EP-4735044-A1 - POLYOXOMETALATES AS MEMBRANE CARRIERS

Abstract

The present invention relates to a delivery molecule comprising a carrier molecule and a cargo molecule, wherein said carrier molecule is a polyoxometalate which exhibits a charge status of –2 to –6 and wherein said cargo molecule is a hydrophilic moiety and to the use of said delivery molecule in therapy.

Inventors

• ROMPEL, Annette
• NAU, Werner M.
• BARBA-BON, Andrea
• GUMEROVA, Nadiia

Assignees

• Universität Wien

Dates

Publication Date

20260506

Application Date

20240627

Claims (1)

1. UW014P 26 Claims 1. A delivery molecule comprising a carrier molecule and a cargo molecule, wherein said carrier molecule is a polyoxometalate moiety of the general formula [X 1 M 1 M 2 11 O 40 ] (n1)– , wherein X 1 denotes P, Si, Ge, or Al; M 1 denotes Mo, V, Ti, or Nb; M 2 denotes W, or Mo: n 1 denotes 2–6; or of general formula [X 2 M 3 M 4 11 O 39 (L)] (n2)– , wherein X 2 denotes P, Si, or Ge; M 3 denotes Mo, V, Fe, Ga, In, Ni, Co, Cr, or Al;, M 4 denotes W, or Mo; L is a terminal ligand and denotes O 2– or H 2 O coordinated to M 3 , n 2 denotes 3–5; or of general formula [X 3 (OH) 6 M 5 6 O 18 ] 3– , wherein X 3 denotes Al, Ga, Cr, or Fe; and M 5 denotes Mo, or W; and wherein the cargo molecule is a hydrophilic moiety, an inorganic molecule, or an organic molecule. 2. The delivery molecule of claim 1, wherein the carrier molecule and the cargo molecule are directly linked to each other without a linker moiety. 3. The delivery molecule of claim 1 or 2, wherein said polyoxometalate moiety is of general formula [X 1 M 1 M 2 11 O 40 ] (n1)– , wherein X 1 denotes P, Si, Ge, or Al; M 1 denotes Mo, V, Ti, or Nb; M 2 denotes W; and n 1 denotes 2–6. 4. The delivery molecule of claim 3, wherein X 1 denotes P, or Si; M 1 denotes Mo, or V; M 2 denotes W; and n 1 denotes 4. 5. The delivery molecule of claim 4, wherein said polyoxometalate is of formula [PVW 11 O 40 ] 4– , or [SiMoW 11 O 40 ] 4– . UW014P 27 6. The delivery molecule of any one of claims 1 to 5, wherein said polyoxometalate is stable at a pH up to 7.5. 7. The delivery molecule of any one of claims 1 to 6, wherein said polyoxometalate moiety is bound to said cargo molecule through supramolecular interactions. 8. The delivery molecule of any one of claims 1 to 7, wherein said cargo molecule is a hydrophilic molecule. 9. The delivery molecule of claim 8, wherein said hydrophilic molecule is a hydrophilic peptide or hydrophilic protein. 10. The delivery molecule of any one of claims 1 to 9, wherein said cargo molecule is a pharmaceutically active compound. 11. The delivery molecule of claim 10, wherein said pharmaceutically active compound is a pharmaceutically active hydrophilic peptide or protein, a hydrophilic organic compound, or a hydrophilic inorganic compound. 12. The delivery molecule of any one of claims 1 to 11, wherein said carrier molecule is present in a range of about 0.01 to 100 µM, or of about 0.1 to 10 µM, or of about 0.5 to 5 µM. 13. The delivery molecule of any one of claims 1 to 12 for use in treating a disease curable by said pharmaceutically active compound. 14. The delivery molecule of any one of claims 1 to 12 for use according to claim 13, wherein the pharmaceutically active compound is delivered to or removed from a site within a subject. 15. The delivery molecule of any one of claims 1 to 12 for use according to claim 13 or 14, wherein said delivery molecule passes a barrier within a subject based on a superchaotropic effect. 16. The delivery molecule of any one of claims 1 to 12 for use according to any one of claims 13 to 15, wherein said barrier is a cell membrane. 17. An in vitro method for delivering a cargo molecule to a cell comprising the steps of (a) providing a cell, and (b) contacting said cell with a delivery molecule according to any one of claims 1 to 11. 18. A delivery molecule according to any one of claims 1 to 12 as a medicament. 19. A delivery molecule according to any one of claims 1 to 12 for use in the treatment of a disease curable by a pharmaceutically active compound. UW014P 28 20. A pharmaceutical composition comprising the delivery molecule according to any one of claims 1 to 12.

Description

UW014P 1 POLYOXOMETALATES AS MEMBRANE CARRIERS Description Field of the Invention [0001] The present invention relates to the field of delivering a molecule into a cell via a carrier moiety. Background Art [0002] Efficient foreign protein delivery into living cells can completely bypass transcription translation processes related to gene expression, reducing the time required for target protein synthesis from days to hours. [0003] The design of carriers to assist the passage of bioactive therapeutic compounds through the cellular membrane presents a challenge in life sciences. Different approaches have been attempted to date, mainly focusing on the use of synthetic pores, nanoparticles and lipide formulations, cell-penetrating peptides and counterions activators. However, these systems have been deprived of their pharmaceutical application due to limitations such as endocytic entrapment, aggregation propensity, membrane-lytic activity, and related toxicity. [0004] In WO2011/045296A a composition for delivering a peptide or a protein into a cell is disclosed. The composition comprises a polycationic agent and a polyanionic agent, wherein the polyanionic agent is an inorganic polyphosphate or a polyoxometalate. Zhang Z. et al. describe interactions between nanoparticles and cells by the development of polyoxometalates nanoparticle-peptide conjugates and investigation of their intracellular trafficking behaviors [1]. A method for transducing a protein or peptide into a cell, comprising a step of transporting the protein or peptide into the cell by using a conjugate formed by binding the protein or peptide with a polymer having a cation value of more than 2 and no more than 30,000 is disclosed in EP1316318A. [0005] The systematic understanding of the peculiar effects that different ions exert on the biological matter can be traced back to Hofmeister, who studied their interactions with proteins. This has led to the formulation of the classical Hofmeister scale, where ions were subsequently classified as being kosmotropic if they showed salting-out properties towards proteins and as chaotropic if they displayed salting-in effects. Subsequently, these hydration effects have been generalized, the notion that the effects are a consequence of property changes of the bulk liquid has been abandoned, and, instead, direct interactions between chaotropic ions and dissolved UW014P 2 organic matter (“chaotropic effect”) have moved into the focus. Although inorganic cluster anions of the boron and polyoxometalate (POMs) type have been intensively researched for many decades, their chaotropicity has moved into the focus of attention when it was found that these large cluster ions behave as “superchaotropic” ions, that is, they exceed the chaotropic behavior of the hitherto described anions by far. Since the utilization of dodecaborates (B12X122‒) as membrane carriers has been introduced [2] and their activity could be correlated with their superchaotropic nature, the exploration of this new application line to POMs is timely. [0006] Bijelic A. et al. disclose that the combination of polyoxometalates (POMs) with drugs might be a promising strategy in cancer treatment. Disclosed are various POM-drug hybrids, e.g., the combination of different POMs with the anticancer drug 5-FU, with bisphosphonates, with quinoline antibiotics, or with amino acids [3]. [0007] Geisberger et al. disclose nanocomposites comprising a carrier molecule (trimethyl chitosan (TCM) and carboxymethyl chitosan (CMC)) and a cargo molecule (POM) [4]. Geisberger et al. showed that TCM are suitable drug carriers encapsulating bio-active POMs. [0008] Therefore, there is still the need for a carrier molecule which may act as a new class of chaotropic membrane carrier to facilitate the transport of hydrophilic molecules across the cellular membrane. Summary of invention [0009] It is the object of the present invention to provide a delivery molecule which facilitates the transport of molecules of interest across the cellular membrane. The object is solved by the subject matter of the present invention. The present invention relates to a delivery molecule which enables a cargo molecule to be translocated into cells, and a method for transducing the cargo molecule into the cells using said delivery molecule. [0010] According to the invention, there is provided a delivery molecule comprising a carrier molecule and a cargo molecule, wherein said carrier molecule is a polyoxometalate moiety of the general formula [X1M1M211O40](n1)–, wherein X1 denotes P, Si, Ge, or Al; M1 denotes Mo, V, Ti, or Nb; M2 denotes W, or Mo: n1 denotes 2–6; or of general formula [X2M3M411O39(L)](n2)–, wherein UW014P 3 X2 denotes P, Si, or Ge; M3 denotes Mo, V, Fe, Ga, In, Ni, Co, Cr, or Al;, M4 denotes W, or Mo; L is a terminal ligand and denotes O2– or H2O coordinated to M3, n2 denotes 3–5; or of general formula [X3(OH)6M56O18]3–, wherein X3 denotes Al, Ga, Cr, or Fe; and M5 denotes Mo,