WO1998013059A1 - Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques - Google Patents

Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques Download PDF

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Publication number
WO1998013059A1
WO1998013059A1 PCT/US1997/017410 US9717410W WO9813059A1 WO 1998013059 A1 WO1998013059 A1 WO 1998013059A1 US 9717410 W US9717410 W US 9717410W WO 9813059 A1 WO9813059 A1 WO 9813059A1
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peptide
aminobenzyl
amino
hydrolyzable
prodrug
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PCT/US1997/017410
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English (en)
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Raymond Firestone
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Bristol-Myers Squibb Company
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Priority to AU45995/97A priority Critical patent/AU739028B2/en
Priority to CA002264227A priority patent/CA2264227A1/fr
Priority to JP10515981A priority patent/JP2001501211A/ja
Priority to EP97944519A priority patent/EP0961619A4/fr
Publication of WO1998013059A1 publication Critical patent/WO1998013059A1/fr

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    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention is directed to hydrolyzable prodrugs for delivery of therapeutic drugs to metastatic cells, particularly anticancer drugs.
  • Metastasis is the hallmark of cancer.
  • a tumor that does not metastasize is termed "benign” because it poses a threat of survival that is small compared to a "malignant" tumor that does metastasize (McGuire, New En ⁇ . J. Med.. 320:525 (1989)).
  • Metastasis involves a sequence of events that few cells can successfully complete (Sanchez, Am. J. Med. ScL 292:376 (1986); Poste, Nature. 283:139 (1980)). Metastatic cells must break away from the primary tumor, survive attack by the immune system during transit in the blood, lodge somewhere while resisting the shear force of the moving blood stream, penetrate basement membrane to reach a safe haven where they can multiply, and finally create a blood supply of their own when the demand for nourishment of the growing metastatic tumor exceeds what is available locally by diffusion. Metastatic cells are not a representative sample of the tumor (itself highly heterogeneous) (Poste, Ann. New York Acad. Sci., 397:34 (1982); Heppner, Cancer Res..
  • metastases are very small and therefore comparatively accessible to chemotherapy, they are highly resistant to present day drugs, for in spite of heavy medication, survival rates for e.g., phases 2 and 3 breast carcinoma (lymph node involvement signaling spread) are very low compared to phase 1 (no spread). In the absence of spread, the survival rate is 70% or greater; in the presence of spread, it is less than 10% (McGuire, New En ⁇ . J. Med.. 320:525 (1989)). Inhibiting as contrasted with killing metastases can only prolong life a short while because by the time cancer is typically diagnosed, metastasis has already taken place.
  • such anti -metastatic reagents should be usable against many types of metastases and not depend for their activity on characteristics of the primary tumor cells that might not be shared by the metastases.
  • such anti-metastatic reagents should be readily absorbed and lack toxicity, particularly in patients who are already subject to regimens consisting of multiple drug treatment.
  • a hydrolyzable prodrug according to the present invention comprises an amino-terminal capped peptide covalently linked to a therapeutic drug through a self- immolating spacer of sufficient length to prevent the occurrence of steric hindrance.
  • the amino-terminal capped peptide is a substrate for a peptidohydrolase located on the surface of a metastatic cell
  • the peptidohydrolase is cathepsin B or collagenase IV.
  • the peptidohydrolase is cathepsin B.
  • the amino-terminal capped peptide is benzyloxycarbonylphenylalanyllysine, benzyloxycarbonylvalinyllysine, D- phenylalanylphenylalanyllysine, benzyloxycarbonylvalinylcitrulline, t-butyloxyca ⁇ >onylphenylalanylysine, benzyloxycarbonyl- alanyllarginylarginine, benzyloxycarbonylphenylalanyl-N-tosylarginine,2- aminoethylthio-succinimidopropionylvalinylcitrulline, 2-aminoethylthio- succinimidopropionyllysylphenylalanyllysine, acetylphenyialanyllysine, or benzyloxycarbonylphenylalanyl-O-benzoylthreonine.
  • the therapeutic drug is an anticancer drug.
  • the anticancer drug is doxorubicin, mitomycin C, taxol, esperamycin, or camptothecin.
  • a particularly preferred anticancer drug is doxorubicin.
  • PABC p_-aminobenzyl carbonyl
  • the hydrolyzable prodrug can further comprise a peptide derived from a protein to which metastatic cells adhere in establishing colonies covalently linked to the therapeutic drug.
  • the peptide is a RGD-derived active peptide or a YIGSR-derived active peptide.
  • the peptide is YIGSR (SEQ ID NO:1) or GRGDS (SEQ ID NO:2).
  • Preferred hydrolyzable prodrugs according to the present invention include benzyloxycarbonylphenylalanyllysyl-rj-aminobenzyl carbamoyldoxorubicin, acetylphenylalanyllysyl- ⁇ -aminobenzyl carbamoyldoxorubicin, acetylphenylalanyliysyl-g-aminobenzyl carbamoylmitomycin C, benzyloxycarbonylphenylalanyllysyl-p_-aminobenzyl carbonyl-7-paclitaxel, acetylphenylalanyllysyl-p-aminobenzyl carbonylcamptothecin, 2-aminoethylthio-succinimidopropionyl- valinyicitrullinyl-BHMS-didoxorubicin, 2-aminoethylthio- succinimidopropionyl
  • Another aspect of the present invention is a method for delivering a therapeutic drug to a metastatic cell comprising the steps of: (1) contacting a hydrolyzable prodrug according to the present invention with a metastatic cell;
  • composition comprising:
  • Figure 1 is a depiction, showing structural formulas and reaction conditions, of the initial stages in the synthesis of the hydrolyzable prodrug Ac-Phe-Lys-PABC-Dox;
  • Figure 2 is a similar depiction of the final stages in the synthesis of Ac-Phe-Lys-PABC-Dox;
  • Figure 3 is a similar depiction of the synthesis of the hydrolyzable prodrug Ac-Phe-PABC-MMC, beginning with an intermediate in the synthesis of Ac-Phe-Lys-PABC-Dox prior to the coupling of the doxorubicin residue;
  • Figure 4 is a similar depiction of the initial stages of the synthesis of the hydrolyzable prodrug Z-Phe-Lys-PABC-Paclitaxel
  • Figure 5 is a similar depiction of the final stages of the synthesis of the hydrolyzable prodrug Z-Phe-Lys-PABC-Paclitaxel
  • Figure 6 is a similar depiction of the early stages of the synthesis of the hydrolyzable prodrug CA-SP-Lys-Phe-Lys-BHMS-Dox 2 ;
  • Figure 7 is a similar depiction of the intermediate stages of the synthesis of CA-SP-Lys-Phe-Lys-BHMS-Dox 2 ;
  • Figure 8 is a similar depiction of the final stages of the synthesis of CA-SP-Lys-Phe-Lys-BHMS-Dox 2 ;
  • Figure 9 is a table showing the killing of BT-20 tumor cells, which are high-cathepsin B-secreting cells, and MCF-10A tumor cells, which are low-cathepsin B-secreting cells, by several hydrolyzable prodrugs and control compounds in the presence or absence of the cathepsin inhibitor CA- 074;
  • Figure 10 is a table showing the killing of BT-20 tumor cells at various times and prodrug concentrations with several hydrolyzable prodrugs and a control compound;
  • Figure 1 1 is a table showing the killing of BT-20 and MCF-10A tumor cells at various times and prodrug concentrations with the hydrolyzable prodrug CA-SP-Lys-Phe-Lys-BHMS-Dox 2 ;
  • Figure 12 is a table showing the stability of hydrolyzable prodrugs according to the present invention under physiological conditions in the presence or absence of cathepsin B.
  • One new approach to developing reagents specific for metastatic cells takes advantage of the properties of the metastatic cells themselves, particularly those properties possessed by the metastatic cells that allow them to spread through the body and adhere to specific tissues.
  • One such property is the ability of metastatic cells to penetrate basement membrane (Sanchez, Am. J. Med. Sci. 292:376 (1986); Poste, Nature. 283:139 (1980)), shared only by the peripheral cells of the primary tumor (Poole, Nature. 273:545 (1978); Shamberger, Nature. 213:617 (1967); Graf, Lab. Invest.. 45:587 (1981 ); Baici, Inv. Metas.. 4:13 (1984); Duffy, Eur. J. Cancer Clin. Oncol.. 23:583 (1987)) and by virtually no normal body cells.
  • Metastatic cells do this by means of hydrolytic enzymes which they secrete into the medium (Duffy, Eur. J. Can. Clin. Oncol.. 23:583 (1987); MacKay, Cancer Res.. 50:5997 (1990); Goldfarb, Sem. Thromb. Hemostas.. 12:294 (1986); Pietras, Gynec. Oncol.. 7:1 (1979)) or in their plasma membranes (Sylven, Virchows Arch. B.. 17:97 (1974); Sloane, Biomed. Biochim. Acta. 50:549 (1991 ); Keren, Cancer Res.. 48:1416 (1989); Pietras, J. Biol. Chem..
  • Tumors are proteolvtic (Fischer. Arch. Entw. Mech. Arg.. 104:210 (1925); Duffy, Eur. J. Cancer Clin. Oncol.. 23:583 (1987); Strauli et al., ed., "Proteinases and Tumor Invasion” (Raven Press, New York, 1980)), and this power is correlated with metastatic propensity (Duffy, Eur. J. Cancer Clin. Oncol.. 23:583 (1987); Sylven, Virchows Arch. B.. 17:97 (1974); Sloane,
  • Enzymes known to be secreted by metastasizing cells include cathepsin B (Sloane, Biomed. Biochim. Acta. 50:549 (1991 ); Keren, Cancer Res.. 48:1416 (1989); Pietras, J. Biol. Chem.. 256:8536 (1981 ); Weiss, Proc. Am. Assoc. Cancer Res...
  • cytotoxic drugs at the sites of metastatic foci.
  • Preferred drugs are those that are readily ingested by cells such as doxorubicin (Dox) (also known as adriamycin (ADM)), mitomycin C (MMC), taxol, camptothecin (CPT), and esperamycin, as well as derivatives of these drugs.
  • Dox doxorubicin
  • MMC mitomycin C
  • CPT camptothecin
  • esperamycin esperamycin
  • anticancer drugs have substantial hydrophobic moieties so that they can pass through the plasma membrane of metastatic cells.
  • Other anticancer drugs can be derivatized with appropriate hydrophobic moieties to improve their permeability to the lipid bilayer of the plasma membrane of the metastatic cell.
  • a particularly useful enzyme with prodrugs according to the present invention is cathepsin B, principally because it is an exopeptidase (Takahashi, J. Biol. Chem.. 261 :9375 (1986); Koga, J. Biochem.. 110:179 (1991)) for which numerous peptide substrates are already known (Dingle, ed., “Lysosomes” (North-Holland, Amsterdam, 1977); Strauli et al., eds., “Proteinases and Tumor Invasion” (Raven Press, New York, 1980); Neuberger, ed., "Hydrolytic Enzymes” (Elsevier, Amsterdam, 1987)).
  • Cathepsin B is a lysosomal enzyme that is ubiquitous within cells (Dingle, ed., “Lysosomes” (North-Holland, Amsterdam, 1977); Strauli et al., eds., “Proteinases and Tumor Invasion” (Raven Press, New York, 1980); Neuberger, ed., “Hydrolytic Enzymes” (Elsevier, Amsterdam, 1987)), but almost never secreted normally. If small amounts of cathepsin B do escape during exocytosis or unprogrammed cell death, it loses all activity within 15 minutes at neutral pH (Sheahan, Cancer Res..
  • the plasma membrane is obviously a highly desirable place to activate a latent cytotoxic drug which should be delivered, not only as directly as possible to the target cells, but also to neighboring cancer cells that might not display as much cathepsin B as the majority, owing to the high genetic instability (Fidler, Cancer Treat. Rep.. 68:193 (1984)) of metastasizing cells.
  • a preferred reagent for delivering therapeutic drugs to metastasizing cells is a hydrolyzable prodrug comprising an amino-terminal capped peptide covalently linked to a therapeutic drug through a self-immolating spacer of sufficient length to prevent the occurrence of steric hindrance.
  • the amino-terminal capped peptide is a substrate for a peptidohydrolase located on the surface of a metastatic cell.
  • the peptidohydrolase is cathepsin B or collagenase
  • the peptidohydrolase is cathepsin B.
  • the amino-terminal capped peptide that acts as a substrate for the peptidohydrolase is typically one of benzyloxycarbonylphenylalanyllysine, benzyloxycarbonylvalinyllysine, D-phenylalanylphenylalanyllysine, benzyloxycarbonylvalinylcitrulline, t-butyloxycarbonylphenylalanylysine, benzyloxycarbonylalanyllarginylarginine, benzyloxycarbonylphenylalanyl-N- tosylarginine,2-aminoethylthio-succinimidopropionylvalinylcitrulline, 2- aminoethylthio-succinimidopropionyllysylphenylalanyllysine,
  • the amino-terminal capped peptide is benzyloxycarbonylphenylalanyllysine or acetylphenylalanyllysine.
  • substrates containing paired basic residues can be hydroiyzed by cathepsin B (J.K. McDonald & S. Ellis, Life Sci.. 17:1269-1276 (1975)).
  • the amino-terminal residue must be "capped” or protected with a protecting group.
  • protecting groups are well-known in peptide chemistry and include, for example, benzyloxycarbonyl (also known as carbobenzoxy and generally abbreviated as Z), acetyl, 2-aminoethylthio-succinimidopropionyl, t-butyloxycarbonyl, and other amino-terminal protecting groups such as those disclosed in M. Bodanszky, "Principles of Peptide Synthesis” (2d Ed., Springer-Verlag, Berlin, 1993).
  • These groups include triphenylmethyl, ⁇ - methoxybenzyloxycarbonyl, adamantyloxycarbonyl, biphenylylisopropyloxycarbonyl, formyl. isonicotinyloxycarbonyl, o- nitrophenylsulfenyl, 9-fluorenylmethyloxycarbonyl, derivatives of benzyloxycarbonyl substituted on the aromatic ring of the benzyl group, or, in some cases, in which the phenyl moiety of the benzyl group is replaced with another fully aromatic moiety such as furan or pyndine, phthaloyl, dithiasuccinyl, p-toluenesulfonyl (tosyl), and other groups.
  • the amino-terminal protecting group can be a D- amino acid such as D-phenylalanine.
  • the amino-terminal protecting group is a D-amino acid
  • the carboxyl group of the D-amino acid forms a peptide bond with the amino-terminal residue of the amino-terminal protected peptide.
  • the protecting group is benzyloxycarbonyl or acetyl, so that the amino-terminal protected peptide is benzyloxycarbonylphenylalanyllysine or acetylphenylalanyllysine.
  • the hydrolyzable prodrug includes a spacer of sufficient length to prevent the occurrence of ste c hindrance between the amino-terminal protected peptide and the therapeutic drug. If the spacer is too short, the therapeutic drug may prevent the binding of the substrate for the peptidohydrolase to the active site of the peptidohydrolase by stenc hindrance.
  • a particularly suitable spacer is ⁇ _-am ⁇ nobenzyl carbonyl ("PABC"). This has an approximate length of 10 angstroms.
  • Derivatives of p-aminobenzyl carbonyl can also be used, such as compounds substituted on the aromatic moiety of the benzyl group.
  • spacer groups can be used.
  • the length of the spacer should be greater than about 10 angstroms; spacers of significantly greater length can be used, and can incorporate, for example, additional aliphatic or aromatic moieties. In general, such spacers should be relatively unbranched so as not to introduce stenc hindrance of their own.
  • the chemical functionality terminating the spacer can vary but one end is able to react with the carboxyl-terminal residue of the substrate for the peptidohydrolase. Typically, this is an amino group.
  • the other functionality terminating the spacer is capable of reacting with the therapeutic drug. In one preferred embodiment, this functionality reacts at an amino group of the drug to form a carbamate or urethane linkage as part of the spacer.
  • This spacer also reacts at an amino group of the drug to form a carbamate or urethane linkage.
  • This spacer is bifunctional and can bind two drug moieties such as doxorubicin.
  • such spacers have the property of self-immolation.
  • a self-immolating spacer is one in which the residual portion of the spacer attached to the therapeutic drug subsequent to the hydrolysis of the peptide bond by the peptidohydrolase is then further cleaved by spontaneous, nonenzymatic hydrolysis in an aqueous medium to restore the original unconjugated drug.
  • Both PABC and BHMS are self-immolating.
  • the spacer is p_-aminobenzyl carbonyl ("PABC") and the therapeutic drug is doxorubicin
  • PABC p_-aminobenzyl carbonyl
  • doxorubicin the portion of the spacer remaining attached to the drug after hydrolysis of the peptide bond by cathepsin B, then subsequently undergoes spontaneous hydrolysis to ⁇ _-aminobenzyl alcohol, carbon dioxide, and doxorubicin.
  • the therapeutic drug is an anticancer drug.
  • other therapeutic drugs can be incorporated into hydrolyzable prodrugs according to the present invention and can be delivered to metastatic cells.
  • Preferred anticancer drugs incorporated into hydrolyzable prodrugs according to the present invention include doxorubicin, taxol, camptothecin, mitomycin C, and esperamycin, as well as derivatives thereof.
  • Other anticancer drugs that have hydrophobic moieties that allow them to be taken up efficiently by metastatic cells or that can be derivatized with such moieties can also be used.
  • hydrolyzable prodrugs include benzyloxycarbonylphenylalanyllysyl- ⁇ -aminobenzyl carbamoyldoxorubicin, acetylphenylalanyliysyl-p_-aminobenzyl carbamoyldoxorubicin, acetylphenylalanyllysyl-p_-aminobenzyl carbamoylmitomycin C, benzyloxycarbonylphenylalanyllysyl- _-aminobenzyl carbonyl-7-paclitaxel, acetylphenylalanyllysyl-p_-aminobenzyl carbonylcamptothecin, 2- aminoethylthio-succinimidopropionyl-valinylcitrullinyl-bis(hydroxymethyl)- styryl-bisdoxorubicin, 2-aminoethylthi
  • Synthesis of hydrolyzable prodrugs according to the present invention can be accomplished by condensation reactions that are well known in the art. Examples of syntheses are given below in Examples 1 -6.
  • the synthetic procedure comprises: (1 ) synthesizing the peptide that is the substrate of the peptidohydrolase by conventional peptide synthetic techniques, with the ⁇ -amino group of the amino-terminal amino acid residue protected and appropriate protection for reactive side chains of the amino acids; (2) linking the g-aminobenzyl moiety to the carboxyl group of the carboxyl-terminal amino acid; (3) activating the j-aminobenzyl moiety for covalent linkage of the therapeutic drug; (4) covalently linking the therapeutic drug, which may have certain reactive side chains protected as well; and (5) removing the remaining protecting groups on the peptide and the therapeutic drug.
  • the synthetic procedure comprises: (1) synthesizing a peptide that is the substrate of the peptidohydrolase by conventional peptide synthetic techniques, with appropriate protective groups as above; (2) linking the BHMS moiety to the carboxyl group of the carboxyl-terminal amino acid of the peptide; (3) activating the BHMS moiety for coupling of the therapeutic drug; (4) coupling the therapeutic drug to the activated BHMS moiety; (5) removing any protecting groups on amino acid side chains, such as the ⁇ -amino group of lysine; and (6) modifying the amino-terminal blocking group so that the desired capping group is present.
  • the substrate for cleavage by the peptidohydrolase is a tripeptide or peptide with more than three amino acids
  • the peptide can be extended at its amino-terminus after the coupling of the carboxyl-terminus to the spacer. This involves removing the amino-terminal protecting group of the peptide, activating the carboxyl group of the amino acid to be added, and coupling it to the deblocked amino group to form a peptide bond. This step can be repeated if a longer peptide is desired. Then, the therapeutic drug is coupled to the completed peptide and synthesis of the hydrolyzable prodrug is completed as above.
  • the hydrolyzable prodrug further comprises a peptide derived from a protein that adheres to metastatic cells.
  • peptides include peptides derived from the protein fibronectin (GRGDS)(SEQ ID NO:1)(Humphries, Science 233:467 (1986); Olden. Ann. New York Acad. Sci. 421 (1989); Dedhar, Bjo Essays. 12:583 (1990)) and laminin (YIGSR)(SEQ ID NO:2)(lwamoto, Science. 238:1132 (1987); Saiki, Brit. J. Cancer 59:194 (1989)).
  • GAGDS protein fibronectin
  • YIGSR laminin
  • the peptide is covalently linked to the amino side of the amino-terminal capped peptide that is the substrate for the peptidohydrolase, either directly as an amide, or indirectly via attachment to the capping group, benzyloxycarbonyl, acetyl, maleimidopropionyl or the like, which has been modified to accept the peptide.
  • the linkage can be through either the amino or carboxyl group of the peptide, or, in some cases, through functional groups of the peptide such as the carboxyl of aspartic acid, the hydroxyl of serine or other functional groups of other residues.
  • various cross-linking reagents can be used.
  • carbodiimides such as dicyclohexylcarbodiimide
  • Other reactive groups are known and are described, for example, in G.T. Hermanson, "Bioconjugate Techniques” (Academic Press, San Diego, 1996), in S.S. Wong, “Chemistry of Protein Conjugation and Crosslinking” (CRC Press, Boca Raton, Fla. 1991), and in T.E. Creighton, Ed., "Protein Function: A Practical Approach” (IRL Press, Oxford 1989).
  • the peptide can be linked, for example, to a maleimidopropionyl cap via a cysteine whose thiol group is added to the maleimido group, or to a glycine or other amino acid cap (replacing the acetyl cap) via acylation of the amino group of the glycine, or by attaching the peptide to the reposition of the benzyloxycarbonyl cap, or by other methods known to the art.
  • the linkage of these peptides such as YIGSR (SEQ ID NO: 2) to the prodrug may be with or without intervening links which might or might not consist of other amino acids.
  • conjugation or crosslinking methods can also be used to attach the peptides such as the peptides from laminin or fibronectin to other portions of the hydrolyzable prodrug,. tn most cases, attaching the peptide to the self-immolating spacer would either prevent hydrolysis of the substrate by the peptidohydrolase or result in steric hindrance.
  • a number of peptides derived from the fibronectin and laminin peptides can be linked to the hydrolyzable prodrugs. These peptides can be classified in terms of their structure and homology to the fibronectin or laminin sequence as follows:
  • Fibronectin-derived peptides include: (1) the GRDGS (SEQ ID NO: 1) pentapeptide derived from the fibronectin sequence (I. Hardan et al., "Inhibition of Metastatic Cell Colonization in Murine Lungs and Tumor- Induced Morbidity by Non-Peptidic Arg-Gly-Asp Mimetics," Int. J. Cancer 55: 1023-1028 (1993)); (2) derivatives of the fibronectin pentapeptide sequence with conservative amino acid substitutions, such as GRGES (SEQ ID NO: 3) (R.J.
  • GRGDSPA SEQ ID NO: 8
  • GRGDXPC extended peptides with ammo acid substitutions, such as GRGDXPC, where X is a naturally-occurring L-amino acid other than M, C, H, Y, G, or P
  • GRGDNPC SEQ ID NO: 9
  • GRGDXPA GRGDXPA
  • X is a naturally-occurring L-amino acid other than M, C, H, Y, G, or P
  • GRGDSG SEQ ID NO: 1 1
  • YIGSR Multimeric Forms of Tyr-lle-Gly-Ser-Arg
  • GRGDXG where X is a naturally-occurring L-amino acid other than M, C, H, Y, G, or P
  • GRDGXPA where X is a naturally-occurring L-amino acid other than M, C, H, Y, G, or P
  • Laminin-derived peptides include: (1 ) the YIGSR (SEQ ID NO:
  • CDPGYIGSR SEQ ID NO: 17
  • peptides including substituted peptides and extended sequences with amino acid substitutions, in which a D-amino acid replaces one of the naturally occurring L-amino acids, such as CDPGYI(dA)SR and YIG(dA)SR (G.J. Ostheimer et al., "NMR Constrained Solution Structures for Laminin Peptide 11.” J. Biol. Chem.
  • An additional aspect of the present invention is a method for delivery of a therapeutic drug to a metastatic cell.
  • a method for delivery of a therapeutic drug to a metastatic cell comprises the steps of:
  • a hydrolyzable prodrug comprising an amino- terminal capped peptide covalently linked to a therapeutic drug through a self-immolating spacer of sufficient length to prevent the occurrence of steric hindrance with a metastatic cell, the amino-terminal capped peptide being a substrate for a peptidohydrolase located on the surface of the metastatic cell;
  • the therapeutic drug is an anticancer drug.
  • the hydrolyzable prodrug is delivered to the metastatic cells under conditions under which the prodrug is stable in the absence of enzymatic hydrolysis.
  • prodrugs are stable in plasma at pH 7.4 at 37 9 C. for at least 6 days in the absence of a peptidohydrolase such as cathepsin B.
  • the prodrugs are stable for 16 days or more or 20 days or more in the absence of cathepsin B.
  • the prodrug can be delivered to the metastatic cells either in vivo or in vitro.
  • the hydrolyzable prodrugs of the present invention are administered in a quantity sufficient to kill at least a fraction of the metastatic cells.
  • the hydrolyzable prodrugs of the present invention can be administered in vivo using conventional modes of administration including, but not limited to, intravenous, intraperitoneal, oral or intralymphatic. Other routes of injection can alternatively be used. Oral or intraperitoneal administration is generally preferred.
  • the composition can be administered in a variety of dosage forms which include, but are not limited to, liquid solutions or suspensions, tablets, pills, powders, suppositories, polymeric microcapsules or microvesicles, liposomes, and injectable or infusible solutions. The preferred dosage form depends on the mode of administration and the quantity administered.
  • compositions for administration according to the present can include conventional pharmaceutically acceptable carriers and adjuvants known in the art such as human serum albumin, ion exchangers, alumina, lecithin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, and salts or electrolytes such as protamine sulfate.
  • conventional pharmaceutically acceptable carriers and adjuvants known in the art such as human serum albumin, ion exchangers, alumina, lecithin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, and salts or electrolytes such as protamine sulfate.
  • the most effective modes of administration and dosage regimen for the hydrolyzable prodrugs as used in the methods of the present invention depend on the severity and course of the disease, the patient's health, the response to treatment, the particular type of metastatic cells characteristic of the particular primary tumor, the location of the metastases, pharmacokinetic considerations such as the condition of the patient's liver and/or kidneys that can affect the metabolism and/or excretion of the administered hydrolyzable prodrugs, and the judgment of the treating physician. Accordingly, the dosages should be titrated to the individual patient.
  • the invention is further exemplified by the following Examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention.
  • hydrolyzable prodrug is acetylphenyialanyllysyl-p-aminobenzyl carbonylcamptothecin (Ac-Phe-Lys-PABC-CPT).
  • Fmoc-Phe-Lys-(Boc)- PABC-CPT 200 mg, 0.18 mmol was suspended in 6.0 mi of methylene chloride and 1.0 ml of diethylamine added. The suspension gradually dissolved as the solution and was stirred for 3 h. The solvent and diethylamine were removed under vacuum. The resulting foamy solid was redissolved in methylene chloride and then acetic anhydride (0.068 ml, 0.72 mmol) and diisopropylethylamine (0.13 mol) added. The reaction mixture was stirred overnight, transferred to a separatory funnel, and washed with pH 7 buffer.
  • This bifunctional spacer can bind two doxorubicin molecules.
  • This compound also has a capping group of 2-aminoethylthio (CA) linked to the valine residue through a succinimidopropionyl (SP) group.
  • CA 2-aminoethylthio
  • SP succinimidopropionyl
  • Fmoc-Lys The first step in the synthesis of the hydrolyzable prodrug Ac-Phe-Lys-PABC-Dox is the synthesis of Fmoc- Lys (MMT).
  • This lysine derivative has its ⁇ -amino group protected with the protecting group 9-fluorenylmethoxycarbonyl and its ⁇ -amino group protected with the blocking group monomethoxytrityl.
  • hydrolyzable prodrug according to the present invention with an acetyl capping group and mitomycin C (MMC) as the anticancer drug was synthesized.
  • the peptide substrate for cathepsin B is Phe-Lys. Synthesis of Ac-Phe-Lvs(MMT)-PABC-MMC.
  • the first step in the synthesis is the coupling of the phenylalanyl moiety with the lysine moiety, whose ⁇ - amino group is protected with a monomethoxytrityl (MMT) residue. Coupling is accomplished with the use of a succinimidyi derivative of the phenylalanine, whose carboxyl group is thereby activated.
  • the first step in the synthesis of the bifunctional hydrolyzable prodrug CA-SP- Lys-Phe-Lys-BHMS-Dox 2 is a synthesis of the bifunctional linker bis(hydroxymethyl)p_-aminostyrene (BHMS).
  • Raney nickel (5.28 ml, 50% slurry in H 2 0) and hydrazine monohydrate (21 ml, 1.5 equiv.) were added to a stirred solution of 2-(p-nitrobenzylidene)-propane-1 ,3-diol (P. Vanelle et al., Eur. J. Med. Chem.
  • the BT-20 cell line was maintained in E-MEM-10 (minimal essential medium (Earle's Salts) supplemented with 10% fetal bovine serum, penicillin (100 U/ml) and streptomycin (100 ⁇ g/ml)) in 5% C0 2 at 37° C.
  • E-MEM-10 minimal essential medium (Earle's Salts) supplemented with 10% fetal bovine serum, penicillin (100 U/ml) and streptomycin (100 ⁇ g/ml)
  • MCF 10A cell line was maintained in DMEM/Ham's F12 supplemented with 5% horse serum, EGF (20 ng/ml), insulin (0 5 ⁇ g/ml), hydrocortisone (0.5 ⁇ g/ml), penicillin (100 U/ml), and streptomycin (100 ⁇ g/ml) in 5% C0 2 at 37 9 C Corning tissue culture multiwell plates (24 wells/plate) were seeded with 10 5 cells/16 mm well in 2 ml maintenance medium, refed 48 h after seeding and were ready to use in cytotoxicity assays 4 8h later, with the cells just reaching confiuency.
  • cytotoxicity assay protocol employing MCF 10A (low cathepsin B secreters) and BT-20 (high cathepsin B secreters) and inhibition of cytotoxicity with L- trans-epoxysuccmyl-leucylamido (4-guan ⁇ do) butane (cysteine protease inhibitor) or CA-074 (N-(L-3-trans-propylcarbamoylox ⁇ rane-2-carbonyl)-L- ⁇ soleucyl-L-prol ⁇ ne)(spec ⁇ f ⁇ c cathepsin B inhibitor) was standardized with the only variations occurring with compound, molar concentration, time of exposure, and presence or absence of inhibitors Maintenance medium was aspirated from the cell walls after feeding, and the cells washed twice with 2 ml/well Hanks balanced salt solution (HBSS).
  • HBSS Hanks balanced salt solution
  • Compound (1) was Ac-Phe-Lys-PABC-Dox
  • Compound (2) was Ac-Phe-Lys-PABC-MMC
  • Compound (3) was Ac-Phe- Lys-PABC-CPT
  • Compound (4) was Z-Phe-Lys-PABC-7-Paclitaxel
  • Compound (5) was CA-SP-Val-Cit-BHMS-Dox 2
  • Compound (6) was CA- SP-Lys-Phe-Lys-BHMS-Dox 2
  • Compound (7) was Z-Phe-Lys-Dox
  • Compound (8) was 2-Hydroxyethytthio-SP-D-Phe-Lys-PABC-Dox.
  • MMC is mitomycin C
  • CPT is camptothecin
  • Z is benzyloxycarbonyl
  • CA is 2-aminoethylthio
  • SP is succinimidopropionyl
  • PABC is p_-aminobenzyl carbonyl
  • CA-074 The killing of high cathepsin B-secreting cells was inhibited by CA-074.
  • CA-074 does not inhibit this killing because it does not enter lysosomes.
  • Compounds (7) and (8) are control compounds, weaker cytotoxic agents than Compounds (1) and (2) because they are less susceptible to cathepsin B- mediated hydrolysis to an active drug because of their particular structures.
  • Compound (7) lacks the PABC-self-immolating linker that facilitates enzymatic cleavage, resulting in probable steric hindrance that places the bulky doxorubicin moiety in the active site of the cathepsin B.
  • Compound (8) has the amino acids in the unnatural D instead of the natural L configuration.
  • Figure 10 depicts the percent cell kill at various times and prodrug concentrations with BT-20 cells.
  • the results with CA-074 present at 40 ⁇ M are given in parentheses. The results indicate that all test compounds show dose- and time-dependent killing of BT-20 (cathepsin B+) ceils.
  • the cathepsin B inhibitor CA-074 strongly inhibits cytotoxicity.
  • Compound (8), the compound containing the amino acids in the D- configuration, is very much less active.
  • tumor cells do indeed secrete enough cathepsin B to release enough cytotoxic drug to kill the cells efficiently. Tumor cells that secrete less cathepsin B are resistant to the hydrolyzable prodrugs.
  • Cathepsin B inhibitors strongly reduce cytotoxicity of the prodrugs, showing that cathepsin B is the principal means of unmasking them.
  • a prodrug lacking the self-immolating linkers PABC or BHMS has much reduced cytotoxicity, showing that it is an enzyme, presumably cathepsin B, that releases active drug. This is because the absence of the self-immolating linker results in steric hindrance.
  • a prodrug with amino acids in the unnatural D configuration has much reduced cytotoxicity, again showing the role of cathepsin B.
  • Figure 12 shows the stability of a number of hydrolyzable prodrugs according to the present invention linked to doxorubicin using a PABC-self-immolating linker.
  • These hydrolyzable prodrugs release anticancer drug under cathepsin B catalysis at 37°C, pH 7.4, at reasonable rates, and are stable for days or weeks in freshly drawn human plasma under the same conditions.
  • the present invention provides an efficient way to treat cancer cells secreting peptidohydrolases on their surface, particularly metastatic cells.
  • the hydrolyzable prodrugs of the present invention are usable against many types of metastases and do not depend for their activity on characteristics of the primary tumor cells that might not be shared by the metastases. Hydrolyzable prodrugs of the present invention are readily absorbed and lack toxicity.

Abstract

Les promédicaments hydrolysables selon l'invention sont activés par des protéases situées dans les membranes cellulaires de cellules métastatiques, de sorte que soient produits des médicaments anticancéreux actifs pouvant être absorbés par les cellules métastatiques. En général, un promédicament hydrolysable selon l'invention, comprend un peptide coiffé d'un N-terminal et qui constitue un substrat pour une peptidohydrolase située à la surface d'une cellule métastatique liée de manière covalente à un médicament thérapeutique par l'intermédiaire d'un espaceur à auto-immolation présentant une longueur suffisante pour empêcher l'apparition d'un empêchement stérique. Le médicament thérapeutique est généralement un médicament anti-cancéreux, généralement de la doxorubicine, du taxol, de la camptothécine, de la mitomycine C ou de l'espéramycine. Généralement, la peptidohydrolase qui hydrolyse le substrat du promédicament hydrolysable est de la cathepsine B.
PCT/US1997/017410 1996-09-27 1997-09-25 Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques WO1998013059A1 (fr)

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AU45995/97A AU739028B2 (en) 1996-09-27 1997-09-25 Hydrolyzable prodrugs for delivery of anticancer drugs to metastatic cells
CA002264227A CA2264227A1 (fr) 1996-09-27 1997-09-25 Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques
JP10515981A JP2001501211A (ja) 1996-09-27 1997-09-25 転移細胞への抗癌薬の輸送用加水分解性プロドラッグ
EP97944519A EP0961619A4 (fr) 1996-09-27 1997-09-25 Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques

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AU4599597A (en) 1998-04-17
AU739028B2 (en) 2001-10-04

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