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Last Updated: March 28, 2024

Claims for Patent: 9,687,466


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Summary for Patent: 9,687,466
Title:Use of dianhydrogalactitol and analogs and derivatives thereof to treat glioblastoma multiforme
Abstract: The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of glioblastoma multiforme. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N.sup.7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism.
Inventor(s): Bacha; Jeffrey A. (Vancouver, CA), Brown; Dennis (Menlo Park, CA), Dunn; Sandra (Vancouver, CA), Steino; Anne (Vancouver, CA)
Assignee: DELMAR PHARMACEUTICALS, INC. (Vancouver, CA)
Application Number:14/245,738
Patent Claims:1. A method to improve the efficacy and/or reduce the side effects of the administration of a substituted hexitol derivative selected from the group consisting of dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, a conjugate of dianhydrogalactitol, a conjugate of diacetyldianhydrogalactitol, a conjugate of dibromodulcitol, a prodrug of dianhydrogalactitol, a prodrug of diacetyldianhydrogalactitol, and a prodrug of dibromodulcitol for treatment of glioblastoma multiforme (GBM) comprising the steps of: (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the administration of the substituted hexitol derivative for treatment of GBM; and (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the administration of the substituted hexitol derivative for treatment of GBM.

2. The method of claim 1 wherein the substituted hexitol derivative is dianhydrogalactitol.

3. The method of claim 1 wherein the factor or parameter is selected from the group consisting of: (a) dose modification; (b) route of administration; (c) schedule of administration; (d) administration to promote preferential accumulation in brain tissue; (e) selection of disease stage; (f) patient selection; (g) patient/disease phenotype; (h) patient/disease genotype; (i) pre/post-treatment preparation (j) toxicity management; (k) pharmacokinetic/pharmacodynamic monitoring; (l) drug combinations; (m) chemosensitization; (n) chemopotentiation; (o) post-treatment patient management; (p) alternative medicine/therapeutic support; (q) bulk drug product improvements; (r) diluent systems; (s) solvent systems; (t) excipients; (u) dosage forms; (v) dosage kits and packaging; (w) drug delivery systems; (x) drug conjugate forms; (y) compound analogs; (z) prodrugs; (aa) multiple drug systems; (ab) biotherapeutic enhancement; (ac) biotherapeutic resistance modulation; (ad) radiation therapy enhancement; (ae) novel mechanisms of action; (af) selective target cell population therapeutics; (ag) use with ionizing radiation; (ah) use with an agent that counteracts myelosuppression; and (aj) use with an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier.

4. The method of claim 3 wherein the substituted hexitol derivative is dianhydrogalactitol.

5. The method of claim 3 wherein the improvement is made by dose modification and the dose modification is at least one dose modification selected from the group consisting of: (i) continuous i.v. infusion for hours to days; (ii) biweekly administration; (iii) doses greater than 5 mg/m.sup.2/day; (iv) progressive escalation of dosing from 1 mg/m.sup.2/day based on patient tolerance; (v) use of caffeine to modulate metabolism; (vi) use of isoniazid to modulate metabolism; (vii) selected and intermittent boosting of dosage administration; (viii) administration of single and multiple doses escalating from 5 mg/m.sup.2/day via bolus; (ix) oral dosages of below 30 mg/m.sup.2; (x) oral dosages of above 130 mg/m.sup.2; (xi) oral dosages up to 40 mg/m.sup.2 for 3 days and then a nadir/recovery period of 18-21 days; (xii) dosing at a lower level for an extended period; (xiii) dosing at a higher level; (xiv) dosing with a nadir/recovery period longer than 21 days; (xv) dosing at a level to achieve a concentration of the substituted hexitol derivative in the cerebrospinal fluid (CSF) of equal to or greater than 5 .mu.M; (xvi) dosing at a level to achieve a cytotoxic concentration in the CSF; (xvii) the use of the substituted hexitol derivative as a single cytotoxic agent; (xviii) administration on a 33-day cycle with a cumulative dose of about 9 mg/m.sup.2; (xix) administration on a 33-day cycle with a cumulative dose of about 10 mg/m.sup.2; (xx) administration on a 33-day cycle with a cumulative dose of about 20 mg/m.sup.2; (xxi) administration on a 33-day cycle with a cumulative dose of about 40 mg/m.sup.2; (xxii) administration on a 33-day cycle with a cumulative dose of about 80 mg/m.sup.2; (xxiii) administration on a 33-day cycle with a cumulative dose of about 160 mg/m.sup.2; (xxiv) administration on a 33-day cycle with a cumulative dose of about 240 mg/m.sup.2; (xxv) administration so that the plasma half-life is about 1-2 hours; (xxvi) administration so that the C.sub.max is <200 ng/ml; and (xxvii) administration so that the substituted hexitol derivative has a half-life of >20 hours in the cerebrospinal fluid.

6. The method of claim 3 wherein the improvement is made by route of administration and the route of administration is at least one route of administration selected from the group consisting of: (i) topical administration; (ii) oral administration; (iii) slow release oral delivery; (iv) intrathecal administration; (v) intraarterial administration; (vi) continuous infusion; (vii) intermittent infusion; (viii) intravenous administration; (ix) administration through a longer infusion; (x) administration through IV push; and (xi) administration to maximize the concentration of the substituted hexitol derivative in the CSF.

7. The method of claim 6 wherein the route of administration is intravenous administration and the intravenous administration is intravenous administration for 30 minutes.

8. The method of claim 3 wherein the improvement is made by schedule of administration and the schedule of administration is at least one schedule of administration selected from the group consisting of: (i) daily administration; (ii) weekly administration; (iii) weekly administration for three weeks; (iv) biweekly administration; (v) biweekly administration for three weeks with a 1-2 week rest period; (vi) intermittent boost dose administration; (vii) daily administration for one week for multiple weeks; and (viii) administration on days 1, 2, and 3 of a 33-day cycle.

9. The method of claim 3 wherein the improvement is made by selection of disease stage and wherein the selection of disease stage is at least one selection of disease stage selected from the group consisting of: (i) use in an appropriate disease stage for GBM; (ii) use with an angiogenesis inhibitor to prevent or limit metastatic spread; (iii) use for newly diagnosed GBM; (iv) use for recurrent GBM (v) use for resistant or refractory GBM; and (vi) use for childhood GBM.

10. The method of claim 3 wherein the improvement is made by patient selection and wherein the patient selection is at least one patient selection carried out by a criterion selected from the group consisting of: (i) selecting patients with a disease condition characterized by a high level of a metabolic enzyme selected from the group consisting of histone deacetylase and ornithine decarboxylase; (ii) selecting patients with a low or high susceptibility to a condition selected from the group consisting of thrombocytopenia and neutropenia; (iii) selecting patients intolerant of GI toxicities; (iv) selecting patients characterized by over- or under-expression of a gene selected from the group consisting of c-Jun, a GPCR, a signal transduction protein, VEGF, a prostate-specific gene, and a protein kinase; (v) selecting patients characterized by carrying extra copies of the EGFR gene for GBM; (vi) selecting patients characterized by mutations in at least one gene selected from the group consisting of TP53, PDGFRA, IDH1, and NF1 for GBM; (vii) selecting patients characterized by methylation or lack of methylation of the promoter of the MGMT gene; (viii) selecting patients characterized by the existence of an IDH1 mutation; (ix) selecting patients characterized by the presence of IDH1 wild-type gene; (x) selecting patients characterized by the presence of 1p/19q co-deletion; (xi) selecting patients characterized by the absence of an 1p/19q co-deletion; (xii) selecting patients characterized by an unmethylated promoter region of MGMT (O.sup.6-methylguanine methyltransferase); (xiii) selecting patients characterized by a methylated promoter region of MGMT; (xiv) selecting patients characterized by a high expression of MGMT; (xv) selecting patients characterized by a low expression of MGMT; and (xvi) selecting patients characterized by a mutation in EGFR.

11. The method of claim 10 wherein the patient selection is selecting patients characterized by a mutation in EGFR and the mutation in EGFR is EGFR Variant III.

12. The method of claim 3 wherein the improvement is made by analysis of patient or disease phenotype and wherein the analysis of patient or disease phenotype is a method of analysis of patient or disease phenotype carried out by a method selected from the group consisting of: (i) use of a diagnostic tool, a diagnostic technique, a diagnostic kit, or a diagnostic assay to confirm a patient's particular phenotype; (ii) use of a method for measurement of a marker selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, a protein that is a gene product of jun, and a protein kinase; (iii) surrogate compound dosing; and (iv) low dose pre-testing for enzymatic status.

13. The method of claim 3 wherein the improvement is made by analysis of patient or disease genotype and the analysis of patient or disease genotype is a method of analysis of patient or disease genotype carried out by a method selected from the group consisting of: (i) use of a diagnostic tool, a diagnostic technique, a diagnostic kit, or a diagnostic assay to confirm a patient's particular genotype; (ii) use of a gene chip; (iii) use of gene expression analysis; (iv) use of single nucleotide polymorphism (SNP) analysis; (v) measurement of the level of a metabolite or a metabolic enzyme; (vi) determination of mutation of PDGFRA gene; (vii) determination of mutation of IDH1 gene; (viii) determination of mutation of NF1 gene; (ix) determination of copy number of the EGFR gene; (x) determination of status of methylation of promoter of MGMT gene; (xi) determination of the existence of an IDH1 mutation; (xii) determination of the existence of IDH1 wild-type; (xiii) determination of the existence of a 1p/19q co-deletion; (xiv) determination of the absence of a 1p/19q co-deletion; (xv) determination of the existence of an unmethylated promoter region of the MGMT gene; (xvi) determination of the existence of a methylated promoter region of the MGMT gene; (xvii) determination of the existence of high expression of MGMT; and (xviii) determination of the existence of low expression of MGMT.

14. The method of claim 13 wherein the method determines a parameter selected from: (i) the copy number of the EGFR gene and (ii) the methylation status of the promoter of the MGMT gene.

15. The method of claim 3 wherein the improvement is made by pre/post treatment preparation and the pre/post-treatment preparation is a method of pre/post treatment preparation selected from the group consisting of: (i) the use of colchicine or an analog thereof; (ii) the use of a diuretic; (iii) the use of a uricosuric; (iv) the use of uricase; (v) the non-oral use of nicotinamide; (vi) the use of a sustained-release form of nicotinamide; (vii) the use of an inhibitor of poly-ADP ribose polymerase; (viii) the use of caffeine; (ix) the use of leucovorin rescue; (x) infection control; and (xi) the use of an anti-hypertensive agent.

16. The method of claim 3 wherein the improvement is made by toxicity management and the toxicity management is a method of toxicity management selected from the group consisting of: (i) the use of colchicine or an analog thereof; (ii) the use of a diuretic; (iii) the use of a uricosuric; (iv) the use of uricase; (v) the non-oral use of nicotinamide; (vi) the use of a sustained-release form of nicotinamide; (vii) the use of an inhibitor of poly-ADP ribose polymerase; (viii) the use of caffeine; (ix) the use of leucovorin rescue; (x) the use of sustained-release allopurinol; (xi) the non-oral use of allopurinol; (xii) the use of bone marrow transplants; (xiii) the use of a blood cell stimulant; (xiv) the use of blood or platelet infusions; (xv) the administration of an agent selected from the group consisting of filgrastim, G-CSF, and GM-CSF; (xvi) the application of a pain management technique; (xvii) the administration of an anti-inflammatory agent; (xviii) the administration of fluids; (xix) the administration of a corticosteroid; (xx) the administration of an insulin control medication; (xxi) the administration of an antipyretic; (xxii) the administration of an anti-nausea treatment; (xxiii) the administration of an anti-diarrheal treatment; (xxiv) the administration of N-acetylcysteine; and (xxv) the administration of an antihistamine.

17. The method of claim 3 wherein the improvement is made by pharmacokinetic/pharmacodynamic monitoring and the pharmacokinetic/pharmacodynamic monitoring is a method selected from the group consisting of: (i) multiple determinations of blood plasma levels; and (ii) multiple determinations of at least one metabolite in blood or urine.

18. The method of claim 3 wherein the improvement is made by drug combination and the drug combination is a drug combination selected from the group consisting of: (i) use with topoisomerase inhibitors; (ii) use with fraudulent nucleosides; (iii) use with fraudulent nucleotides; (iv) use with thymidylate synthetase inhibitors; (v) use with signal transduction inhibitors; (vi) use with cisplatin or platinum analogs; (vii) use with monofunctional alkylating agents; (viii) use with bifunctional alkylating agents; (ix) use with alkylating agents that damage DNA at a different place than does dianhydrogalactitol; (x) use with anti-tubulin agents; (xi) use with antimetabolites; (xii) use with berberine; (xiii) use with apigenin; (xiv) use with amonafide; (xv) use with colchicine or analogs; (xvi) use with genistein; (xvii) use with etoposide; (xviii) use with cytarabine; (xix) use with camptothecins; (xx) use with vinca alkaloids; (xxi) use with 5-fluorouracil; (xxii) use with curcumin; (xxiii) use with NF-.kappa.B inhibitors; (xxiv) use with rosmarinic acid; (xxv) use with mitoguazone; (xxvi) use with tetrandrine; (xxvii) use with temozolomide; (xxviii) use with VEGF inhibitors; (xxix) use with cancer vaccines; (xxx) use with EGFR inhibitors; (xxxi) use with tyrosine kinase inhibitors; and (xxxii) use with poly (ADP-ribose) polymerase (PARP) inhibitors.

19. The method of claim 18 wherein the drug combination is use with a class of agent selected from the group consisting of: (i) EGFR inhibitors; (ii) tyrosine kinase inhibitors; (iii) PARP inhibitors; and (iv) an alkylating agent, wherein the alkylating agent is an alkylating agent selected from the group consisting of BCNU, BCNU wafers (Gliadel), ACNU, CCNU, bendamustine (Treanda), lomustine, and temozolomide (Temodar).

20. The method of claim 18 wherein the drug combination is use with an alkylating agent selected from the group consisting of: (a) a monofunctional alkylating agent; (b) a bifunctional alkylating agent; and (c) an alkylating agent that damages DNA at a different place than dianhydrogalactitol.

21. The method of claim 3 wherein the improvement is made by chemosensitization and the chemosensitization comprises the use of a substituted hexitol derivative as a chemosensitizer in combination with an agent selected from the group consisting of: (i) topoisomerase inhibitors; (ii) fraudulent nucleosides; (iii) fraudulent nucleotides; (iv) thymidylate synthetase inhibitors; (v) signal transduction inhibitors; (vi) cisplatin or platinum analogs; (vii) alkylating agents; (viii) anti-tubulin agents; (ix) antimetabolites; (x) berberine; (xi) apigenin; (xii) amonafide; (xiii) colchicine or analogs; (xiv) genistein; (xv) etoposide; (xvi) cytarabine; (xvii) camptothecins; (xviii) vinca alkaloids; (xix) topoisomerase inhibitors; (xx) 5-fluorouracil; (xxi) curcumin; (xxii) NF-.kappa.B inhibitors; (xxiii) rosmarinic acid; (xxiv) mitoguazone; (xxv) tetrandrine; (xxvi) a tyrosine kinase inhibitor; (xxvii) an inhibitor of EGFR; and (xxviii) an inhibitor of PARP.

22. The method of claim 3 wherein the improvement is made by chemopotentiation and the chemopotentiation comprises the use of a substituted hexitol derivative as a chemopotentiator in combination with an agent selected from the group consisting of: (i) topoisomerase inhibitors; (ii) fraudulent nucleosides; (iii) fraudulent nucleotides; (iv) thymidylate synthetase inhibitors; (v) signal transduction inhibitors; (vi) cisplatin or platinum analogs; (vii) alkylating agents; (viii) anti-tubulin agents; (ix) antimetabolites; (x) berberine; (xi) apigenin; (xii) amonafide; (xiii) colchicine or analogs; (xiv) genistein; (xv) etoposide; (xvi) cytarabine; (xvii) camptothecins; (xviii) vinca alkaloids; (xix) 5-fluorouracil; (xx) curcumin; (xxi) NF-.kappa.B inhibitors; (xxii) rosmarinic acid; (xxiii) mitoguazone; (xxiv) tetrandrine; (xxv) a tyrosine kinase inhibitor; (xxvi) an inhibitor of EGFR; and (xxvii) an inhibitor of PARP.

23. The method of claim 3 wherein the improvement is made by post-treatment management and the post-treatment management is a method selected from the group consisting of: (i) a therapy associated with pain management; (ii) administration of an anti-emetic; (iii) an anti-nausea therapy; (iv) administration of an anti-inflammatory agent; (v) administration of an anti-pyretic agent; and (vi) administration of an immune stimulant.

24. The method of claim 3 wherein the improvement is made by a bulk drug product improvement and the bulk drug product improvement is a bulk drug product improvement selected from the group consisting of: (i) salt formation; (ii) preparation as a homogeneous crystal structure; (iii) preparation as a pure isomer; (iv) increased purity; (v) preparation with lower residual solvent content; and (vi) preparation with lower residual heavy metal content.

25. The method of claim 3 wherein the improvement is made by use of a diluent and the diluent is selected from the group consisting of: (i) an emulsion; (ii) dimethyl sulfoxide (DMSO); (iii) N-methylformamide (NMF) (iv) DMF; (v) ethanol; (vi) benzyl alcohol; (vii) dextrose-containing water for injection; (viii) Cremophor; (ix) cyclodextrin; and (x) PEG.

26. The method of claim 3 wherein the improvement is made by use of a solvent system and the solvent system is selected from the group consisting of: (i) an emulsion; (ii) dimethylsulfoxide (DMSO); (iii) N-methylformamide (NMF) (iv) DMF; (v) ethanol; (vi) benzyl alcohol; (vii) dextrose-containing water for injection; (viii) Cremophor; (ix) cyclodextrin; and (x) PEG.

27. The method of claim 3 wherein the improvement is made by use of an excipient and the excipient is an excipient selected from the group consisting of: (i) mannitol; (ii) albumin; (iii) EDTA; (iv) sodium bisulfate; (v) benzyl alcohol; (vi) a carbonate buffer; and (g) a phosphate buffer.

28. The method of claim 3 wherein the improvement is made by a dosage form and the dosage form is a dosage form selected from the group consisting of: (i) tablets; (ii) capsules; (iii) topical gels; (iv) topical creams; (v) patches; (vi) suppositories; and (vii) lyophilized dosage fills.

29. The method of claim 3 wherein the improvement is made by use of a drug delivery system and the drug delivery system is a drug delivery system selected from the group consisting of: (i) nanocrystals; (ii) bioerodible polymers; (iii) liposomes; (iv) slow release injectable gels; and (v) microspheres.

30. The method of claim 3 wherein the improvement is made by use of a drug conjugate form and the drug conjugate form is a drug conjugate form selected from the group consisting of: (i) a polymer system; (ii) polylactides; (iii) polyglycolides; (iv) amino acids; (v) peptides; and (vi) multivalent linkers.

31. The method of claim 3 wherein the improvement is made by use of a prodrug system and the prodrug system is selected from the group consisting of: (i) the use of enzyme sensitive esters; (ii) the use of dimers; (iii) the use of Schiff bases; (iv) the use of pyridoxal complexes; and (v) the use of caffeine complexes.

32. The method of claim 3 wherein the improvement is made by use of a multiple drug system and the multiple drug system is selected from the group consisting of: (i) use of multi-drug resistance inhibitors; (ii) use of specific drug resistance inhibitors; (iii) use of specific inhibitors of selective enzymes; (iv) use of signal transduction inhibitors; (v) use of repair inhibition; and (vi) use of topoisomerase inhibitors with non-overlapping side effects.

33. The method of claim 3 wherein the improvement is made by biotherapeutic enhancement and the biotherapeutic enhancement is performed by use in combination as sensitizers/potentiators with a therapeutic agent or technique that is selected from the group consisting of: (i) cytokines; (ii) lymphokines; (iii) therapeutic antibodies; (iv) antisense therapies; (v) gene therapies; (vi) ribozymes; (vii) RNA interference; and (viii) vaccines.

34. The method of claim 3 wherein the improvement is made by use of biotherapeutic resistance modulation and the biotherapeutic resistance modulation is use against glioblastoma multiforme tumors resistant to a therapeutic agent or technique selected from the group consisting of: (i) biological response modifiers; (ii) cytokines; (iii) lymphokines; (iv) therapeutic antibodies; (v) antisense therapies; (vi) gene therapies; (vii) ribozymes; (viii) RNA interference; and (ix) vaccines.

35. The method of claim 3 wherein the improvement is made by radiation therapy enhancement and the radiation therapy enhancement is a radiation therapy enhancement agent or technique selected from the group consisting of: (i) hypoxic cell sensitizers; (ii) radiation sensitizers/protectors; (iii) photosensitizers; (iv) radiation repair inhibitors; (v) thiol depleters; (vi) vaso-targeted agents; (vii) DNA repair inhibitors; (viii) radioactive seeds; (ix) radionuclides; (x) radiolabeled antibodies; and (xi) brachytherapy.

36. The method of claim 3 wherein the improvement is by use of a novel mechanism of action and the novel mechanism of action is a therapeutic interaction with a target or mechanism selected from the group consisting of: (i) inhibitors of poly-ADP ribose polymerase; (ii) agents that affect vasculature or vasodilation; (iii) oncogenic targeted agents; (iv) signal transduction inhibitors; (v) EGFR inhibition; (vi) protein kinase C inhibition; (vii) phospholipase C downregulation; (viii) Jun downregulation; (ix) histone genes; (x) VEGF; (xi) ornithine decarboxylase; (xii) ubiquitin C; (xiii) Jun D; (xiv) v-Jun; (xv) GPCRs; (xvi) protein kinase A; (xvii) protein kinases other than protein kinase A; (xviii) prostate specific genes; (xix) telomerase; (xx) histone deacetylase; and (xxi) tyrosine kinase inhibitors.

37. The method of claim 3 wherein the improvement is made by use of selective target cell population therapeutics and the use of selective target cell population therapeutics is a use selected from the group consisting of: (i) use against radiation sensitive cells; (ii) use against radiation resistant cells; and (iii) use against energy depleted cells.

38. The method of claim 3 wherein the improvement is made by use of a substituted hexitol derivative together with ionizing radiation.

39. The method of claim 3 wherein the improvement is made by use of an agent that counteracts myelosuppression.

40. The method of claim 39 wherein the agent that counteracts myelosuppression is a dithiocarbamate.

41. The method of claim 3 wherein the improvement is made by use with an agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier.

42. The method of claim 41 wherein the agent that increases the ability of the substituted hexitol to pass through the blood-brain barrier is selected from the group consisting of: (i) a chimeric peptide of the structure of Formula (D-III): ##STR00008## wherein: (A) A is somatostatin, thyrotropin releasing hormone (TRH), vasopressin, alpha interferon, endorphin, muramyl dipeptide or ACTH 4-9 analogue; and (B) B is insulin, IGF-I, IGF-II, transferrin, cationized (basic) albumin or prolactin; or a chimeric peptide of the structure of Formula (D-III) wherein the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-III(a)): A-NH(CH.sub.2).sub.2S--S--B (cleavable linkage) (D-III(a)), wherein the bridge is formed using cysteamine and EDAC as the bridge reagents; or a chimeric peptide of the structure of Formula (D-III) wherein the disulfide conjugating bridge between A and B is replaced with a bridge of Subformula (D-III(b)): A-NH.dbd.CH(CH.sub.2).sub.3CH.dbd.NH--B (non-cleavable linkage) (D-III(b)), wherein the bridge is formed using glutaraldehyde as the bridge reagent; (ii) a composition comprising either avidin or an avidin fusion protein bonded to a biotinylated substituted hexitol derivative to form an avidin-biotin-agent complex including therein a protein selected from the group consisting of insulin, transferrin, an anti-receptor monoclonal antibody, a cationized protein, and a lectin; (iii) a neutral liposome that is pegylated and incorporates the substituted hexitol derivative, wherein the polyethylene glycol strands are conjugated to at least one transportable peptide or targeting agent; (iv) a humanized murine antibody that binds to the human insulin receptor linked to the substituted hexitol derivative through an avidin-biotin linkage; and (v) a fusion protein comprising a first segment and a second segment: the first segment comprising a variable region of an antibody that recognizes an antigen on the surface of a cell that after binding to the variable region of the antibody undergoes antibody-receptor-mediated endocytosis, and, optionally, further comprises at least one domain of a constant region of an antibody; and the second segment comprising a protein domain selected from the group consisting of avidin, an avidin mutein, a chemically modified avidin derivative, streptavidin, a streptavidin mutein, and a chemically modified streptavidin derivative, wherein the fusion protein is linked to the substituted hexitol by a covalent link to biotin.

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