| 主权项 |
1. A method of making a combinatorial formulation library comprising a plurality of therapeutic agent-loaded polymeric nanoparticulate delivery systems, the method comprising:
a) determining the partition coefficient of a therapeutic agent, wherein the therapeutic agent is selected from an siRNA and an anticancer drug;
wherein the anticancer drug is selected from the group consisting of tamoxifen, paclitaxel, doxorubicin, camptothecin, topotecan, irinotecan, KRN 5500 (KRN), dexamethasone, methylprednisone, prednisone, prednisolone, ellipticin; b) solubilizing the therapeutic agent in an aqueous solution; c) combinatorially combining the solubilized therapeutic agent with each of a first plurality of derivatized water-soluble polymers encapsulating the therapeutic agent to form a plurality of nanoparticle cores by self-assembly; d) combinatorially combining each of the plurality of nanoparticle cores with each of a second plurality of derivatized water-soluble polymers to form a plurality of hydrogel-encapsulated nanoparticles by self-assembly;
wherein if the therapeutic agent is an siRNA, each of the first plurality of derivatized water-soluble polymers is selected from thiolated dextran derivatives and each of the second plurality of derivatized water-soluble polymers is selected from lipid-modified dextran derivatives;wherein if the therapeutic agent is an anticancer drug, each of the first plurality of derivatized water-soluble polymers is selected from lipid-modified dextran derivatives and each of the second plurality of derivatized water-soluble polymers is selected from thiolated dextran derivatives; and
wherein if the partition coefficient is less than 100, then the lipid-modified dextrans are derived from a fatty acid selected from the group consisting of a C2-C14;wherein if the partition coefficient is greater than 100, then the lipid-modified dextrans are derived from a fatty acid selected from the group consisting of a C14-C28; e) combinatorially combining each of the plurality of hydrogel-encapsulated nanoparticles with a plurality of activated PEG derivatives to form a plurality of therapeutic agent-loaded polymeric nanoparticulate delivery systems; wherein each of the therapeutic agent-loaded polymeric nanoparticulate delivery systems differs from one another by at least one of:
(i) the weight ratio of therapeutic agent to first derivatized water-solubilized polymer to second derivatized water-soluble polymer to activated PEG derivative;(ii) the identity of at least one of:
(1) the first derivatized water-solubilized polymer;(2) the second derivatized water-soluble polymer; and(3) the activated PEG derivative;thereby making a combinatorial formulation library comprising a plurality of therapeutic agent-loaded polymeric nanoparticulate delivery systems. |
