camera, and also by dissection analysis. Efficient liver accumulation of HPMA copolymer-dox-gal was seen in the gamma camera images within 20 min, both in normal and tumour-bearing animals. Quantitatively liver uptake was approximately 40% dose administered/g liver. Images of the tumour-bearing animals showed clearly a much lower accumulation of HPMA copolymer-dox-gal in the colon carcinoma deposits within the liver (3-9% dose/g tumour), and this lack of uptake was verified by ex vivo imaging of the tumour-containing liver and also by dissection analysis. It can be concluded that 123I-labelled HPMA copolymer conjugates offer great potential as effective imaging agents and can be used for future non-invasive clinical studies. This nuclear imaging method will enable optimisation of the dosing schedule by identification of doses of HPMA copolymer-dox-gal that display receptor saturation (and hence diminished targeting efficiency). In addition this conjugate can provide negative images of liver-associated tumour deposits that do not express the asialoglycoprotein receptor.

Animals↗
PubMed1995

Determination of the immunoreactivity of radiolabelled monoclonal antibody fragments by binding to immobilised anti-idiotypic antibodies.

The feasibility of using immobilised anti-combining site (anti-idiotypic) antibodies as targets for assessing the immunoreactivity of radiolabelled anti-tumour monoclonal antibodies has been assessed. With two anti-tumour monoclonal antibodies (anti-CEA and anti-gp72) it was possible to quantify binding of their 125I labelled Fab fragment preparations to their anti-idiotypic monoclonal antibodies immobilised on cyanogen bromide activated Sepharose. Binding was specific for immobilised anti-idiotypic antibodies reactive with the anti-tumour antibody fragments. Moreover binding was inhibited by unlabelled Fab or intact monoclonal antibody, but not by an irrelevant antibody or its Fab fragment. The use of anti-idiotypic antibodies for quantifying immunoreactions of radiolabelled antibodies has advantages over the use of initial target antigen, which may be available only in inconvenient forms, such as cultured tumour cells.

Animals↗
PubMed1995

Gamma scintigraphy of 111In-labelled branched chain polypeptides (BCP) with a poly(L-lysine) backbone in mice with mammary carcinoma: effect of charge on biodistribution and tumour imaging potential.

Radiolabelled synthetic branched chain polypeptides (BCP) represent a new and novel range of materials with potential as radiopharmaceuticals. Preliminary imaging studies have been undertaken with 111In-labelled BCP in mice with subcutaneously transplanted mammary carcinoma. Four polypeptides each with a poly(L-lysine) backbone and side chains of DL-alanine residues were studied. These were AK, which is polycationic, EAK which is amphoteric, having additional glutamic acid residues at the end of the side chains, and AcEAK (anionic) and SucEAK (highly polyanionic) where the terminal glutamic acid amino groups were acetylated or succinylated respectively. Radiolabelling was achieved by previous conjugation with DTPA. Serial images up to 48 hours showed marked retention of 111In-labelled polycationic AK and polyanionic SucEAK in the liver and spleen, with renal uptake also being visible in the case of AK. 111In-labelled EAK and AcEAK showed longer blood survival with some liver uptake, but tumour uptake was also visualized by 24 hours with both of these polypeptides. These studies demonstrate the feasibility of using 111In-labelled synthetic branched chain polypeptides as radiopharmaceuticals for gamma scintigraphy and the visualization of tumours by modification of the side chain structure. These materials warrant further study.

Animals↗
PubMed1995

Circulating antigen: bad or good for immunoscintigraphy?

There is ample evidence to show that circulating antigen can restrict effective localization of radiolabelled murine monoclonal antibodies in human tumours growing as xenografts in Nude mice. This is the result of the formation of immune complexes in the circulation. Surprisingly this effect is not seen in patients with circulating antigen, although immune complexes are formed in the circulation, and immunoscintigraphy is not compromised. Moreover, at least in some situations, the presence and level of circulating antigen correlates positively with the sensitivity of tumour imaging, and circulating antigen can be used as a criterion of patient selection for immunoscintigraphy. The reason for the dichotomy between mouse and man is unclear, and seems to be the subject of little or no current research. The introduction of chimeric or fully human monoclonal antibodies in place of murine monoclonal antibodies means that clinical situations will now mimic more precisely the animal models. The species of antibody complexing with antigen will be homologous to the patients, and this could result in handling of those complexes in a manner different from the handling of complexes with foreign (i.e. murine) antibodies. Clearly this subject warrants further investigation.

Animals↗
PubMed1995

Targeting of bladder cancer with monoclonal antibody NCRC48--a possible approach for intravesical therapy.

OBJECTIVE: To determine the localization of the anti-MUC1 mucin monoclonal antibody (mAb) NCRC48 to bladder cancer following intravesical administration. PATIENTS AND METHODS: mAb NCRC48 (330-500 micrograms) radiolabelled with 111indium (11-17 MBq) was administered intravesically to 12 unselected patients with radiological evidence of bladder cancer. Tumour localization was assessed by gamma-camera imaging and by tissue biodistribution studies on biopsies obtained at cystoscopy at about 2 or 24 h after the procedure. After 24 h, whole blood radioactivity was measured and 3 weeks after the procedure the serum level of human anti-mouse antibodies was estimated using an ELISA method. RESULTS: Eleven patients had tumours confirmed at cystoscopy (grades 1-3, stages pTa-pT2). The mean uptake of NCRC48 by tumour and by normal urothelium (expressed as the percentage of the instilled dose/g x 10(3) +/- SD) at 2 h was 3.42 +/- 3.68 and 0.41 +/- 0.77 (P < 0.05). After 24 h, the values for tumour and normal urothelium were 1.17 +/- 1.18 and 0.17 +/- 0.11, respectively. Areas of increased activity on the scintigrams were consistent with the position of the tumours at cystoscopy. No radioactivity was detected in blood at 24 h and there was no evidence of a human anti-mouse antibody response. CONCLUSION: The MUC1 mucin may be a suitable antigen to study the potential of therapeutic strategies based on monoclonal antibody targeting of superficial bladder cancer and may allow the development of more effective agents in the treatment of this condition.

Aged↗
PubMed1994

Possible consequences of human antibody responses on the biodistribution of fragments of human, humanized or chimeric monoclonal antibodies: a note of caution.

The effect of anti-combining site antibody responses on the biodistribution of monoclonal antibodies intended for diagnostic or therapeutic purposes is considered. The new generation of chimeric, humanized or human antibodies may well still be immunogenic in man, due to reaction against their combining sites. The likely consequence of this immunogenicity is clearance of antibodies from the circulation. This is already appreciated, and can be modelled in animal studies. However the effect of such anti-combining site responses on the biodistribution of F(ab')2 or Fab fragments of chimeric or human antibodies, or the new generation of fragments such as Fv, is a yet unknown. Animal modelling studies suggest that anti-combining site responses may have totally unexpected consequences. They may not lead to clearance of fragments. Indeed survival of fragments can be greatly prolonged, but target recognition prevented.

Animals↗
PubMed1994

Evaluation of 153Sm-diethylenetriaminepentaacetic acid for radiolabelling of pharmaceutical dosage forms by neutron activation.

153Sm-DTPA provides a suitable alternative to 99mTc-DTPA and 111In-DTPA as a water soluble tracer for the evaluation of pharmaceutical preparations. The chelate was handled biologically in a similar way to 99mTc-DTPA and 111In-DTPA. The chelate can be incorporated into the formulation as a non-radioactive excipient and the intact dosage form can then be neutron activated to produce 153Sm.

Administration, Inhalation↗
PubMed1994

Influence of a syngeneic anti-idiotypic antibody response to a mouse anti-tumour monoclonal antibody on biodistribution of its radiolabelled Fc-intact monovalent Fab/c fragment.

It has previously been shown that a syngeneic anti-idiotypic (anti-id) antibody response generated in Balb/c mice to the monoclonal antibody (Mab) NCRC-2 can cause its clearance from the circulation. However, there was a positive prolongation of the survival of the Fab fragment, which is monovalent but also lacks Fc. The present study was carried out to examine the effect against the Fab/c fragment of this Mab, since this is also monovalent but has intact Fc. There was accelerated clearance, rather than retention. This suggests that anti-id responses prolong survival of fragments because they lack Fc, rather than only because of their monovalency. Such monovalent, Fc deficient fragments, are the type of human antibody fragments most easily obtained by genetic engineering techniques for clinical use. The present findings have implication for the effects of patients' immune responses on the biodistribution of such fragments.

Animals↗
PubMed1994

Scintigraphic determination of the biodistribution of an 111In-labelled poly(L-lysine) backbone branched polypeptide drug carrier in tumour-bearing mice.

A branched polypeptide drug carrier, with a poly(L-lysine) backbone, has been labelled with 111In and its biodistribution imaged in mice with transplanted B16 melanoma. Levels of tracer in tumours were not great enough for tumours to be discerned on gamma-camera images, and this was confirmed by subsequent dissection analysis. Tumour levels of 111In from labelled polymer were about 3% of the dose g-1 two days after injection. Similar levels of tracer were found in tumour tissue of mice injected with mouse immunoglobulin or serum albumin labelled with 111In by DTPA chelation, or injected with free 111In-chloride to label serum transferrin. There was rapid excretion of a sub-component of the 111In-labelled polymer visible in the images. Gel permeation chromatography suggested that the polymer was heterogeneous, some components having Stoke's radii below that allowing renal clearance. Gel permeation chromatography was used to separate labelled polymer into fractions having high, intermediate and low renal clearance. The low-excretion fraction showed a two-fold increase in tumour levels, compared with native polymer, although as this fraction showed greater survival in the blood and body as a whole, discrimination between tumour and normal tissue was not increased.

Animals↗
PubMed1994

Gamma scintigraphy in the delivery, biodistribution and targeting of therapeutic agents.

The established clinical role of radionuclide imaging includes the diagnosis and monitoring of a wide range of clinical conditions. The therapeutic use of radionuclides has centred on a relatively small number of pathological conditions, particularly within the field of oncology. More recently there has been growing interest in the use of radionuclide imaging in drug evaluation and research (RIDER). Studies have been undertaken in order to increase the understanding of the in in vivo behaviour of pharmaceutical dosage forms in addition to the in vivo behaviour of molecular and cellular anti-tumour agents. The imaging facilities required for such undertakings are available in most nuclear medicine departments, although the expertise for radiolabelling and the requirements for the production of drug conjugates and pharmaceutical formulations are limited to a small number of centres. This paper discusses the application of radionuclide imaging in drug research with particular reference to the role of gamma-scintigraphy in monitoring the biodistribution and pharmacokinetics of immune mediated drug conjugates intended for the treatment of malignant disease. Examples described include the evaluation of oral and inhaled drug delivery systems and the biodistribution and in vivo kinetics of parenteral administrations.

Animals↗
PubMed1993

Influence of syngeneic monoclonal anti-idiotypic antibodies to murine monoclonal antibodies against tumour-associated antigens on the biodistribution of their target antibodies and their fragments.

The effect of syngeneic anti-idiotypic (anti-id) antibodies on the biodistribution of three murine monoclonal antibodies (mAb) against human tumour-associated antigens, and also on that of their fragments, has been examined in mice using, as a model system, purified anti-id mAb against three different target mAb. With the IgG2b mAb NCRC-2, pretreatment of mice 24 h previously with its IgG1 anti-id mAb NCRC-60 caused clearance of subsequently administered NCRC-2. With the univalent Fab/c fragment of NCRC-2 there was little effect, even with anti-id to Fab/c pretreatment ratios of 20:1, although immune complexes were present in the circulation. With Fab of NCRC-2, anti-id mAb prolonged blood survival by reducing renal clearance, immune complexes surviving in the circulation. With the IgG1 mAb NCRC-23, immune complexes formed in vivo with the IgG2b anti-id mAb NCRC-59, but with only little hepatic clearance. With the Fab and F(ab')2 fragments of NCRC-23, blood survival was increased in mice pretreated with anti-id mAb, and with Fab this was clearly due to reduced renal clearance. The third mAb, the IgG3 NCRC-48, formed complexes with its IgG2a anti-id mAb NCRC-62, but these survived in the circulation with no accelerated clearance of the target mAb. These results are different from those previously seen with endogenous anti-id responses. They indicate the diversity of effects that anti-id mAb can have on the biodistribution of their target mAb, and emphasise the difficulty of using such anti-id mAb to modulate the pharmacokinetics of target mAb.

Animals↗
PubMed1993

Immunoscintigraphy of ovarian carcinoma using a monoclonal antibody (111In-NCRC48) defining a polymorphic epithelial mucin (PEM) epitope.

An anti-polymorphic epithelial mucin (PEM) monoclonal antibody NCRC48 (IgG3) has been tested for its capacity to localize in tumours according to accepted guidelines for human administration. Following radiolabelling with 111In, 1 mg antibody was administered to 19 patients with a clinical suspicion of ovarian malignancy. Initial imaging and biodistribution studies confirm the safety of this conjugate although six out of 11 patients tested developed an antibody response to the monoclonal antibody. Immunoscintigraphy with this antibody was compared with magnetic resonance imaging and ultrasound in relation to the final tumour histology, the final accuracies being 79, 79 and 64% respectively. Positive localization of antibody was confirmed in malignant tissue with little evidence of uptake in benign tissue.

Adenocarcinoma↗