““Challenges in Developing Preclinical Challenges in Developing Preclinical Models of Hepatocellular CarcinomaModels of Hepatocellular Carcinoma””

San Diego, January, 2010

Cedo Bagi M.D., Ph.D.Senior Research Fellow, GS&T

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Challenges in Developing HCC ModelsChallenges in Developing HCC Models

1. Importance of the liver in pharmaceutical sciences2. Management of primary liver tumors and metastases of other tumors to the liver are huge clinical problem

Xenograft and orthotopic modelsBiomarkers and imagingLiver vasculature: Implications for tumor growth and tumor metastases to liverDrug administration and tumor targetingHCC cell lines and liver biopsiesNeed for combination therapiesChimeric mice models (humanized liver models)HBV/HCV and HCC models

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XenograftXenograft and and OrthotopicOrthotopic HCC ModelsHCC Models

• Body weight• Caliper • AFP• Human albumin • Liver function and • Serum chemistry • Histology• Histochemstry• IVIS imaging• Ultrasound• X-ray + contrast• MRI/PET

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• Importance of functional and nutritional vasculature for liver function; Tumor vasculature

• Theories behind tumor growth and metastases• seed and soil• anatomical• mechanical• haemodynamic

central vein

portal triad

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3zo

nes 1

- 3

• Basic lobular architecture - Blood flows from the portal tract into the hepatic sinusoids and leaves the lobule via the terminal (“central”) venule

portal triad

central vein

Liver vasculature Liver vasculature -- Implication for Implication for tumor growth and metastasestumor growth and metastases

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Flow distribution• total liver blood flow represents approximately 25% of the cardiac output (1500ml/min)• total liver blood flow is 100-130 ml/min per 100 g liver independent of species• 25-30% comes through HA (500 ml/min), accounts for 65% oxygen supply• HA plays important role in liver blood vessel and connective tissue perfusion and bile duct integrity• there are both common and separate channels for arterial (spotty) and portal (uniform) blood supply

Liver vasculature Liver vasculature -- Implication for Implication for tumor growth and metastasestumor growth and metastases

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Hepatic artery Hepatic artery cannulationcannulation ––Implications for tumor growthImplications for tumor growth

• Nude Rats, n = 20• Day 0: Huh7.5 cell implantation • Day 11: Serum AFP, randomize• Day 12, 13: HA Surgery• Days 18, 25, 32: Serum AFP• Day 32: Necropsy

rat mouse

• Body weight• Liver weight • Tumor weight• AFP• Serum chemistry• Liver function

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• Hepatic Artery Cannulation procedure reduced tumor growth;• Effect of cannulation on tumor growth should be considered when

designing studies using the HA dose route

Serum AFP at the end of study

Hepatic artery Hepatic artery cannulationcannulation ––Implications for tumor growthImplications for tumor growth

HA

canula

cannulation

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MucrobubbleMucrobubble delivery systemdelivery system

3. Tumor vasculature: 3. Tumor vasculature: Implication for drug deliveryImplication for drug delivery

Project Objective:

• Microbubbles (MB) provide an optimal, internal, minimally invasive drug-delivery vehicle. They measure 2 to 4 microns, which is smaller than the size of a red blood cell.

• This dimension enables these small vehicles to easily course within the flow of the smallest blood vessels.

• Once injected, Microbubbles can transport therapeutics throughout the circulatory system, with their path tracked by ultrasonic imaging.

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Contrast Uptake in the Liver Contrast Uptake in the Liver

Study goal:Assess liver take rate of contrast agent by using 3 different routs of contrast injection:

1. tail vain2. portal vain3. hepatic artery

• Species: rats• Contrast agent: VisualSonics Micromarker bubbles• Volume of contrast injected: 50ml• Visual Sonics Ultra Sound system used in the study

Liver vasculature Liver vasculature --Implication for drug deliveryImplication for drug delivery

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hepatic arteryhepatic arteryportal vainportal vaintail vaintail vain

Liver vasculature Liver vasculature --Implication for drug deliveryImplication for drug delivery

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