Lactate response system and methods
Compositions and methods are provided concerning a lactate-responsive drug release system. In some embodiments, there are methods and compositions for treating cancer that take advantage of the tumor environment to deliver therapeutic agents to the tumor while reducing problems associated with circulating drugs in the patients body.
1 . A lactate-triggered, benefit agent release composition comprising:
(a) a chemical-responsive matrix comprising a mesoporous silica nanoparticle (MSN) functionalized with an H 2 O 2 -sensitive arylboronate derivative linker that binds a cyclodextrin cap to the MSN surface;
(b) a lactate reacting enzyme immobilized on the surface of the MSN or on the surface of the cyclodextrin cap; and
(c) a benefit agent provided within the MSN and retained therein by the cyclodextrin cap;
wherein the lactate reacting enzyme is capable of converting lactate into H 2 O 2 and the H 2 O 2 cleaves the H 2 O 2 -sensitive arylboronate derivative linker releasing the cyclodextrin cap from the MSN surface and enabling the benefit agent to escape from the MSN.
2 . The lactate-triggered, benefit agent release composition of claim 1 , wherein the lactate reacting enzyme is selected from the group consisting of lactate oxidase and lactate 2-monooxygenase.
3 . The lactate-triggered, benefit agent release composition of claim 1 , wherein the benefit agent is a therapeutic agent or a diagnostic agent.
4 . The lactate-triggered, benefit agent release composition of claim 3 , wherein the therapeutic agent is a small molecule, a peptide or polypeptide, a nucleic acid, nanoparticle, microparticle, ion, salt, bacteria, virus, live cells, or a radiopharmaceutical.
5 . The lactate-triggered, benefit agent release composition of claim 3 , wherein the therapeutic agent is a chemotherapeutic, an immunotherapeutic, a gene therapy agent, toxin, or a radiotherapeutic.
6 . The lactate-triggered, benefit agent release composition of claim 1 , further comprising a B component or a modified B component from an AB Toxin Complex, wherein the modified B component is at least 50, 60, 70, 80, 90%, or more homologous to a B component and comprises a region that interacts with an A component from the AB Toxin Complex.
7 . The lactate-triggered, benefit agent release composition of claim 6 , wherein the B component is Cholera toxin, Diptheria toxin, Pertussis toxin, E. coli heat-labile toxin LT, Shiga toxin, Pseudomonas exotoxin A, Botulinum, toxin, Tetanus toxin, Anthrax toxin LF, Bortella pertussis AC, Bacillus anthracis EF, or Staphylococcus aureus Exfoliatin B.
8 . A method for delivering a benefit agent to a lactate target area of a subject to be treated, the method comprising:
providing a benefit agent release composition comprising a chemical-responsive matrix comprising a mesoporous silica nanoparticle (MSN) functionalized with an H 2 O 2 -sensitive arylboronate derivative linker that binds a cyclodextrin cap to the MSN surface, a lactate reacting enzyme immobilized on the surface of the MSN or on the surface of the cyclodextrin cap, and a benefit agent provided within the MSN and retained therein by the cyclodextrin;
wherein the lactate reacting enzyme converts lactate into H 2 O 2 and the H 2 O 2 cleaves the H 2 O 2 -sensitive arylboronate derivative linker releasing the cyclodextrin cap from the MSN surface and enabling the benefit agent to escape from the MSN when the benefit agent release composition is exposed to a lactate target area, wherein the lactate target area has a lactate concentration that is higher than ambient physiological lactate concentration.
9 . The method of claim 8 , wherein the release of the benefit agent targets a benefit agent release to an area comprising higher than ambient physiological lactate concentration.
10 . The lactate-triggered, benefit agent release composition of claim 5 , wherein the benefit agent is doxorubicin.