CA2013580A1 - Method for enhancing transmembrane transport of exogenous molecules - Google Patents

Method for enhancing transmembrane transport of exogenous molecules

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Publication number
CA2013580A1
CA2013580A1 CA002013580A CA2013580A CA2013580A1 CA 2013580 A1 CA2013580 A1 CA 2013580A1 CA 002013580 A CA002013580 A CA 002013580A CA 2013580 A CA2013580 A CA 2013580A CA 2013580 A1 CA2013580 A1 CA 2013580A1
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Canada
Prior art keywords
water soluble
biotin
cell
soluble vitamin
biotinylated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA002013580A
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French (fr)
Inventor
Philip S. Low
Mark A. Horn
Peter F. Heinstein
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Purdue Research Foundation
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Purdue Research Foundation
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Publication date
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Publication of CA2013580A1 publication Critical patent/CA2013580A1/en
Abandoned legal-status Critical Current

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Abstract

ABSTRACT

A method is provided for enhancing transmembrane transport of exogenous molecules. A
complex between a water soluble vitamin and an exogenous molecule is formed and contacted with the cell membrane thereby initiating receptor mediated transmembrane transport of the vitamin complex. The transmembrane transport of exogenous molecules including proteins and polynucleotides, as vitamin complexes, has been promoted in plant, mammalian, and bacterial cells.

Description

:

. 2~13~

- METHOD FOR E~HANCING TRA~SMEMBRA~E
TRANSPORT OF EXOGE~OUS NO~ECULES
' ~

FIELD OF TNVENTION
This invention relates to a method for enhancing transmembrane transport of exogenous molecules. The method takes advantage of ~1) the multiplicity of location and receptors in the membrane surfaces of most cells and ~2~ the associated receptor ~
mediated transmembrane processes. A complex between a --water soluble vitamin and an exogenous molecule is formed and contacted with the membrane surface thereby -initiating receptor mediated transmembrane transport of the vitamin complex. The transmembrane transport of exogenous molecules including proteins and polynucleotides, as vitamin complexes, has been promoted in plant, mammalian, and bacterial cells.
.
2~5 BACKGROUND AND SUMMARY OF THE INVENTION
Transmembrane transport of e~ogenous or nutrient molecules is critical for normal cell function. Because practitioners have recognized the importance of that~fundamental cellular process to many areas of medical and biological science,~including~ dxug therapy and DNA transfection, there has been significant research efforts directed to the understanding and application of æuch processes. Transmembrane delivery of specific molecules has been encouraged through the -~
use of protein carriers, antibody carriers, liposomal '. ~
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delivery systems, electroporation, direct injection, cell fusion, viral carriers, os,motic shock, and calcium-phospate mediated trans,fection. However, many of those technigues are limitedl in both the types of cells and the conditions of use for successful transmembrane transport of exo~enous molecular species.
Further, many of these known technigues are limited in the type and size of exogenous molecule that can be transported across a membrane without loss of lS bioactivity One method for transmembrane delivery of exogenous molecules having a wide applicability is based on the mechanism of receptor mediated endocytotic activity. Unlike many other methods, receptor mediated endocytotic activit~ can be used successfully both in vivo and in vitro. Receptor mediated endocytosis involves the movement of ligands bound to membrane receptors into the interior of an area bounded by the membrane through invagination of the membrane. -The process is initiated or activated by the binding of a receptor specific ligand to the receptor. Many receptor mediated endocytotic systems have been characterized, including galactose, mannose, mannose 6-phosphate, transferrin, asialoglycoprotein, transco~olamin (vitamin B-12)~ a-2 macroglobulins, insulin, and other peptide grow~h factors such as epiaermal growth factor ~EGF).
Receptor mediated endocytotic activity has been utilized for transmembrane delivery of e~ogenous molecules such as p~oteins and nucleic acids.
Generally, the ligand is chemically con]ugated by "

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covalent, ionic or hydrogen boncling to egogenous molecule of interest, (i.e., the exogenous compound) forming a conjugate molecule having a moiety (the ligand portion) that is still recognized in the conjugate by a target receptor. Using this technique the phototoxic protein psoralen has been conjugated to insulin and internalizPd by the insulin receptor endocytotic pathway ~Gasparro, Biochem. Biophys. Res. Comm. 141~2), pp.
502-509, Dec. 15, 1986); the hepatocytes specific receptor for galactose terminal asialo-glycoproteins has been utilized for the hepatocytes-specific transmembrane delivery of asialoorosomucoid-poly-L-lysine non-covalently complexed to a DNA plasmid (Wu, G.Y., J.
Biol Chem., 262(10), pp. 4429-4432, 1987); and the cell receptor for epidermal growth factor has been utilized : to deliver polynucleotides covalently linked to EGF to the cell interior (Myers, European Patent Application 86810614.7, Filed December 29, 1986, Publication Date June 6, 88).
The method of the present invention enhances the transmembrane transport of 3n exogenous molecule across a membrane having receptors for water soluble vitamins that initiate transmembrane transport following binding with a water soluble vitamin or a pharmacologic agent that mimics the binding of a water soluble vitamin. The;present method has been successfully applied to mammalian, plant, and bacterial cells. The vitamin receptor mediated transmembrane transport forming the basis o~ this invention is ini~iated by the binding of water soluble vitamins, such as biotin, ;

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2~3~0 ascorbic acid, cobalamine, or folates, to their respective receptor associated with the membrane. A
preferred target receptor for the method of the present invention is the biotin receptor. Biotin is a necessary cellular growth factor that has been ~ound to be preferentially bound by biotin receptor proteins associated with cellular membranes. Biotinylating reagents suitable for covalently bonding a biotin moiety to polynucleotides, proteins, or other desired molecules are commercially availâble. The bindin~ of the vitamin moiety to its cell surface receptor initiates transmembrane transport of the water soluble vitamin or, in the case of the present invention, the complex consisting of the vitamin and the exogenous molecule.
~he present invention makes use of a receptor-mediated transmembrane transport to deliver exogenous molecules complexed with the water soluble vitamin, across a membrane. A complex is first formed between a water soluble vitamin and a predetermined exogenous molecule. The complex is then contacted with a ceIl having receptors for water soluble vitamins and an associated receptor mediated transmembrane transport - activity for a time sufficient to permit transmembrane transport of the complex by water soluble vitamin receptor mediated transmembrane transport activity. In this manner, exogenous molecules are either transported, or transported at an enhanced rate, across the membrane.
The method of the present invention is particularly ilseful,in increasing the internal~zation yields (cellular uptake) of exo~enous molecules that -: .. - :: , . . .

20~3~0 ....

normally are resistant to cellular internalization.
Proteins and polynucleotides previously recognized as difficult to move across cell membranes can be internalized by the method of the present invention.
1~ For example, transfection and expression of an encoded protein product by an internalized biotin-complexed functional gene has been demonstrated. Biotin, conjugated with a D~A plasmid containing a gene sequence coding for chloramphenicol acetyltransferase (CAT), was transported into E. coli via a biotin receptor mediated endocytotic pathway and expressed. Transport of biotinylated protein products into both mammalian and plant cells has also been achieved in both in vivo and in vitro systems.
The method of the present invention can also be accomplished utilizing chemical analogues or derivatives of water soluble vitamins that are cross reactive with a watér-soluble-vitamin receptor.
. -: ~, ., DETAILED DE~CRIPTION OF THE INVENTION ~ ~-The method of the present invention requires the presence of appropriate receptors for water soluble vitamins associated with a membrane. The membrane can either define an intracellular volume s~ch as the endoplasmic reticulum or other organelles such as mitochondria,-or a}ternatively can define the boundary of the cell. Transmembrane transport across a cell boundary commonly occurs by an endocytotic transport ; ~
mechanism. General~y, it has been found that water ~-soluble vitamin rëceptors mediate cellular . . .

2~3~

internalization of water soluble vitamins through endocytotic activity. The receptors can be natural constituents of the cell or they c3n be emplaced in the cell membrane by external physical manipulation.
Alternatively, expression of an inserted foreiyn gene for the protein or apoprotein corre6ponding to the water soluble vitamin receptor by a transfected cell can ensure the presence of a water soluble vitamin receptor on a target cell.
Water soluble vitamins known or believed to have suitable cellular receptors or purposes of the present invention include but are not limited to biotin, biotin analogues such as 6-N-biotinyl-L-lysine (biocytin), biotin sulfoxide, oxybiotin (oxobiotin), 5,6, dimethylbenzimidazoloylcyanocobamide (cyanocobalamin - vitamin B-12), 5,6,-dimethylbenzimidazoloyla~uaocobamide (aquocobalamin - vitamin B-12a), 5,6,-dimethylbenzimidazoloylhydroxocobamide (hydroxocobalamin - vitamin B-12b), adenosylcobalamin, methylcobalamin, folic acids such as folacin, methotrexate, pteropolyglutamic acid, pteridines, niacin, pantothenic acid, riboflavin, and thiamin.
Preliminary esperiments usiny the water soluble vitamin pyridoxine showed little uptake potentiating .

activity. It is possible that pyridoxine and pyridoxine analogues are not suitable for use in accordance with the present invention.
Because of.,the ready availability of biotinylating reagents and biotinylating methods ~. ;

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suitable for use with peptides, proteins, oligonucleotides, and polynucleotides, a preferred water soluble vitamin for the purpos~3s of the present invention is biotin. Biotin iS also a preferred water soluble vitamin because it is a necessary growth factor or a wide ~ariety of cells, and biotin receptors that mediate endocytotic activity have been identi~ied in mammalian, plant, and bacterial cells.
Formation of a complex between a water soluble vitamin such as biotin and an exogenous molecule of interest is readily accomplished for a great many molecules and macromolecules. Biotin moieties can be easily conjugated to proteins by making the carboxyl group of biotin reactive toward the free amino-groups of ~ -the proteins. A biotinylating reagent such as -D-biotin-N-hydroxy-succinimide ester or biotinyl-p-nitrophenyl ester can be used. The activated ester reacts under mild conditions with amino groups to incorporate a biotin residue into the desired molecule.
The procedure to be followed for biotinylating macromolecules using D-biotin-N-hydro~y-succinimide ester is well known in the art (Hofmann et al., J.Am.Chem.Soc. 100, 3585-3590 (1978)). Procedures suitable for biotinylating an e~ogenous molecule using biotinyl-p-nitrophenyl ester as a biotinylating reagent are also well known in the art (Bodanszk et al., J.Am.Chem.Soc. 99,~235 (1977)). Other reagents such as D-biotinyl-E-aminocaproic acid N-hydro~y-succinimide ester in which c-aminocaproic acid serves as a spacer 2~3~

link to reduce steric hindrance can also be used for the purposes of the present invention.
Oliqonucleotides and polynucleotides can also be biotinylated using both indirect and direct methods.
Indirect methods include end-labeling of a polynucleotide with a biotinylated nucleotide, or nick translation that incorporates biotinylated nucleotides.
Nick translation or end labeling of DNA can be accomplished using methods described in Maniatis et al., Molecular Cloning. A LaboratorY Manual, pp. 109-116, Cold Spring Harbor Press ~1982).
Direct methods refer to those procedures in - which biotin is directly attached to a target polynucleotide using a biotinylating reagent.
Photoactivatible reagents such as the acetate salt of N-(4-azido-2-nitrophenyl)-N-(3-biotinylaminopropyl)-N-methyl-1,3-propanediamine (photobiotin) can be used to biotinylate DNA according to the method of Forstsr et al., Nuc. Acids Res. 13:745-761. An alternative method uses a biotin hydrazide reagent in a bisulfite catalyzed reaction capable of transamination of nucleotide bases such as cytidine according to the method described by Reisfeld et al., B.8.R.C. 142:519-526 tl988). This method simply requires a 24 hour incubation of DNA or 30 R~A with biotin hydrazide at lOmg/ml in;an acetate buffer, pH 4.5, containing 1 M bisulfite. Biotin hydrazide can also be used to biotinylate carbohydrates containing a free aldehyde.~
Water solu~le vitamin receptor mediated cellular uptake of biotinylated polynucleotides provides ~ :` 2~3~
. .

an alternative mechanism for triansfection of cells. The technique of the present invent;on is particularly valuable because it is applicable to certain cell types, such as plant cells, which are normally resistant to standard transfection technique~. Delivery of foreign gen~s to the cell interior can be enabled or enhanced by the present invention. Once delivered to the cellular interior, these foreign genes can be inserted and expressed with the aid of a natural or exogenous promoter to produce a desired protein. In addition to proteins, other useful macromolecules can be produced.
For example, an antisense-RNA sequence capable of binding interference with endogeneous messenger RNA.
The~delivery of proteins and other non-nucleotide mo~Iecules by water soluble vitamin receptor mediated uptake is also useful. Antibodies, bîoactive peptides, toxic peptides, or pharmaceutically valuable peptides can ~e delivered to the cellular interior by means of the present invention. This is of particular value for in vivo, therapeutic applications involving the delivery of molecules that are not normally internalized by a target cell. ~
The following examples are provided to illustrate further the range of exogenous molecules and cell types to which the method of the present invention - -can be applied E~ample 1 - RAT PHEOCHRO~OCYTOMA CELL UPTAKE OF BIOTIN
CONJUGATED INSULIN. .r Rat pheochromocy~oma ~PC-12) cells w~re obtained from America Type Culture Collection and were 2~35~t~

--10- ' grown (37C, 5% CO2 in humidif;ed air) attached to plastic flasks for 2 to 3 weeks until confluent in a medium of 85% RMPI 1690, 10% v/v heat inactivated horse serum, and 5% fetal calf serum containing 1 streptomycin-penicillin.
Biotin and fluorescein labeled insulin was prepared. To 1 ml of a 1 mg~ml ~olution of insulin protein in phosphate buffered saline was added simultaneously 100 ~1 of a 1 mg/ml solution of fluoroscein isothiocyanate (FITC) in dimethylformamide (DMF) and 100 ~1 of a 1 mg/ml solution of N-hydroxysuccinirnido biotin in dimethylsulfoxide (DMSO). The two labeling reagents were allowed to react at room temperature for 4 hours, after which the unreacted reagents were quenched with 10 ~1 ethanolamine. The quenched reaction mixture was then dialyzed against double distilled water until unreacted fluorescein derivatives no longer dialyzed into the water. The covalent attachment of biotin and fluorescein to the desired protein was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis.
- As a control, non-biotinylated fluorescein labeled insulin was prepared. 1 ml of a 1 mg~ml solution of insulin was added 0.5 ml of a 1 mg/ml solution of ~luorescein isothiocyanate (FITC) in dimethylformamide (DMF). The reaction was allowed to proceed for 4 hours in the dark at room temperature.
After 4 hours the rçaction was quenched with 10 ~1 ethanolamine, and the lab-led insulin solution was ?~
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dialyzed against double distilled water until unreacted FITC no longer appeared in the solution.
The rat PC12 cells were grown in modified RMPI
1640 medium as a monoIayer on t:he bottom of a culture flask. Before removing the cells, the monolayer was washed with a 20 ml portion of fresh Locke'~ ~olution.
The cells were then displaced into 20 ml of the Locke's solution by gentle agitation with a stream Locke's solution. The suspended cells were pelleted by centrifugation at 10,000 x 9 for 10 seconds and after resuspending in Locke's solution in separate polycarbonate tubes (40ml/tube) to a final density of 1.14 x 106 cells/ml, the following amounts of proteins were added to the cell suspensions: 40 ~g fluorescein-labeled insulin was added to the first tube, and to the control tube was added 40 ~g biotin-conjugated insulin labelled with fluorescein.
The tubes were allowed to incùbate at 37C. At intervals of 5, 15 and 33 minutes, Q.5 ml of each cell suspension was removed and pelleted at 10,000 ~ g for 10 seconds. The cell pellet was washed and repelleted twice in 1 ml Locke's solution and then fixed by additlon of 200 ~1 of a 2%~formalin solution in phosphate buffered saline. Thirteen microliters of the fi~ed cell suspension was then added to a microscope ælide and viewed with the fluorescent microscope to detect internalized proteins. No evidence of internalization was noted for the fluorescein labelled insulin acting as a,control. Cellular internalization was indicated for the biotinylated 1nsulin labelled with Si " ~

~3~

fluorescein, with the amount internalized increasing with time.

Example 2 - RAT PHEOCHROMOCYTO~ CELL UPTAKE OF BIOTIN
CONJUGATED HEMOGLOBIN:
Following the same general procedure set forth in Example l hemoglobin was biotinylated, and the biotinylated orm was shown to be preferentially internalized by rat pheochromocytoma cel~s as compared to non-biotinylated hemoglobin~
.
Example 3 - SOYBEAN CELL UPTAKE OF BOVINE SERUM ALBUMIN:
Soybean cell suspension cultures of Glycine max Merr Var ~ were maintained by transferring cells to fresh W-38 growth medium every 7 days.
To 20 ml of a suspension culture of soybean cells was added 10 ~9 of either fluorescein-labeled (control) or fluorescein and biotin labelled bovine serum albumin. The cells were allowed to incubate for up to 6 hours. At varying time intervals l ml of the - cell suspension was filtered to remove the growth medium, washed with 50 ml fresh growth medium, and resuspended in 20 ml of the same medium. The cell suspension was then viewed with a flourescent microscope to determine whether cellular internalization of the labelled bovine serum albumin had occurred. Cellular i internalization was indicated only for biotinylated bovine serum albumin.

: ::

-13- ~ ~-Example 4 - SOYBEAN CELL UPTAKE OF INSULIN: -~ ollowing the same general procedure set forthin Example 3 insulin was biotinylated, and the biotin~lated form of insulin was ~hown to be preferentially internalized by soybean cells as compared to non-biotinylated insulin.
,:
Example 5 - SOYBEAN CELL UPTAKE ~F HEMOGLOBIN:
Following the same general procedure set forth in Example 3 hemoglobin was biotinylated, and the biotinylated form of hemoglobin was shown to be preferentially internalized by soybean cells as compared -~
to non-biotinylated hemoglobin.
-Example 6 - CARROT CELL UPTAKE OF BOVINE SERUM ALBUMIN:
Carrot cells of wild type origin were established and maintained in MS growth medium supplemented with 0.1 mg~L 2,4-dichlorophenoxyacetic acid. Bovine serum albumin was labelled with fluorescein alone as a control or with fluorescein and biotin following the procedures detailed in Example 3.
The carrot cells were then i~cubated in the presence of the respective labelled bovine serum albumin for 7 hours. All other conditions~were the same as those described in Example 3 above. Cellular internalization was found only in those cells contacted with-biotin labelled bovine serum albumin.

Example 7 - CARROT C~LL UPTAKE OE INSULIN:
Following the same general procedure set forth - in Example 6 insuIin was biotinylated, and the .

, ~-, : .

biotinylated form was shown to be preferentially internalized by ~arrot cells as compared to non-biotinylated insulin.

Example 8 - CARROT CELL UPTAKE OF HEMOGLOBIN:
Following the same general procedure set forth in Example 6 hemoglobin was biotinylated, and the biotinylated form was shown to be preferentially internalized by carrot cells as compared to non-biotinylated hemoglobin Example 9 - SOYBEAN CELL DEGRADATION OF HEMOGLO~IN:
To determine whether hemoglobin was rapidly degraded following cellular internalization by transmembrane transport, soybean cells were allowed to internalize and metabolize biotinylated hemoglobin for a period of 8 hours under conditions described in Example 5, after which the soybean cells were rapidly homogenized in a sodium dodecyl sulfate solution to disaggregate and denature all protein material. The solubilized polypeptides were separated according to molecular weight by polyacrylamide gel electrophoresis and then electroblotted onto nitrocellulose paper. The positions of the biotin-labeled peptides were then visualized on the nitrocellulose blot by staining with horseradish peroxidase-linked avidin and the colored substrate, p-chloronaphthol. All of the biotin-linked material was found to migrate with an apparent molecular weight of ~16,000 d~ltons, about equal to the molecular weight of the parent globin chains of i ~ 20~3~

hemoglobin, indicating no brealcdown of the parent globin chains had occurred during the 8 hour incubation period.

E~ample 10 ~ IN VIVO DELIVERY To RATS OF SOYBEAN TRYPSIN
INHIBITOR:
æoybean trypsin inhibitor (SBTI) ~-6 mg~ was labeled with radioactive 125I using 8 iodobeads (Bio Rad) in I m~ buffer which was then dialyzed to ~emove unreacted 125I. After dividing into two e~ual fractions, one fraction was biotinylated with N-hydroxysuccinimidyl biotin and the other fraction was left as an unmodified control. Mice (~25 g) were then injected with either the biotinylated SBTI or the - control SBTI by insertion of a hypodermic syringe -containing a 25 gauge needle into the tail vein of the mousè. After 15 minutes, each mouse was sacrificed and then perfused with heparin-containing isotonic saline via the direct cardiac influx and efflux method. When the various tissues appeared to be blood-free, the perfusion was terminated and each tissue/organ was removed, weighed, and counted for 125I-SBTI in a gamma -~
counter. Although some radioactivity was detected in the mice treated with non-biotinylated 125I-SBTI, between 4 and l00 times more 125I-SBTI was found in the mice treated with biotinylated SBTI, indicatin~
sucoessful in vivo delivery to murine cellular tissue.

- -< ,,,i, .
;,,, ~ ,.
~- ~ . - .
, :~, :. : .

2~3~
, .

Counts per minute/qram wet wei~ht Tissu~ Control_~BT:L Biot n SBTI

10 hiver 535 1967 ~ung 107 2941 Kidney 5152 8697 :~ Intestine 0 700 Muscle 0 I065 15 Heart 0 739 Brain 0 267 Example 11 - SOYBEAN TRANSFECTION OF SALMON SPERM DNA:
Protein free salmon-sperm DNA, either in a highly polymerized form (> 50,000 base pair length) or .
- in-a sheared form (< 500 base pair length), was transaminated at the cytosine residues. The : transaminated DNA (1 mg) was labeled with fluorescein via the addition of 0.5 mg of fluorescein isothiocyanate.
(FITC) in dimethylsulfoxide (DMSO). The resulting reaction mi~ture was dividéd into two portions and the labeling reaction was quenched in :one portion by addition of 10 ~L of ethanolamine. This quenched portion served as the non-biotin~lated control. The remaining DNA was then covalentIy labeled with biotin via reaction with 0.5.mg of N~hydroxysuccinimidyl biotin in DMSO. After purification, the two derivatives (1 ~g/mlj were separately incuba~ed with soybean suspension culture ells at ro-om temperature for 6 hours and then the cells were washed with 50 ml fresh growth ,:......
: , ~ .. . .. . . .

2013~

medium and observed by fluorescence microscopy. Only - the biotinylated DNA entered the soybean cells.

Esample 12 - E. COLI ~RANSFECTION AND EXPRESSION OF
AMPICILLIN RESISTANT GENE~
~lasmid DNA (pUC8) was biotinylated via nick ~ ~
translation in the presence of biotin-14-dATP using a "~ ~ , commercially available,nick translation kit (Bethesda ~'-Research Laboratories). The biotinylated DNA and unmodified DNA (1 ~g~ were added to E. coli strain Cu 1230 that had been made competent by treatment with MgC12 and CaC12,following the method of Maniatis et ,~
al., Mol,ecular Clonina: A Laborator~ Manual, pp.
250-251, Cold Spring Harbor Press (1987). After ' ' transformation, the successful transformants were ~ ~' selected by plating cells on LB media which contained 50 -, ~g/ml ampicillin and then incubated overnight at 37C. Colonies which survived the ampicillin were ; ~' counted and the transformation efficiency was determined. The number of surviving E. coli colonies was at least 100-fold greater in E. Co'li transformed with the biotinylated plasmids.

:

,:
, 7715q , t!

Claims (11)

1. A method for enhancing transport of an exogenous molecule into a plant cell, said method comprising the step of contacting the plant cell with the exogenous molecule complexed with a water soluble vitamin or water soluble vitamin receptor binding agent for a time sufficient to permit transmembrane transport of said complex.
2. The method of claim 1 wherein the water soluble vitamin is biotin or analogs thereof.
3. The method of claim 1 or 2 wherein the exogenous molecule is a nucleic acid.
4. The method of claim 1 or 2 wherein the exogenous molecule is a protein.
5. A method for enhancing transport of a nucleic acid into a cell, said method comprising the step of contacting the cell with the nucleic acid complexed with a water soluble vitamin or water soluble vitamin receptor binding agent for a time sufficient to permit transmembrane transport of said complex.
6. The method of claim 5 wherein the water soluble vitamin is biotin or analogs thereof.
7. The method of claim 5 or 6 wherein the cell is an animal cell.
8. The method of claim 5 or 6 wherein the cell is a plant cell.
9. The method of claim 5 or 6 wherein the cell is a prokaryote.
10. A method for enhancing transport of an exogenous molecule into cellular tissue of a host having a circulatory system, said method comprising the step of injecting the host with the exogenous molecule complexed with a water soluble vitamin or water soluble vitamin receptor binding agent,
11. The method of claim 10 wherein the water soluble vitamin is biotin n or analogs thereof.
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IL93983A (en) 1997-02-18
US5108921A (en) 1992-04-28
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EP0466816A4 (en) 1992-05-20
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IL93983A0 (en) 1991-01-31
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PT93646A (en) 1990-11-20
EP0466816A1 (en) 1992-01-22
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