Chemotactic, drug-containing polymersomes
The present invention relates to polymersomes that contain an encapsulated drug and that exhibit chemotaxis in response to a chemical stimulus. The chemotactic polymersomes can be targeted in vivo to a location of therapeutic interest with high specificity and selectivity. The present invention also provides related pharmaceutical compositions and therapeutic methods.
1. A method comprising
administering a chemotactic, drug-containing polymersome to a subject; and
delivering said chemotactic, drug-containing polymersome to the brain tissue of said subject by transcytosis of said chemotactic, drug-containing polymersome across the blood-brain barrier of said subject; wherein said chemotactic, drug-containing polymersome comprises:
(a) a polymersome that comprises a targeting moiety on its external surface, wherein the targeting moiety is adapted to enable the polymersome to cross the blood-brain barrier;
(b) an enzyme encapsulated within the polymersome, wherein the enzyme comprises glucose oxidase; and
(c) a drug encapsulated within the polymersome;
wherein:
(i) the polymersome is permeable to a signalling molecule that is a substrate for the enzyme, wherein the signalling molecule is glucose;
(ii) the enzyme is capable of converting the signalling molecule into one or more product molecules;
(iii) the polymersome is permeable to the one or more product molecules;
(iv) the permeability to the one or more product molecules of a first region of the polymersome is greater than the permeability to the one or more product molecules of a second region of the polymersome, the second region being diametrically opposed to the first region; and
(v) the first region of the polymersome comprises a first polymer and the second region of the polymersome comprises a second polymer, the second polymer being different from the first polymer.
2. The method of claim 1 , wherein the molar ratio of the first polymer to the second polymer is less than 1:1.
3. The method of claim 2 , wherein the molar ratio of the first polymer to the second polymer is less than 1:4.
4. The method of claim 1 , wherein the targeting moiety is an antibody or antibody fragment, a peptide, an aptamer, a small molecule, a vitamin or a carbohydrate that is attached to the external surface of the polymersome.
5. The method of claim 1 , wherein the targeting moiety is a pendant group of a polymer comprised by the polymersome.
6. The method of claim 1 , wherein the targeting moiety targets the LRP-1 receptor.
7. The method of claim 6 , wherein the targeting moiety is a peptide comprising the sequence TFFYGGSRGKRNNFKTEEY (SEQ ID No. 1).
8. The method of claim 1 , wherein the enzyme comprises glucose oxidase in combination with catalase.
9. The method of claim 1 , wherein the drug is selected from a neuroprotectants, immunomodulatory drugs, NSAIDs, corticosteroids, DMARDs, immunosuppressants, TNF-alpha inhibitors and anti-cancer drugs.