Adriamycin‐loaded albumin microspheres: Preparation, in vivo distribution and release in the rat

Murray²,

Kerr³

et al. 1991

Summary Cytotoxic microspheres have been developed for intra-arterial use in patients with liver metastases. Following injection, the distribution of microspheres reflects the pattern of hepatic arterial blood-flow. Vasoactive agents, such as angiotensin II, by producing vasoconstriction in normal liver, might divert arterial blood toward tumour and thereby enhtance the delivery of drug-loaded particles. Using a double isotope technique, the distribution of radiolablled microspheres to tumour and normal liver tissue was measured before and after angiotensin II infusion in nine patients with multiple liver metastases. The median increase in tumour: normal ratio following angiotensin II infusion was by a factor of 2.8 (range 0.8-11.7, P<0.05). This novel approach to regional chemotherapy, using a combination of angiotensin II infusion and cytotoxic microspheres, increases the exposure of tumour to cytotoxic agents and may, therefore, enhance tumour response rates.Sixty percent of patients dying after resection of colorectal cancer are known to have liver metastases at the time of death (Welch & Donaldson, 1979;Ridge & Daly, 1985). The results of systemic chemotherapy have been disappointing; escalation of dose or multi-drug regimes may increase the response rate but are associated with unacceptable toxicity.It is known that liver metastases derive their blood-supply predominantly from the hepatic artery (Ridge et al., 1987) and attention has therefore turned to the concept of regional chemotherapy. In theory, the administration of cytotoxic drugs via the hepatic artery should increase drug levels within the tumour while minimising systemic toxicity (Kato et al., 1981). To date, however, improved survival following bolus intra-hepatic arterial chemotherapy has not been demonstrated (Malik & Wrigley, 1988; Allen-Mersh, 1989). This may be because, following bolus injection, the tumour-bearing liver is exposed to high drug levels only transiently (Goldberg et al., 1988).One means of retaining anti-cancer agents more effectively within the liver might be to load the active agent into embolising particles. There have been reports of chemotherapeutic agents such as adriamycin and mitomycin C being carried in biodegradable particles which act as slowrelease systems when administered via the hepatic artery (McArdle et al., 1988;Fujimoto et al., 1985). Unfortunately, the distribution of arterially administered particles reflects the pattern of arterial blood-flow within the liver, and the proportion of drug reaching hypovascular tumours will be low.Previous studies in animal models have suggested that vasoactive agents such as noradrenaline and angiotensin II modify the pattern of arterial blood-flow by causing temporary arteriolar constriction in normal blood-vessels (Burton et al., 1985). Hepatic tumour vasculature is immature, possessing neither smooth muscle nor an adrenergic nerve supply, and is therefore unable to respond to arterio-constrictors in the same way as normal vasculature (Hafstrom et al., 1980;Mattson et a...

Section: Methodsmentioning

confidence: 99%

The use of angiotensin II as a potential method of targeting cytotoxic microspheres in patients with intrahepatic tumour

Murray²,

Kerr³

et al. 1991

“…We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al, 1988;Willmott et al, 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow.…”

mentioning

confidence: 99%

Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases

Thomson²,

Bradnam³

et al. 1991

Summary Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging.The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P <0.05).The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.Post-mortem studies have shown that up to 70% of patients dying after a potentially curative resection for colorectal cancer, die with liver metastases. The prognosis of patients with colorectal liver metastases is generally poor, survival being in the range of 3 to 9 months (Woods, 1984;Nielsen et al., 1971).Surgical resection of colorectal hepatic metastases may be effective in patients with limited disease (Bradpiece et al., 1987), but may not be feasible in the majority of patients where multiple tumours are present. Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al., 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.It is known that established colorectal liver metastases receive their blood supply from the hepatic artery and the administration of anti-cancer drugs via an indwelling hepatic arterial catheter is now widely practised (Ridge et al., 1987). Unfortunately, although the tumour response rates may increase when chemotherapeutic agents are administered intraarterially rather than systemically (Berger, 1981) a significant increase in survival among treated patients has not been demonstrated by randomised controlled trial (Malik & Wrigley, 1988).Novel chemotherapeutic drug delivery systems including cytotoxic loaded or radioactive microspheres for administration by the arterial route, have been developed. We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al., 1988;Willmott et al., 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow. How...

“…This consituted the disperse phase of a water in oil emulsion which was prepared with a Silverson mixer. The droplets were stablised by the addition of 240 ItI 15% glutaraldehyde solution and the resulting microspheres separated and made ready for in vivo use as described elsewhere (Willmott et al, 1985). For each batch of particles, the 50% weight average fell within the range of 25-40ytm.…”

Section: Methodsmentioning

confidence: 99%

Arteriovenous shunting in patients with colorectal liver metastases

Thomson²,

McCurrach³

et al. 1991

SummaryThe outlook for patients with colorectal liver metastases is poor. Microspheres have been combined with cytotoxics and administered via the hepatic artery in an attempt to improve tumour drug exposure within the liver. However, it has been suggested that arteriovenous connections might occur in association with intrahepatic tumours causing loss of regional advantage, and that the administration of microspheres further exacerbates arteriovenous shunting. In seven patients with colorectal liver metastases, base-line shunting was measured using a tracer quantity of radio-labelled albumin microspheres. The shunted fraction of a 'therapeutic quantity' of microspheres was subsequently measured in the same group of patients using albumin microspheres carrying a different radio-label. Base-line shunt for 0.5 x 106 microspheres was found to be 2.2 ± 1.8% (mean ± s.d.); the percentage shunt of a therapeutic quantity (40 -80 x 106) of microspheres was 3.0±0.8%. We conclude that arteriovenous shunting in patients with colorectal liver metastases is minimal, and is not significantly increased by the administration of therapeutic quantity of microspheres during regional chemotherapy.Conventional treatment of colorectal liver metastases has yielded disappointing results, and attention has turned to hepatic arterial chemotherapy. The potential advantages of regional therapy over systemic drug administration are that high drug levels can be achieved in the tumour-bearing organ and that systemic drug concentrations fall when the drug is retained within the organ, thereby minimising toxicity.Particle-bound regional chemotherapy has been used in an attempt to improve drug uptake by the target organ. There are two mechanisms of value. Firstly, cytotoxic drugs have been co-administered with biodegradable microspheres which temporarily slow hepatic arterial blood-flow in the tumourbearing liver and increase uptake of drug by the cells (Dakhil et al., 1982;Thom et al., 1989). Secondly, anti-cancer agents, including Adriamycin, mitomycin C, 5 fluorouracil, cis-platin and cytocidal radio-nuclides have been loaded into particles which act as controlled release vehicles in the target tissue Fujimoto et al., 1985;Okamoto et al., 1986;Herba et al., 1988).If, however, arteriovenous shunting were associated with liver metastases (Zeissman et al., 1983), a proportion of arterially administered drug would bypass vascular beds in the tumour-bearing liver and be carried to the lungs. The effect would be to reduce tumour drug exposure, increase systemic side-effects and in the case of some particle-bound cytotoxics, increase pulmonary toxicity.With both approaches for enhancing regional therapy, relatively large numbers of particles may be required, either because of the relatively low drug pay-loads associated with some cytotoxic-loaded microspheres, or in order to optimise the arrest of arterial blood-flow. Unfortunately, there have been reports that very high levels of shunting occur when large numbers of microspheres are injected into th...