Delivery of molecular and cellular medicine to solid tumors

https://doi.org/10.1016/S0168-3659(97)00237-XGet rights and content

Abstract

To reach cancer cells in a tumor, a blood-borne therapeutic molecule or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps experimentally and theoretically, and then integrate the resulting information in a unified theoretical framework. This paradigm of analysis and synthesis has allowed us to obtain a better understanding of physiological barriers in solid tumors, and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.

Introduction

Cancer is the second leading cause of death in the United States and in many industrialized countries [1]. After the primary tumor has been surgically removed and/or sterilized by radiation, the residual disease is usually managed with a variety of systemic therapies (Table 1). For these therapies to be successful, they must satisfy two requirements: (a) the relevant agent must be effective in the in vivo orthotopic microenvironment of tumors, and (b) this agent must reach the target cells in vivo in optimal quantities. The goal of our research is to examine the latter issue — the delivery of diagnostic and therapeutic agents to solid tumors and normal host tissues.

All conventional and novel therapeutic agents can be divided into three categories – molecules, particles and cells (Table 1). A blood-borne molecule or particle that enters the tumor vasculature reaches cancer cells via distribution through the vascular compartment, transport across the microvascular wall, and transport through the interstitial compartment. For a molecule of given size, charge and configuration, each of these transport processes may involve diffusion and convection. In addition, during the journey the molecule may bind nonspecifically to proteins or other tissue components, bind specifically to the target(s), or be metabolized [2]. Although lymphokine-activated killer (LAK) cells (lymphocytes activated by the lymphokine interleukin-2) or tumor-infiltrating lymphocytes (TIL) are capable of deformation, adhesion and migration, they encounter the same barriers that restrict their movement in tumors. Some of these physiological parameters are also important for heat transfer in normal and tumor tissues during hyperthermic treatment of cancer [3].

The overall aim of our research is to develop a quantitative understanding of each of the above mentioned steps involved in the delivery of various agents. More specifically, our goals are to understand (1) how angiogenesis takes place and what determines blood flow heterogeneities in tumors, (2) how blood flow influences the metabolic microenvironment in tumors, and how microenvironment affects the biological properties of tumors (e.g., vascular permeability; cell adhesion), (3) how material moves across the microvascular wall, and (4) how it moves through the interstitial compartment and the lymphatics. In addition, we are examining the role of cell deformation and adhesion in the delivery of cells. Following analysis of these processes for molecules, particles and cells, we integrate this information in a unified framework for scale-up from mice to men (Fig. 1). In this article, I will briefly describe various experimental and theoretical approaches used in our laboratory, our recent findings in these six areas, and finally, how we have taken some of these concepts from bench to bedside for potential improvement in cancer detection and treatment.

Section snippets

Experimental and theoretical approaches

We have utilized five approaches to gain insight into the pathophysiology of solid tumors:

  • 1.

    A tissue-isolated tumor which is connected to the host's circulation by a single artery and a single vein 4, 5. This technique was originally developed by P.M. Gullino at the National Cancer Institute in 1961 for rats [6]; we have recently adapted it to mice 7, 8and humans [9].

  • 2.

    A modified Sandison rabbit ear chamber 10, 11, a modified Algire mouse dorsal chamber 12, 13, and a cranial window in mice and rats

Distribution through vascular space

The tumor vasculature consists of both vessels recruited from the preexisting network of the host vasculature, and vessels resulting from the angiogenic response of host vessels to cancer cells 38, 39. Movement of molecules through the vasculature is governed by the vascular morphology (i.e. the number, length, diameter and geometric arrangement of various blood vessels) and the blood flow-rate 25, 40, 41, 42.

Although the tumor vasculature originates from the host vasculature and the mechanisms

Metabolic microenvironment

The temporal and spatial heterogeneities in blood flow are expected to lead to a compromised metabolic microenvironment in tumors. To quantify the spatial gradients of key metabolites, we have recently adapted two optical techniques: fluorescence ratio-imaging microscopy (FRIM) and phosphorescence quenching microscopy (PQM) 51, 52, 53, 54, 55. As shown in Fig. 6, both pH and pO2 decrease as one moves away from tumor vessels leading to acidic and hypoxic regions in tumors. While low pO2 and pH

Transport across the microvascular wall

Once a blood-borne molecule has reached an exchange vessel, its extravasation, Js (g/s), occurs by diffusion and convection and, to some extent, presumably by transcytosis [60]. Diffusive flux is proportional to the exchange vessel's surface area, S (cm2), and the difference between the plasma and interstitial concentrations, CpCi (g/m). Convection is proportional to the rate of fluid leakage, Jf (m/s), from the vessel. Jf, in turn, is proportional to S and the difference between the vascular

Transport through interstitial space and lymphatics

Once a molecule has extravasated, its movement through the interstitial space occurs by diffusion and convection [79]. Diffusion is proportional to the concentration gradient in the interstitium, and convection is proportional to the interstitial fluid velocity, ui (cm/s). The latter, in turn, is proportional to the pressure gradient in the interstitium. Just as the interstitial diffusion coefficient, D (cm2/s), relates the diffusive flux to the concentration gradient, the interstitial

Transport of cells

So far we have discussed the parameters that govern the transport of molecules and particles (e.g., liposomes) in tumors. When a leukocyte enters a blood vessel, it may continue to move with flowing blood, collide with the vessel wall, adhere transiently or stably, and finally extravasate. These interactions are governed by both local hydrodynamic forces and adhesive forces. The former are determined by the vessel diameter and fluid velocity, and the latter by the expression, strength and

Pharmacokinetic modeling: scale up from mouse to human

So far we have analyzed each of the steps in the delivery of molecules and cells to and within solid tumors. Can we take this information and integrate it in a unified framework? We have been successful to some extent in this endeavor, using physiologically-based pharmacokinetic modeling. This approach, pioneered by two chemical engineers, K. Bischoff and R.L. Dedrick in the 1960s, has been applied successfully to describe and scale up the biodistribution of low molecular mass agents (for a

Bench to bedside

The physiological factors that contribute to the poor delivery of therapeutic agents to tumors include heterogeneous blood supply, interstitial hypertension, relatively long transport distances in the interstitium and cellular heterogeneities (Fig. 5). How can these physiological barriers be exploited or overcome? Can we take our findings about these barriers from the bench to the bedside? Two recently developed strategies that have the potential to improve the detection and treatment of solid

Acknowledgements

I am grateful to my former and current collaborators who have made working on this difficult and often frustrating problem a real joy. They and others working independently on this problem have contributed significantly to the accomplishments summarized in this article. I wish to thank Pietro M. Gullino, Marcos Intaglietta and Herman D. Suit for their encouragement, wise counsel and unconditional support. I also thank Carol Lyons and Stuart Friedrich for typing this manuscript, Larry Baxter and

References (151)

  • P.A Netti et al.

    Effect of transvascular fluid exchange on arterio–venous pressure relationship: Implication for temporal and spatial heterogeneities in tumor blood flow

    Microvasc. Res.

    (1996)
  • J.W Baish et al.

    A novel approach to examine the role of vascular heterogeneity in nutrient and drug delivery for tumors: An invasion percolation model

    Microvasc. Res.

    (1996)
  • S Patan et al.

    Intussusceptive microvascular growth in solid tumors: A novel mechanism of tumor angiogenesis

    Microvasc. Res.

    (1996)
  • G.R Martin et al.

    Fluorescence ratio imaging measurement of pH gradients: calibration and application in normal and tumor tissues

    Microvasc. Res.

    (1993)
  • L.E Gerlowski et al.

    Microvascular permeability of normal and neoplastic tissues

    Microvasc. Res.

    (1986)
  • F Yuan et al.

    Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice

    Microvasc. Res.

    (1993)
  • Y Boucher et al.

    Lack of general correlation between interstitial fluid pressure and pO2 in tumors

    Microvasc. Res.

    (1995)
  • D.A Berk et al.

    Fluorescence photobleaching with spatial Fourier analysis: measurement of diffusion in light-scattering media

    Biophys. J.

    (1993)
  • E.M Johnson et al.

    Diffusion and partitioning of proteins in charged agarose gels

    Biophys. J.

    (1995)
  • M.E Johnson et al.

    Lateral diffusion of small compounds in human stratum corneum and model lipid bilayer systems

    Biophys. J.

    (1996)
  • E.N Kaufman et al.

    Quantification of transport and binding parameters using fluorescence recovery after photobleaching: Potential for in vivo applications

    Biophys. J.

    (1990)
  • E.N Kaufman et al.

    Measurement of mass transport and reaction parameters in bulk solution using photobleaching: Reaction limited binding regime

    Biophys. J.

    (1991)
  • T Beardsley

    Trends in cancer epidemiology: A war not won

    Sci. Am.

    (1994)
  • R.K Jain

    Barriers to drug delivery in solid tumors

    Sci. Am.

    (1994)
  • E.M Sevick et al.

    Blood flow and venous pH of tissue-isolated Walker 256 carcinoma during hyperglycemia

    Cancer Res.

    (1988)
  • E.M Sevick et al.

    Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure

    Cancer Res.

    (1989)
  • P.M. Gullino, Techniques in tumor pathophysiology, in: H. Busch (Ed.), Methods in Cancer Research, Academic Press, New...
  • P.E.G Kristjansen et al.

    Intratumor pharmacokinetics, flow resistance, and metabolism during gemcitabine infusion in ex vivo perfused human small cell lung cancer

    Clin. Cancer Res.

    (1996)
  • J.R Less et al.

    Geometric resistance to blood flow and vascular network architecture in human colorectal carcinoma

    Microcirculation

    (1997)
  • M Leunig et al.

    Angiogenesis and growth of isografted bone: quantitative in vivo assay in nude mice

    Lab. Invest.

    (1994)
  • M Leunig et al.

    Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice

    Cancer Res.

    (1992)
  • F Yuan et al.

    Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows

    Cancer Res.

    (1994)
  • D.S. Milstone, D. Fukumura, R.C. Padget, P.E. O'Donnell, V.M. Davis, O.J. Benavidez, R.J. Melder, R.K. Jain, M.A....
  • M Dellian et al.

    Quantitation and physiological characterization of bFGF and VEGF/VPF induced vessels in mice: Effect of microenvironment on angiogenesis

    Am. J. Pathol.

    (1996)
  • H.C Lichtenbeld et al.

    Perfusion of single tumor microvessels: Application to vascular permeability measurement

    Microcirculation

    (1996)
  • R.J Melder et al.

    Imaging of activated natural killer cells in mice by positron emission tomography: preferential uptake in tumors

    Cancer Res.

    (1993)
  • A Sasaki et al.

    Low deformability of lymphokine-activated killer cells as a possible determinant of in vivo distribution

    Cancer Res.

    (1989)
  • T.T Traykov et al.

    Effect of glucose and galactose on red blood cell membrane deformability

    Int. J. Microcirc.: Clin. Exp.

    (1987)
  • L Munn et al.

    Kinetics of adhesion molecule expression and spatial organization using targeted sampling fluorometry

    Biotechniques

    (1995)
  • L.T Baxter et al.

    Biodistribution of monoclonal antibodies: Scale-up from mouse to man using a physiologically based pharmacokinetic model

    Cancer Res.

    (1995)
  • L.T Baxter et al.

    Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice

    Cancer Res.

    (1994)
  • C.J Eskey et al.

    Residence time distributions of various tracers in tumors: implications for drug delivery and blood flow measurement

    J. Natl. Canc. Inst.

    (1994)
  • R.K Jain et al.

    Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure

    Cancer Res.

    (1988)
  • R.K Jain et al.

    Dynamics of drug transport in solid tumors: Distributed parameter model

    J. Bioeng.

    (1977)
  • R.K Jain et al.

    Pharmacokinetics of methotrexate in solid tumors

    J. Pharmacokin. Biopharm.

    (1979)
  • P.A Netti et al.

    Time dependent behavior of interstitial pressure in solid tumors: Implications for drug delivery

    Cancer Res.

    (1995)
  • R.N Pierson et al.

    Extracellular water measurements: Organ tracer kinetics of bromide and sucrose in rats and man

    Am. J. Physiol.

    (1978)
  • F Yuan et al.

    Pharmacokinetic analysis of two-step approaches using bifunctional and enzyme-conjugated antibodies

    Cancer Res.

    (1991)
  • J. Folkman, Tumor angiogenesis, in: P.M. Mendelsohn, M.A.P. Howley, L.A. Liotta (Eds.), The Molecular Basis of Cancer,...
  • R.K Jain

    Determinants of tumor blood flow: a review

    Cancer Res.

    (1988)
  • Cited by (175)

    • Applications of nanotechnology in lung cancer

      2022, Applications of Nanotechnology in Drug Discovery and Delivery
    • A drug delivery perspective on intratumoral-immunotherapy in renal cell carcinoma

      2021, Urologic Oncology: Seminars and Original Investigations
      Citation Excerpt :

      Drugs deposited in the subcutaneous space can be reabsorbed back into the systemic circulation through partition into blood capillaries [28] and lymphatic vessels [29]. Such processes may be enhanced by the interstitial hypertension in epithelial tumors [30]. In a series of studies using human tumor xenografts, Jain et al. have shown that the increased pressure results in an outward convective current, moving the interstitial fluid (and drugs dissolved within) away from the tumor mass.

    • Hypoxia-responsive block copolymer radiosensitizers as anticancer drug nanocarriers for enhanced chemoradiotherapy of bulky solid tumors

      2018, Biomaterials
      Citation Excerpt :

      Notably, 5-nitroimidazole derivatives have attracted more attention due to relatively high biosafety as compared with 2-nitroimidazoles which had severe neurotoxicity despite of high radiosensitization activity in all solid murine tumor models [47,48]. However, the small-molecule radiosensitizers have the intrinsic limitations to diffuse into the hypoxic regions of tumor tissues due to the dense matrix structure and elevated levels of interstitial fluid pressure [27,49]. Well-designed nanoparticles with suitable physicochemical properties have been demonstrated to penetrate into deep tumor tissues, such as relatively small size [29,50,51].

    • Emerging strategies for delivering antiangiogenic therapies to primary and metastatic brain tumors

      2017, Advanced Drug Delivery Reviews
      Citation Excerpt :

      the basement membrane (a double membrane, with the endothelial BM on the vascular wall side, and the parenchymal BM formed by astrocytes on the brain parenchyma side), and finally (3.) diffusion through the brain parenchyma and/or modified physical architecture of the brain tumor [132,133]. Despite the key role of the BBB/BTB in drug delivery, some anti-angiogenic therapies may, however, not necessarily require to cross the BBB/BTB in order to be active, since they provide the advantage that they exert their activity on the endothelial cell itself [102].

    View all citing articles on Scopus
    View full text