Microvascular permeability of normal and neoplastic tissues

doi:10.1016/0026-2862(86)90018-X

Microvascular Research

Volume 31, Issue 3, May 1986, Pages 288-305

https://doi.org/10.1016/0026-2862(86)90018-X Get rights and content

Abstract

A novel, noninvasive method was developed for microvascular permeability measurements in non-malignant (mature granulation) and neoplastic (VX2 carcinoma) tissues grown in the rabbit ear chamber. Dextran of 150,000 molecular weight, tagged with fluorescein isothiocyanate (FITC), was used as a representative tracer molecule. In vivo plasma concentration of dextran was measured by photometric analysis of the plasma layer of microvessels in the ear chamber. The plasma concentration in both normal and tumor preparations rose rapidly to a steady state with a time constant of 4.06 ± 0.2 sec, and remained relatively constant at that level for the next 2 hr (elimination time constant = 1.77 ± 0.9 × 10⁵ sec). Extravasation of macromolecules from individual microvessels into the extravascular space was measured with the same photometric technique. Interstitial diffusion coefficients and microvascular permeability coefficients were determined by fitting a one-dimensional permeability-diffusion model to the extravasation data. The diffusivity of dextran in tumor interstitium was 2.2 ± 1.4 × 10⁻⁸ cm²/sec (n = 6) and in granulation tissue interstitium was 6.7 ± 4.4 × 10⁻¹⁰ cm²/sec (n = 6). Microvascular permeability in tumors was 7.26 ± 3.29 × 10⁻⁸ cm/sec (n = 11) and in granulation tissue was 57.24 ± 39.24 × 10⁻⁸ cm/sec (n = 10). These results on increased permeability (8-fold; P < 0.002) and increased diffusivity (33-fold; P < 0.001) in tumors provide a rational basis for the use of largemolecular-weight agents in the detection and treatment of solid tumors.

References (42)

T.W. Dudar et al.
Microcirculatory flow changes during tissue growth
Microvasc. Res.
(1983)
J.O. Fenstermacher et al.
Methods for quantifying transport of drugs across brain barrier systems
Pharmacol. Ther.
(1981)
J.R. Fox et al.
Interstitial diffusion of macromolecules in the rat mesentery
Microvasc. Res.
(1979)
L.E. Gerlowski et al.
Physiologically based pharmacokinetics: Principles and applications
J. Pharm. Sci.
(1983)
K.A. Granath et al.
Molecular weight distribution analysis by gel chromatography on sephadex
J. Chromatogr.
(1967)
A. Hirano et al.
Vascular structures in brain tumors
Human Pathol.
(1975)
P.F. McDonagh et al.
The preparation and use of fluorescent-protein conjugates for microvascular research
Microvasc. Res.
(1984)
L.J. Nugent et al.
Monitoring transport in the rabbit ear chamber
Microvasc. Res.
(1982)
L.J. Nugent et al.
Pore and fiber-matrix models for diffusive transport in normal and neoplastic tissues
Microvasc. Res.
(1984)
B.A. Warren
The ultrastructure of the microcirculation at the advancing edge of Walker 256 carcinoma
Microvasc. Res.
(1970)

D.F. Zawicki et al.

Dynamics of neovascularization in normal tissue

Microvasc. Res.

(1981)

N.B. Ackerman et al.

Studies on the capillary permeability of experimental liver metastases

Surg. Gynecol. Obstet.

(1978)

N.H. Areskog et al.

Studies on heart lymph II. Capillary permeability of the dog's heart using dextran as a test substance

Acta Physiol. Scand.

(1964)

K.E. Arfors et al.

Microvascular transport of macromolecules in normal and inflammatory conditions

Acta Physiol. Scand. Suppl.

(1979)

E.J. Bowen et al.

Fluorescence of Solutions

(1953)

R.D.H. Boyd et al.

Permeability of lung capillaries to macromolecules in fetal and newborn lambs and sheep

J. Physiol.

(1968)

T.P. Butler et al.

Bulk transfer of fluid in the interstitial compartment of mammary tumors

Cancer Res.

(1975)

Carslaw et al.

Conduction of Heat in Solids

(1959)

W.C. Dewey

Vascular-extravascular exchange of I¹³¹ plasma proteins in the rat

Amer. J. Physio.

(1959)

H.F. Dvorak et al.

Regulation of extravascular coagulation by microvascular permeability

Science

(1985)

D.G. Garlick et al.

Transport of large molecules from plasma to interstitial fluid and lymph in dogs

Amer. J. Physiol.

(1970)

Cited by (542)

Polymeric prodrug by supramolecular polymerization
2023, Reactive and Functional Polymers
Cancer has become a major public health problem, and chemotherapy is one of the main methods for treating cancer. However, traditional anticancer drugs have shortcomings such as poor selectivity, short half-life, and large toxic side effects. Recently, polymeric prodrugs with therapeutic moieties covalently bonding to polymers have attracted considerable interests in anticancer field, which can self-assemble into nanodrugs with improved the durability, targeting and bioavailability comparing to traditional anticancer drugs. Nevertheless, the chemical composition of polymeric prodrugs is complex due to the polydispersity of a polymer, which greatly limits their clinical translation. In order to obtain polymeric prodrugs with accurate chemical composition, we designed and synthesized an amphiphilic supramolecular polymeric prodrug based on host-guest interaction, which can self-assemble into nano-sized micelles in aqueous medium for anticancer chemotherapy. The novel supramolecular polymeric prodrug we report in this work can combine the general advantages of polymeric prodrug and small molecular prodrug, which should have a bright future in clinical chemotherapy.
Targeting endothelial permeability in the EPR effect
2023, Journal of Controlled Release
The characteristics of the primary tumor blood vessels and the tumor microenvironment drive the enhanced permeability and retention (EPR) effect, which confers an advantage towards enhanced delivery of anti-cancer nanomedicine and has shown beneficial effects in preclinical models. Increased vascular permeability is a landmark feature of the tumor vessels and an important driver of the EPR. The main focus of this review is the endothelial regulation of vascular permeability. We discuss current challenges of targeting vascular permeability towards clinical translation and summarize the structural components and mechanisms of endothelial permeability, the principal mediators and signaling players, the targeted approaches that have been used and their outcomes to date. We also critically discuss the effects of the tumor-infiltrating immune cells, their interplay with the tumor vessels and the impact of immune responses on nanomedicine delivery, the impact of anti-angiogenic and tumor-stroma targeting approaches, and desirable nanoparticle design approaches for greater translational benefit.
Shell-sheddable dendritic polyglycerol sulfates loaded with sunitinib for inhibition of tumor angiogenesis
2023, International Journal of Pharmaceutics
Induced angiogenesis, a specific hallmark of cancer, plays a vital role in tumor progression and can be targeted by inhibitors like sunitinib. Sunitinib is a small hydrophobic molecule suffering from low bioavailability and a short half-life in the bloodstream. To overcome these drawbacks, suitable drug delivery systems need to be developed.
In this work dendritic polyglycerol (dPG), a well-known polymer, was functionalized with a sheddable shell. Therefore, aliphatic chains of different lengths (C₅, C₉, C₁₁) were coupled to dPG through a cleavable ester bond. To restore water solubility and improve tumor targeting, the surface was decorated with sulfate groups. The resulting shell-sheddable dPG sulfates were characterized and evaluated regarding their loading capacity and biocompatibility in cell culture.
The nine-carbon chain derivative (dPG-TNS) was selected as the best candidate for further experiments due to its high drug loading capacity (20 wt%), and a sustained release in vitro. The cellular biocompatibility of the blank carrier up to 1 mg/mL was confirmed after 24 h incubation on HeLa cells. Furthermore, the shell-cleavability of dPG-TNS under different physiological conditions was shown in a degradation study over four weeks. The activity of sunitinib-loaded dPG-TNS was demonstrated in a tube formation assay on Human umbilical vein endothelial cells (HUVECs). Our results suggest that the drug-loaded nanocarrier is a promising candidate to be further investigated in tumor treatments, as it shows similar efficacy to free sunitinib while overcoming its limitations.
Lymphatic uptake of biotherapeutics through a 3D hybrid discrete-continuum vessel network in the skin tissue
2023, Journal of Controlled Release
Subcutaneous administration is a common approach for the delivery of biotherapeutics, which is achieved mainly through the absorption across lymphatic vessels. In this paper, the drug transport and lymphatic uptake through a three-dimensional hybrid discrete-continuum vessel network in the skin tissue are investigated through high-fidelity numerical simulations. We find that the local lymphatic uptake through the explicit vessels significantly affects macroscopic drug absorption. The diffusion of drug solute through the explicit vessel network affects the lymphatic uptake after the injection. This effect, however, cannot be captured using previously developed continuum models. The lymphatic uptake is dominated by the convection due to lymphatic drainage driven by the pressure difference, which is rarely studied in experiments and simulations. Furthermore, the effects of injection volume and depth on the lymphatic uptake are investigated in a multi-layered domain. We find that the injection volume significantly affects the rate of lymphatic uptake through the heterogeneous vessel network, while the injection depth has little influence, which is consistent with the experimental results. At last, the binding and metabolism of drug molecules are studied to bridge the simulations to the drug clearance experients. We provide a new approach to study the diffusion and convection of drug molecules into the lymphatic system through the hybrid vessel network.
Addressing the diagnosis and therapeutics of malignant tumor cells
2023, Biomarkers in Cancer Detection and Monitoring of Therapeutics: Discovery and Technologies: Volume 1
Cancer kills around a quarter of the people in the developed world. Cancer is a wide term that encompasses over 277 different forms of cancer. Different stages of cancer have been identified, demonstrating that multiple gene mutations are involved in cancer pathogenesis. The aberrant cell growth is caused by these gene alterations. Many cancer patients are diagnosed as an emergency presentation, which is linked to poorer clinical and patient-reported outcomes than individuals who are diagnosed voluntarily or through screening. Even when there is a screening test for a specific disease, most malignancies present with symptoms to basic care. However, cancer symptoms can also be indications of a benign disease; therefore, the doctor must determine whether cancer is the cause. Cancer is still a major unmet medical need, and many potential cancer targets have yet to be discovered.
External stimuli-responsive nanomedicine for cancer immunotherapy
2023, Encyclopedia of Nanomaterials
Cancer immunotherapy has revolutionized clinical oncology and achieved remarkable success, through the use of immune checkpoint blockade antibodies and chimeric antigen receptor T cell therapy. Despite great promises, unsatisfactory response rates and off-target toxicities restrict widespread applications among cancer patients. The lack of successful clinical translation presents an imperative challenge in developing new immunotherapy agents. Nanoparticle-based drug delivery systems have been developed to increase the uptake of therapeutics by tumors and reduce therapeutics’ toxicities. External stimuli-activatable nanomedicine, therefore, holds considerable potential to improve the efficacy of cancer immunotherapy while minimizing side effects via tumor-specific accumulation, cell-specific targeting, and triggerable drug release profiles. We herein discuss how the emerging applications of various stimuli, including light, ultrasound, radiation, and magnetics, elicit anti-tumor immunity and elevate therapeutic performances.

View all citing articles on Scopus

^☆: Financial assistance was furnished by grants from the National Science Foundation (CPE-81-11626), the National Cancer Institute (CA-36902), and the R. K. Mellon Foundation.

²: Recipient of a Research Career Development Award (CA-00643) for 1980–1985 and a Guggenheim Fellowship for 1983–1984.

View full text

Microvascular permeability of normal and neoplastic tissues☆

Abstract

Microvasc. Res.

Pharmacol. Ther.

Microvasc. Res.

J. Pharm. Sci.

J. Chromatogr.

Human Pathol.

Microvasc. Res.

Microvasc. Res.

Microvasc. Res.

Microvasc. Res.

Microvasc. Res.

Studies on the capillary permeability of experimental liver metastases

Surg. Gynecol. Obstet.

Studies on heart lymph II. Capillary permeability of the dog's heart using dextran as a test substance

Acta Physiol. Scand.

Microvascular transport of macromolecules in normal and inflammatory conditions

Acta Physiol. Scand. Suppl.

Fluorescence of Solutions

Permeability of lung capillaries to macromolecules in fetal and newborn lambs and sheep

J. Physiol.

Bulk transfer of fluid in the interstitial compartment of mammary tumors

Cancer Res.

Conduction of Heat in Solids

Vascular-extravascular exchange of I131 plasma proteins in the rat

Amer. J. Physio.

Regulation of extravascular coagulation by microvascular permeability

Science

Transport of large molecules from plasma to interstitial fluid and lymph in dogs

Amer. J. Physiol.

Vascular-extravascular exchange of I¹³¹ plasma proteins in the rat