CA1311086C - Chimeric peptides for neuropeptide delivery through the blood-brain barrier - Google Patents
Chimeric peptides for neuropeptide delivery through the blood-brain barrierInfo
- Publication number
- CA1311086C CA1311086C CA000543217A CA543217A CA1311086C CA 1311086 C CA1311086 C CA 1311086C CA 000543217 A CA000543217 A CA 000543217A CA 543217 A CA543217 A CA 543217A CA 1311086 C CA1311086 C CA 1311086C
- Authority
- CA
- Canada
- Prior art keywords
- peptide
- blood
- brain
- brain barrier
- chimeric
- 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.)
- Expired - Fee Related
Links
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- 210000001578 tight junction Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000005172 vertebrate brain Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/655—Somatostatins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- C07K14/675—Beta-endorphins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- C07K14/695—Corticotropin [ACTH]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/15—Oxytocin or vasopressin; related peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/16—Somatostatin; related peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S930/00—Peptide or protein sequence
- Y10S930/01—Peptide or protein sequence
- Y10S930/26—Containing cys-cys disulfide bridge between nonadjacent cysteine residues
Abstract
63-293/UC9.10 CHIMERIC PEPTIDES FOR NEUROPEPTIDE DELIVERY
THROUGH THE BLOOD-BRAIN BARRIER
ABSTRACT OF THE INVENTION
Chimeric peptides adapted for delivering neuro-pharmaceutical agents, such as neuropeptides into the brain by receptor-mediated transcytosis through the blood-brain barrier. The chimeric peptides include a peptide which by itself is capable of crossing the blood-brain barrier by transcytosis at a relatively high rate.
The transportable peptide is conjugated to a hydrophilic neuropeptide which by itself is transportable only at a very low rate into the brain across the blood-brain barrier. The resulting chimeric peptide is transported into the brain at a much higher rate than the neuro-peptide alone to thereby provide an effective means for introducing hydrophilic neuropeptides into the brain through the blood-brain barrier.
THROUGH THE BLOOD-BRAIN BARRIER
ABSTRACT OF THE INVENTION
Chimeric peptides adapted for delivering neuro-pharmaceutical agents, such as neuropeptides into the brain by receptor-mediated transcytosis through the blood-brain barrier. The chimeric peptides include a peptide which by itself is capable of crossing the blood-brain barrier by transcytosis at a relatively high rate.
The transportable peptide is conjugated to a hydrophilic neuropeptide which by itself is transportable only at a very low rate into the brain across the blood-brain barrier. The resulting chimeric peptide is transported into the brain at a much higher rate than the neuro-peptide alone to thereby provide an effective means for introducing hydrophilic neuropeptides into the brain through the blood-brain barrier.
Description
8 ~
63-2~3/UC9.10 CHIMERIC PEPTIDES FOR NEUROPEPTI DELIVERY
T OVGH THE BLOOD-BRAIN BARRIE~
BACKGROUND OF THE INVENTION
The present invention relates generally to the introduction of neuropharmaceutical agents into the brain by transcytosis across the blood-brain barrier. More particularly, the present invention relates to chimeric peptides which are capable of transporting neurophar-maceutical agents into the brain by receptor-mediated transcytosis across the blood-brain barrier.
This invention was made with Government support under Grant No. NS-17701 awarded by the National Institutes of Health. The Government has certain rights in this invention.
The vertebrate brain has a unique capillary system which is unlike that in any other organ in the body. The unique capillary system has morphologic characteristics which make up the blood-brain barrier (BBB). The blood-brain barrier acts as a systemwide cellular membranewhich separates the brain interstitial space from the blood.
The unique morphologic characteristics of the brain capillaries which make up the BBB are: ta) epithelial-like high resistance tight junctions which literallycement all endothelia of brain capillaries together, and (b) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs.
Due to the unique characteristics of the blood-brain barrier, hydrophilic drugs and peptides that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
Various strategies have been developed for intro-ducing those drugs into the brain which otherwise would not cross the blood-brain barrier. The most widely used strategies involve invasive procedures where the drug is 1 3 ~
63-293/UC9.10 delivered directly into the brain. The most common procedure is the implantation of a catheter into the ventricular system to bypass the blood-brain barrier and deliver the drug directly to the brain. These procedures have been used in the treatment of brain diseases which have a predilection for the meninges, e.g., leukemic involvement of the brain.
Although invasive procedures for the direct delivery of drugs to the brain ventricles have experienced some success, they have not been entirely successful because they only distribute the drug to superficial areas of the brain tissues, and not to the structures deep within the brain. Further, the invasive procedures are potentially harmful to the patient.
Other approaches to circumventing the blood-brain barrier utilize pharmacolgic-based procedures involving drug latentiation or the conversion of hydrophilic drugs into lipid-soluble drugs. The majority of the laten-tiation approaches involve blocking the hydroxyl, carboxyl and primary amine groups on the drug to make it more lipid-soluble and therefore more easily transported across the blood-brain barrier. Although the phar-macolgic approaches have been used with some success, they may no~ be entirely satisfactory for delivery of peptides through the BBB based on the inventor's ex-perience with cyclosporin transpsort through the BBB.
Cyclosporin is a highly latentiated (lipid-soluble) peptide that crosses the BBB rela~ively slowly.
Another approach to circum~enting the blood-brain barrier involves the intra-arterial infusion of hyper-tonic substances which transiently open the blood-brain barrier to allow passage of hydrophiiic drugs. However, hypertonic substances are potentially toxic and may damage the blood-brain barrier.
There presently is a need to provide improved sub-stances and methods for delivering hydrophilic drugs and ~31~
peptides across the blood-brain barrier and into the brain. It is desirable that such improved substances and methods provide for uniform introduction of the hydrophilic peptide or drug throughout the brain and present as little risk to the patient as possible.
SUMMARY OF THE INVENTION
In accordance with the present invention, new pro-cedures and substances are disclosed which provide uniform distribution of neuropeptides and other drugs throughout the brain while reducing the problems inherent in prior invasive and pharmacologic drug introduction procedures.
The present invention is based on the surprising dis-covery that hydrophilic peptides may be physiologically trans-ported across the blood-brain barrier by coupling or conjugating the drug to a transportable peptide which is capable of crossing the blood-brain barrier by receptor-mediated transcytosis. This di~covery i~ particularly surprising in view of the traditional notion that the blood-brain barrier is a passive barrier which is impenetrable by hydrophilic drugs or peptides.
According to one aspect of the present invention there i5 provided a chimeric peptide adapted for delivering a neuro-pharmaceutical agent into the brain by transcytosis through the blood-brain barrier, said chimeric peptide comprising:
a transportable peptide capable of crossing the blood-brain barrier by transcytosis, said peptide being selected from ,~
~ 3 ~
621g6-495 the group consisting of insulin, transferrin, IGF-I, IGF-II, basic albumin and prolactin; and a neuropharmaceutical agent selected from the group consisting of somatostatin, thyrotropin releaQing hormone, vaso-pressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glytamyl-L-histidyl-L-phenylalanyl-D-lysyl -L-phenylalanine, wherein said neuropharmaceutical agent is con-jugated with said transportable peptide.
The invention invovles novel chimeric peptides which are adapted to deliver a neuropharmaceutical agent into the brain by transcytosis across the blood-brain barrier. The chimeric peptides include a transportable peptide that is capable of crossing the blood-brain barrier at relatively high rate of receptor-mediated transcytosis. The transportable peptide is conjugated with a neuropharmaceutical agent to form the chimeric peptide. The neuropharmaceutical agent is generally a hydro-philic peptide that does not by itself significantly cross the BBB. The conjugation of transportable peptides with neuropharma-ceutical agents was surpri~ingly found to produce chimeric pep-tides which were capable of being , s' .
63-293/UC9.10 transported across the blood-brain barrier.
As a feature of the present invention, the chimeric peptides are believed to be transported across the blood-brain barrier by the physiologic process of transcytosis via receptors in the blood-brain barrier. This insures that the chimeric peptide is distributed uniformly to all parts of the brain. In addition, the introduction of the chimeric peptide into the brain by a physiologic pathway reduces the harmful side effects and risks inherent in the traditional invasive and pharmacolgical approaches.
The present invention also includes methods for administering the chimeric peptides subcutaneously or intranasally and the chimeric peptide containing com-positions utilized in such methods of treatment.
The above-discussed and many other features and attendant advantages of the present invention will become apparent as the invention becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
The figure is a chart showing the results of the tests described in Example No. 2.
DETAILED DESCRIPTION OF THE INVENTION
The chimeric peptides in accordance with the pre-sent invention are useful in delivering a wide variety of neuropharmaceutical agents to the brain. The invention is particularly well suited for delivering neuropharma-ceutical agents which are hydrophilic peptides. Thesehydrophilic peptides are generally not transported across the blood-brain barrier to any significant degree.
Exemplary hydrophilic peptide neuropharmaceutical agents are: thyrotropin releasing hormone (TRH) - used to treat spinal cord injury and Lou Gehrig's disease;
vasopressin - used to treat amnesia, alpha interferon -63-293/UC9.10 used to treat multiple sclerosis; somatostatin - used to treat Alzheimer's disease; endorphin - used to treat pain; L-methionyl (sulfone)-L-glutamyl-L-histidyl-L-phenylalanyl-D-lysyl-L-phenylalanine (an analogue of adrenocorticotrophic hormone (ACTH)-4-9) - used to treat epilipsy; and muramyl dipeptide - used to treat insomnia.
All of these neuropharmaceutical peptides are available commercially or they may be isolated from natural sources by well-known techniques.
The following description will be limited to chimeric peptides in which the neuropharmaceutical agents are hydrophilic peptides (neuropeptides) with it being understood that the invention has application to any neuropharmaceutical agent which by itself is transported at a low or non-existent rate across the blood-brain barrier. The invention also has application where it is desired to increase the rate at which the neuropharma-ceutical agent is transported across the blood-brain barrier.
The chimeric peptide includes the hydrophilic pep-tide drug conjugated to a transportable peptide which is capable of crossing the blood-brain barrier by trans-cytosis at a much higher rate than the hydrophilic neuropeptides. Suitable transportable peptides include:
insulin, transferrin, insulin-like growth factor (IGF-I), insulin-like growth factor II (IGF-II), basic albumin and prolactin.
Transferrin is an 80K glycoprotein that is the principal iron transport protein in the circulation.
Transferrin is also a protein that is enriched in the cerebrospinal fluid (CSF). Transferrin is widely avail-able and may be purchased or isolated from blood or CSF
by well-known procedures.
Insulin, IGF-I and IGF-II are also commonly avail-able. Insulin is available on a wide scale commerciallyand may also be recovered from natural sources by well-63-293/UC9.10 known techniques. IGF-I and IGF-II are available from commercial outlets such as Amgen or Peninsula Labs or they may be isolated from natural sources according to the procedure of Rosenfeld et al. (J. Clin Endocrinol.
Metab. 55, 434, 1982).
Basic albumin or cationized albumin has a iso-electric point (pI) of 8.5 as compared to a pI of 3.9 for natural albumin. Cationized albumin, unlike natural albumin, enters the brain rapidly across the blood-brain barrier. Cationized albumin (pI = 8.5) is prepared preferably by covalent coupling of hexamethylene-diamine (HMD) to bovine serum albumin (pI = 3.5) according to Bergmann, et al., "Cationized Serum Albumin Enhances Response of Cultured Fetal Rat Long Bones To Parathyroid Hormone", Endocrinology, 116:1729-1733 (1985). An exemplary synthesis is as follows: 10 ml of a 10~
solution of albumin in water is slowly added to 60 ml of 2.0 M HMD and the pH of the solution is adjusted to 6-7 with lN HCl. After 30 minutes, 1 g of N-ethyl-N'-3-(dimethylaminopropyl) carbodiimide hydrochloride (EDAC) is added to activate the carboxyl groups of the albumin, followed by the addition of another 1 g EDAC 1 hour later. The pH is constantly adjusted to 6-7 with 0.2N
HCl. The solution is allowed to stand overnight with constant stirring. The next day the solution is dialyzed extensively against distilled water. This solution is then purified by chromatofocusing using the Pharmacia polybuffer exchanger 94 resin and the polybuffer 96 elution buffer.
Prolactin is a hormone which is secreted by the anterior pituitary. Prolactin is widely available com-mercially or it can be isolated from pituitary glands by well-known procedures.
The chimeric peptides are made by conjugating a transportable peptide with the neuropharmaceutical pep-tide.
~ 3 ~
63-2~3/UC9.10 The conjugation may be carried out using bifunc-tional reagents which are capable of reacting with each of the peptides and forming a bridge between the two.
The preferred method of conjugation involves peptide thiolation wherein the two peptides are treated with a reagent such as N-Succinimidyl 3-(2-pyridyldithio) propionate (SPDP) to form a disulfide bridge between the two peptides to form the chimeric peptide. Other known conjugation agents may be used, so long as they provide linkage of the two peptides (i.e. the hydrophilic peptide drug and the transportable peptide) together without denaturing them. Preferably, the linkage can be easily broken once the chimeric peptide has entered the brain.
Suitable examples of conjugation reagents include:
glutaraldehyde and cystamine and EDAC. Conjugation of peptides using glutaraldehyde is described in Poznans~y et al., Insulin: Carrier potential for enzyme and drug therapy. Science 223:1304-1306, 1984. Conjugation of peptides using cystamine and EDAC is described in Ito et al., Transmembrane delivery of polypeptide hormones bypassing the intrinsic cell surface receptors: a con-jugate of insulin with a2-macroglobulin (a2M) recognizing both insulin and a2M receptors and it~ biological activity in relation to endocytic pathways. Mol Cell Endocrinol 36:165, 1984.
Examples of preferred chimeric peptides include those having the general structure O O
A-NHC(CH2)2S-S-(CH2)2CHN-B
where A is somatostatin, thyrotropin releasing hormone (T~I), vasopressin, alpha interferon, endorphin, muramyl dipeptide or ACTH 4-9 analogue; and B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin.
rj ~ ~
63-293/UC9.10 Other examples of preferred chimeric peptides in-clude those listed above wherein the disulfide conju-gating bridge between A and B is replaced with bridges having the following structures:
A~NH(CH2)2S-S-B (cleavable linXage) which are formed when cystamine and EDAC are employed as the bridge reagents;
A-NH=CH(CH2)3CH=NH-B (non-cleavable linkage) which are formed when glutaraldehyde is employed as bridge reagent.
The chimeric peptides can be introduced into the body by any conventional procedure including parenteral injection or intranasal inhalation. Preferably, the chimeric peptides are combined with a compatible phar-maceutical carrier and injected parenterally or if desired combined with a suitable carrier and administered intranasally in accordance with the well-Xnown conven-tional procedures used for intranasal administration of insulin. Suitable carrier solutions include those com-monly used in injectable or nasal-inhaled hormone preparations such aq sterile saline at a pH of around 5 which includes common bacteriostatic agents. The concentration of a chimeric peptide in the carrier will vary depending upon the specific transportable peptide and the specific neuropharmaceutical peptide. Pre-ferably, levels of the chimeric peptide in the carriershould be between about 0.001 weight percent to 0.01 weight percent. As a general rule, the dosage levels and percent of chimeric peptides present in the injection or intranasal solution should correspond to the accepted and established dosages for the particular neuropharma-ceutical peptide as well as the transportable peptide.
0 ~ ~
~ xamples of practlce are as follows:
ExamPle l - Synthesls o~ Somatostatln-Insulln Chlmera Somatostatin, a peptlde deflclent ln the brain of Al~helmer's dlsease, ls a peptlde whlch ls not transported through the blood-braln barrler. Conversely, lnsulln ls a peptlde that ls transported through the blood-braln barrler. The transportabillty of lnsulln through the blood-~raln barrler ls set forth ln my artlcle entltled "Receptor-Medlated Peptlde Transport Through The Hlood-Braln Barrler" (Endocrine Revlews, Vol. 7, No. 3, August 1986).
Somatostatln and lnsulln were con~ugated by peptlde thlolation using a reverslble peptlde-peptlde con~ugation method as descrlbed by Carlsson, et al. ln "Proteln Thlolatlon and Reverslble Proteln-Proteln Con~ugatlon" (Blochem. J. (1978) 173, 723-737). A heteroblfunctlonal reagent, N-succlnlmidyl 3-(2-pyrldyldlthlo)proplonate (SPDP), was used to couple a lyslne or free N-termlnus on lnsulln to a free lyslne or amlno termlnus on somatostatln. Approxlmately 0.3 mg of lnsulln and 26 uCl of 125I-lnsulln ln 2 ml of phosphate buffered sallne was prepared. To half of thls was added 4 lambdas of 20 mM fresh SPDP and thls was lncubated at room temperature for 45 mlnutes.
Separately, 180 uCl of trltlated somatostatln ln 180 uL
of 0.01 N HCl was solublllzed and added to 180 uL of 0.2 M phos-phate buffered sallne. To half of thls, 4 uL of 20 mM SPDP was added and thls was lncubated for 45 mlnutes, followed by acldl-flcatlon wlth 20 uL of 0.75 M sodlum acetate (pH = 4.5) followed by reductlon wlth 20 uL of 0.25 M dlthlothreltol. Thls was lncubated at room temperature for 30 mlnutes followed by brlef dlalysis to remove unreacted small molecules. The con~ugated lnsulln and con~ugated somatostatln were then incubated overnlght `at room temperature followed by dlalysls and countlng for 'X 9 ~ 3~
63-293/UC9.10 tritium and I radioactivity. This resulted in a total of 53 uCi of H-somatostatin coupled to 5.3 uCi of I-insulin in 2 ml of phosphate buffered saline.
The structure of the somatostatin-insulin chimera is shown below.
;~,~ o O
( H)-[somatostatin~-NHC(CH2)2S-S-(CH2)2CNH~[insulin]-(12 I) 10Somatostatin has the following amino acid sequence:
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys.
Insulin is a double chain protein hormone whose structure is well known.
Example 2 - Radioreceptor Assay Vsing Isolated Bovine Brain Microvessels and H-Somatostatin- I-Insulin Chimera Somatostatin was obtained from Peninsula Labora-tories and tritiated by reductive methylation using 3H-sodium borohydride. Insulin was obtained from SigmaChemical Company and was iodinated by oxidative iodina-tion using chloramine T and 125I-iodine. The two com-pounds were coupled together using SPDP as described in Example 1. Bovine brain microvessels were isolated as described in Pardridge, et al., "Rapid Sequestration And Degradation Of Somatostatin Analogues By Isolated Brain Microvessels", (Journal of Neurochemistry, Vol. 44, No.
4, 1985, pp. 1178-1184).
3H-somatostatin was added to one set of micro-vessels for up to 60 minutes incubation at room tem-perature. In another set of incubations, the H-somatostatin- I-insulin chimera was also added. As shown in the figure, the uptake of the chimera was more than double that of the free somatostatin. Moreover, the uptake of the chimera increased with time, whereas there was no increase in time with the free somatostatin. The 63-293/UC9.10 uptake of the free somatostatin likely represents non-specific binding as described in the article mentioned above (Journal of Neurochemistry, Vol. 44, No. 4, 1985).
This example demonstrates the receptor-mediated transcytosis or endocytosis of somatostatin-insulin chimera via the insulin receptor. Previous studies have shown that the receptor-mediated endocytosis of peptides in the isolated brain microvessels is a reliable index of the in ViVG blood-brain barrier receptor transport activity of peptides in vivo (see my previously-mentioned article in Endocrine Reviews, Vol. 7, No. 3, August 1986).
Example 3:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that transferrin is substituted for insulin. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient parenterally or intranasally.
Example 4:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that vasopressin is susbtituted for somatostatin. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient parenterally.
Example 5:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that transferrin is coupled to alpha-interferon. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject paren-~ 63-293/UC9.10 terally or intranasally.
Example 6:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that IGF-II is coupled to beta-endorphin. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject paren-terally or intranasally.
Example 7:
A chimeric peptide is prepared according to thesame procedure as in Example 1 except that insulin is coupled to ACTH 4-9 analogue. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject paren-terally or intranasally.
Example 8:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that cationized albumin is coupled to hexosaminidase A. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject parenterally or intranasally.
Having thus described exemplary embodiments of the present invention, it should be noted by those sXilled in the art that the within disclosures are exemplary only and that various other alternatives, adaptations and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.
63-2~3/UC9.10 CHIMERIC PEPTIDES FOR NEUROPEPTI DELIVERY
T OVGH THE BLOOD-BRAIN BARRIE~
BACKGROUND OF THE INVENTION
The present invention relates generally to the introduction of neuropharmaceutical agents into the brain by transcytosis across the blood-brain barrier. More particularly, the present invention relates to chimeric peptides which are capable of transporting neurophar-maceutical agents into the brain by receptor-mediated transcytosis across the blood-brain barrier.
This invention was made with Government support under Grant No. NS-17701 awarded by the National Institutes of Health. The Government has certain rights in this invention.
The vertebrate brain has a unique capillary system which is unlike that in any other organ in the body. The unique capillary system has morphologic characteristics which make up the blood-brain barrier (BBB). The blood-brain barrier acts as a systemwide cellular membranewhich separates the brain interstitial space from the blood.
The unique morphologic characteristics of the brain capillaries which make up the BBB are: ta) epithelial-like high resistance tight junctions which literallycement all endothelia of brain capillaries together, and (b) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs.
Due to the unique characteristics of the blood-brain barrier, hydrophilic drugs and peptides that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
Various strategies have been developed for intro-ducing those drugs into the brain which otherwise would not cross the blood-brain barrier. The most widely used strategies involve invasive procedures where the drug is 1 3 ~
63-293/UC9.10 delivered directly into the brain. The most common procedure is the implantation of a catheter into the ventricular system to bypass the blood-brain barrier and deliver the drug directly to the brain. These procedures have been used in the treatment of brain diseases which have a predilection for the meninges, e.g., leukemic involvement of the brain.
Although invasive procedures for the direct delivery of drugs to the brain ventricles have experienced some success, they have not been entirely successful because they only distribute the drug to superficial areas of the brain tissues, and not to the structures deep within the brain. Further, the invasive procedures are potentially harmful to the patient.
Other approaches to circumventing the blood-brain barrier utilize pharmacolgic-based procedures involving drug latentiation or the conversion of hydrophilic drugs into lipid-soluble drugs. The majority of the laten-tiation approaches involve blocking the hydroxyl, carboxyl and primary amine groups on the drug to make it more lipid-soluble and therefore more easily transported across the blood-brain barrier. Although the phar-macolgic approaches have been used with some success, they may no~ be entirely satisfactory for delivery of peptides through the BBB based on the inventor's ex-perience with cyclosporin transpsort through the BBB.
Cyclosporin is a highly latentiated (lipid-soluble) peptide that crosses the BBB rela~ively slowly.
Another approach to circum~enting the blood-brain barrier involves the intra-arterial infusion of hyper-tonic substances which transiently open the blood-brain barrier to allow passage of hydrophiiic drugs. However, hypertonic substances are potentially toxic and may damage the blood-brain barrier.
There presently is a need to provide improved sub-stances and methods for delivering hydrophilic drugs and ~31~
peptides across the blood-brain barrier and into the brain. It is desirable that such improved substances and methods provide for uniform introduction of the hydrophilic peptide or drug throughout the brain and present as little risk to the patient as possible.
SUMMARY OF THE INVENTION
In accordance with the present invention, new pro-cedures and substances are disclosed which provide uniform distribution of neuropeptides and other drugs throughout the brain while reducing the problems inherent in prior invasive and pharmacologic drug introduction procedures.
The present invention is based on the surprising dis-covery that hydrophilic peptides may be physiologically trans-ported across the blood-brain barrier by coupling or conjugating the drug to a transportable peptide which is capable of crossing the blood-brain barrier by receptor-mediated transcytosis. This di~covery i~ particularly surprising in view of the traditional notion that the blood-brain barrier is a passive barrier which is impenetrable by hydrophilic drugs or peptides.
According to one aspect of the present invention there i5 provided a chimeric peptide adapted for delivering a neuro-pharmaceutical agent into the brain by transcytosis through the blood-brain barrier, said chimeric peptide comprising:
a transportable peptide capable of crossing the blood-brain barrier by transcytosis, said peptide being selected from ,~
~ 3 ~
621g6-495 the group consisting of insulin, transferrin, IGF-I, IGF-II, basic albumin and prolactin; and a neuropharmaceutical agent selected from the group consisting of somatostatin, thyrotropin releaQing hormone, vaso-pressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glytamyl-L-histidyl-L-phenylalanyl-D-lysyl -L-phenylalanine, wherein said neuropharmaceutical agent is con-jugated with said transportable peptide.
The invention invovles novel chimeric peptides which are adapted to deliver a neuropharmaceutical agent into the brain by transcytosis across the blood-brain barrier. The chimeric peptides include a transportable peptide that is capable of crossing the blood-brain barrier at relatively high rate of receptor-mediated transcytosis. The transportable peptide is conjugated with a neuropharmaceutical agent to form the chimeric peptide. The neuropharmaceutical agent is generally a hydro-philic peptide that does not by itself significantly cross the BBB. The conjugation of transportable peptides with neuropharma-ceutical agents was surpri~ingly found to produce chimeric pep-tides which were capable of being , s' .
63-293/UC9.10 transported across the blood-brain barrier.
As a feature of the present invention, the chimeric peptides are believed to be transported across the blood-brain barrier by the physiologic process of transcytosis via receptors in the blood-brain barrier. This insures that the chimeric peptide is distributed uniformly to all parts of the brain. In addition, the introduction of the chimeric peptide into the brain by a physiologic pathway reduces the harmful side effects and risks inherent in the traditional invasive and pharmacolgical approaches.
The present invention also includes methods for administering the chimeric peptides subcutaneously or intranasally and the chimeric peptide containing com-positions utilized in such methods of treatment.
The above-discussed and many other features and attendant advantages of the present invention will become apparent as the invention becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawing.
BRIEF DESCRIPTION OF THE DRAWING
The figure is a chart showing the results of the tests described in Example No. 2.
DETAILED DESCRIPTION OF THE INVENTION
The chimeric peptides in accordance with the pre-sent invention are useful in delivering a wide variety of neuropharmaceutical agents to the brain. The invention is particularly well suited for delivering neuropharma-ceutical agents which are hydrophilic peptides. Thesehydrophilic peptides are generally not transported across the blood-brain barrier to any significant degree.
Exemplary hydrophilic peptide neuropharmaceutical agents are: thyrotropin releasing hormone (TRH) - used to treat spinal cord injury and Lou Gehrig's disease;
vasopressin - used to treat amnesia, alpha interferon -63-293/UC9.10 used to treat multiple sclerosis; somatostatin - used to treat Alzheimer's disease; endorphin - used to treat pain; L-methionyl (sulfone)-L-glutamyl-L-histidyl-L-phenylalanyl-D-lysyl-L-phenylalanine (an analogue of adrenocorticotrophic hormone (ACTH)-4-9) - used to treat epilipsy; and muramyl dipeptide - used to treat insomnia.
All of these neuropharmaceutical peptides are available commercially or they may be isolated from natural sources by well-known techniques.
The following description will be limited to chimeric peptides in which the neuropharmaceutical agents are hydrophilic peptides (neuropeptides) with it being understood that the invention has application to any neuropharmaceutical agent which by itself is transported at a low or non-existent rate across the blood-brain barrier. The invention also has application where it is desired to increase the rate at which the neuropharma-ceutical agent is transported across the blood-brain barrier.
The chimeric peptide includes the hydrophilic pep-tide drug conjugated to a transportable peptide which is capable of crossing the blood-brain barrier by trans-cytosis at a much higher rate than the hydrophilic neuropeptides. Suitable transportable peptides include:
insulin, transferrin, insulin-like growth factor (IGF-I), insulin-like growth factor II (IGF-II), basic albumin and prolactin.
Transferrin is an 80K glycoprotein that is the principal iron transport protein in the circulation.
Transferrin is also a protein that is enriched in the cerebrospinal fluid (CSF). Transferrin is widely avail-able and may be purchased or isolated from blood or CSF
by well-known procedures.
Insulin, IGF-I and IGF-II are also commonly avail-able. Insulin is available on a wide scale commerciallyand may also be recovered from natural sources by well-63-293/UC9.10 known techniques. IGF-I and IGF-II are available from commercial outlets such as Amgen or Peninsula Labs or they may be isolated from natural sources according to the procedure of Rosenfeld et al. (J. Clin Endocrinol.
Metab. 55, 434, 1982).
Basic albumin or cationized albumin has a iso-electric point (pI) of 8.5 as compared to a pI of 3.9 for natural albumin. Cationized albumin, unlike natural albumin, enters the brain rapidly across the blood-brain barrier. Cationized albumin (pI = 8.5) is prepared preferably by covalent coupling of hexamethylene-diamine (HMD) to bovine serum albumin (pI = 3.5) according to Bergmann, et al., "Cationized Serum Albumin Enhances Response of Cultured Fetal Rat Long Bones To Parathyroid Hormone", Endocrinology, 116:1729-1733 (1985). An exemplary synthesis is as follows: 10 ml of a 10~
solution of albumin in water is slowly added to 60 ml of 2.0 M HMD and the pH of the solution is adjusted to 6-7 with lN HCl. After 30 minutes, 1 g of N-ethyl-N'-3-(dimethylaminopropyl) carbodiimide hydrochloride (EDAC) is added to activate the carboxyl groups of the albumin, followed by the addition of another 1 g EDAC 1 hour later. The pH is constantly adjusted to 6-7 with 0.2N
HCl. The solution is allowed to stand overnight with constant stirring. The next day the solution is dialyzed extensively against distilled water. This solution is then purified by chromatofocusing using the Pharmacia polybuffer exchanger 94 resin and the polybuffer 96 elution buffer.
Prolactin is a hormone which is secreted by the anterior pituitary. Prolactin is widely available com-mercially or it can be isolated from pituitary glands by well-known procedures.
The chimeric peptides are made by conjugating a transportable peptide with the neuropharmaceutical pep-tide.
~ 3 ~
63-2~3/UC9.10 The conjugation may be carried out using bifunc-tional reagents which are capable of reacting with each of the peptides and forming a bridge between the two.
The preferred method of conjugation involves peptide thiolation wherein the two peptides are treated with a reagent such as N-Succinimidyl 3-(2-pyridyldithio) propionate (SPDP) to form a disulfide bridge between the two peptides to form the chimeric peptide. Other known conjugation agents may be used, so long as they provide linkage of the two peptides (i.e. the hydrophilic peptide drug and the transportable peptide) together without denaturing them. Preferably, the linkage can be easily broken once the chimeric peptide has entered the brain.
Suitable examples of conjugation reagents include:
glutaraldehyde and cystamine and EDAC. Conjugation of peptides using glutaraldehyde is described in Poznans~y et al., Insulin: Carrier potential for enzyme and drug therapy. Science 223:1304-1306, 1984. Conjugation of peptides using cystamine and EDAC is described in Ito et al., Transmembrane delivery of polypeptide hormones bypassing the intrinsic cell surface receptors: a con-jugate of insulin with a2-macroglobulin (a2M) recognizing both insulin and a2M receptors and it~ biological activity in relation to endocytic pathways. Mol Cell Endocrinol 36:165, 1984.
Examples of preferred chimeric peptides include those having the general structure O O
A-NHC(CH2)2S-S-(CH2)2CHN-B
where A is somatostatin, thyrotropin releasing hormone (T~I), vasopressin, alpha interferon, endorphin, muramyl dipeptide or ACTH 4-9 analogue; and B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin.
rj ~ ~
63-293/UC9.10 Other examples of preferred chimeric peptides in-clude those listed above wherein the disulfide conju-gating bridge between A and B is replaced with bridges having the following structures:
A~NH(CH2)2S-S-B (cleavable linXage) which are formed when cystamine and EDAC are employed as the bridge reagents;
A-NH=CH(CH2)3CH=NH-B (non-cleavable linkage) which are formed when glutaraldehyde is employed as bridge reagent.
The chimeric peptides can be introduced into the body by any conventional procedure including parenteral injection or intranasal inhalation. Preferably, the chimeric peptides are combined with a compatible phar-maceutical carrier and injected parenterally or if desired combined with a suitable carrier and administered intranasally in accordance with the well-Xnown conven-tional procedures used for intranasal administration of insulin. Suitable carrier solutions include those com-monly used in injectable or nasal-inhaled hormone preparations such aq sterile saline at a pH of around 5 which includes common bacteriostatic agents. The concentration of a chimeric peptide in the carrier will vary depending upon the specific transportable peptide and the specific neuropharmaceutical peptide. Pre-ferably, levels of the chimeric peptide in the carriershould be between about 0.001 weight percent to 0.01 weight percent. As a general rule, the dosage levels and percent of chimeric peptides present in the injection or intranasal solution should correspond to the accepted and established dosages for the particular neuropharma-ceutical peptide as well as the transportable peptide.
0 ~ ~
~ xamples of practlce are as follows:
ExamPle l - Synthesls o~ Somatostatln-Insulln Chlmera Somatostatin, a peptlde deflclent ln the brain of Al~helmer's dlsease, ls a peptlde whlch ls not transported through the blood-braln barrler. Conversely, lnsulln ls a peptlde that ls transported through the blood-braln barrler. The transportabillty of lnsulln through the blood-~raln barrler ls set forth ln my artlcle entltled "Receptor-Medlated Peptlde Transport Through The Hlood-Braln Barrler" (Endocrine Revlews, Vol. 7, No. 3, August 1986).
Somatostatln and lnsulln were con~ugated by peptlde thlolation using a reverslble peptlde-peptlde con~ugation method as descrlbed by Carlsson, et al. ln "Proteln Thlolatlon and Reverslble Proteln-Proteln Con~ugatlon" (Blochem. J. (1978) 173, 723-737). A heteroblfunctlonal reagent, N-succlnlmidyl 3-(2-pyrldyldlthlo)proplonate (SPDP), was used to couple a lyslne or free N-termlnus on lnsulln to a free lyslne or amlno termlnus on somatostatln. Approxlmately 0.3 mg of lnsulln and 26 uCl of 125I-lnsulln ln 2 ml of phosphate buffered sallne was prepared. To half of thls was added 4 lambdas of 20 mM fresh SPDP and thls was lncubated at room temperature for 45 mlnutes.
Separately, 180 uCl of trltlated somatostatln ln 180 uL
of 0.01 N HCl was solublllzed and added to 180 uL of 0.2 M phos-phate buffered sallne. To half of thls, 4 uL of 20 mM SPDP was added and thls was lncubated for 45 mlnutes, followed by acldl-flcatlon wlth 20 uL of 0.75 M sodlum acetate (pH = 4.5) followed by reductlon wlth 20 uL of 0.25 M dlthlothreltol. Thls was lncubated at room temperature for 30 mlnutes followed by brlef dlalysis to remove unreacted small molecules. The con~ugated lnsulln and con~ugated somatostatln were then incubated overnlght `at room temperature followed by dlalysls and countlng for 'X 9 ~ 3~
63-293/UC9.10 tritium and I radioactivity. This resulted in a total of 53 uCi of H-somatostatin coupled to 5.3 uCi of I-insulin in 2 ml of phosphate buffered saline.
The structure of the somatostatin-insulin chimera is shown below.
;~,~ o O
( H)-[somatostatin~-NHC(CH2)2S-S-(CH2)2CNH~[insulin]-(12 I) 10Somatostatin has the following amino acid sequence:
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys.
Insulin is a double chain protein hormone whose structure is well known.
Example 2 - Radioreceptor Assay Vsing Isolated Bovine Brain Microvessels and H-Somatostatin- I-Insulin Chimera Somatostatin was obtained from Peninsula Labora-tories and tritiated by reductive methylation using 3H-sodium borohydride. Insulin was obtained from SigmaChemical Company and was iodinated by oxidative iodina-tion using chloramine T and 125I-iodine. The two com-pounds were coupled together using SPDP as described in Example 1. Bovine brain microvessels were isolated as described in Pardridge, et al., "Rapid Sequestration And Degradation Of Somatostatin Analogues By Isolated Brain Microvessels", (Journal of Neurochemistry, Vol. 44, No.
4, 1985, pp. 1178-1184).
3H-somatostatin was added to one set of micro-vessels for up to 60 minutes incubation at room tem-perature. In another set of incubations, the H-somatostatin- I-insulin chimera was also added. As shown in the figure, the uptake of the chimera was more than double that of the free somatostatin. Moreover, the uptake of the chimera increased with time, whereas there was no increase in time with the free somatostatin. The 63-293/UC9.10 uptake of the free somatostatin likely represents non-specific binding as described in the article mentioned above (Journal of Neurochemistry, Vol. 44, No. 4, 1985).
This example demonstrates the receptor-mediated transcytosis or endocytosis of somatostatin-insulin chimera via the insulin receptor. Previous studies have shown that the receptor-mediated endocytosis of peptides in the isolated brain microvessels is a reliable index of the in ViVG blood-brain barrier receptor transport activity of peptides in vivo (see my previously-mentioned article in Endocrine Reviews, Vol. 7, No. 3, August 1986).
Example 3:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that transferrin is substituted for insulin. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient parenterally or intranasally.
Example 4:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that vasopressin is susbtituted for somatostatin. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient parenterally.
Example 5:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that transferrin is coupled to alpha-interferon. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject paren-~ 63-293/UC9.10 terally or intranasally.
Example 6:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that IGF-II is coupled to beta-endorphin. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject paren-terally or intranasally.
Example 7:
A chimeric peptide is prepared according to thesame procedure as in Example 1 except that insulin is coupled to ACTH 4-9 analogue. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject paren-terally or intranasally.
Example 8:
A chimeric peptide is prepared according to the same procedure as in Example 1 except that cationized albumin is coupled to hexosaminidase A. The resulting chimeric peptide is combined with sterile saline to provide a solution containing 0.01 weight percent chimeric peptide which is administered to the patient or subject parenterally or intranasally.
Having thus described exemplary embodiments of the present invention, it should be noted by those sXilled in the art that the within disclosures are exemplary only and that various other alternatives, adaptations and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.
Claims (10)
1. A chimeric peptide adapted for delivering a neuro-pharmaceutical agent into the brain by transcytosis through the blood-brain barrier, said chimeric peptide comprising:
a transportable peptide capable of crossing the blood-brain barrier by transcytosis, said peptide being selected from the group consisitng of insulin, transferrin, IGF-I, IGF-II, basic albumin and prolactin; and a neuropharmaceutical agent selected from the group consisting of somatostatin, thyrotropin releasing hormone, vaso-pressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glytamyl-L-histidyl-L-phenylalanyl-D-lysyl -L-phenylalanine, wherein said neuropharmaceutical agent is con-jugated with said transportable peptide.
a transportable peptide capable of crossing the blood-brain barrier by transcytosis, said peptide being selected from the group consisitng of insulin, transferrin, IGF-I, IGF-II, basic albumin and prolactin; and a neuropharmaceutical agent selected from the group consisting of somatostatin, thyrotropin releasing hormone, vaso-pressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glytamyl-L-histidyl-L-phenylalanyl-D-lysyl -L-phenylalanine, wherein said neuropharmaceutical agent is con-jugated with said transportable peptide.
2. A chimeric peptide according to claim 1 wherein said transportable peptide and neuropharmaceutical agent are conjuga-ted via a conjugation agent.
3. A chimeric peptide according to claim 2 wherein said conjugation agent is capable of conjugating the transportable peptide to said neuropharmaceutical agent by peptide thiolation or lysine coupling via glutaraldehyde.
4. A chimeric peptide according to claim 3 wherein said transportable peptide is insulin.
5. A chimeric peptide according to claim 4 wherein said neuropharmaceutical agent is somatostatin.
6. A chimeric peptide according to claim 1 having the formula A-NH?(CH2)2S-S-(CH2)?NH-B
wherein A is said neuropharmaceutical agent and B is said transportable peptide.
wherein A is said neuropharmaceutical agent and B is said transportable peptide.
7. A chimeric peptide according to claim 6 wherein A is somatostatin and B is insulin.
8. A composition comprising a chimeric peptide according.
to claim 1 and a pharmaceutically acceptable carrier for said chimeric peptide.
to claim 1 and a pharmaceutically acceptable carrier for said chimeric peptide.
9. A composition according to claim 8 wherein said pharmaceutically acceptable carrier is sterile saline.
10. The use for delivering a neuropharmaceutical agent into the brain of an animal by transcytosis through the blood-brain barrier of a chimeric peptide according to any one of claims 1 to 7 in a sufficient amount to provide transport of said chimeric peptide across said blood-brain barrier.
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US06/891,867 US4801575A (en) | 1986-07-30 | 1986-07-30 | Chimeric peptides for neuropeptide delivery through the blood-brain barrier |
US891,867 | 1986-07-30 |
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DK140801B (en) * | 1975-01-15 | 1979-11-19 | Nordisk Insulinlab | Process for the preparation of a stable long-acting insulin preparation. |
NZ182272A (en) * | 1975-10-14 | 1985-03-20 | Univ Ohio State | Modified polypeptides for the immunological control of fertility,and pharmaceutical compositions |
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US4348387A (en) * | 1979-07-31 | 1982-09-07 | The Rockefeller University | Method and system for the controlled release of biologically active substances to a body fluid |
GB2116979B (en) * | 1982-02-25 | 1985-05-15 | Ward Page Faulk | Conjugates of proteins with anti-tumour agents |
US4522750A (en) * | 1984-02-21 | 1985-06-11 | Eli Lilly And Company | Cytotoxic compositions of transferrin coupled to vinca alkaloids |
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- 1987-07-16 EP EP87905071A patent/EP0276278B1/en not_active Expired - Lifetime
- 1987-07-16 DE DE87905071T patent/DE3787460T2/en not_active Expired - Lifetime
- 1987-07-16 WO PCT/US1987/001699 patent/WO1988000834A1/en active IP Right Grant
- 1987-07-29 CA CA000543217A patent/CA1311086C/en not_active Expired - Fee Related
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EP0276278B1 (en) | 1993-09-15 |
DE3787460T2 (en) | 1994-02-17 |
EP0276278A4 (en) | 1990-01-08 |
EP0276278A1 (en) | 1988-08-03 |
WO1988000834A1 (en) | 1988-02-11 |
US4801575A (en) | 1989-01-31 |
JPH01500901A (en) | 1989-03-30 |
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