BACKGROUND TO THE INVENTION

Ovarian cancer is the most lethal form of cancer among women, accounting for 3% of all cancer cases at 20,000 per year. Metastatic ovarian cancer is an advanced stage malignancy often spreading to the liver, the lungs, the spleen, the intestines, the brain, or the lymph nodes around the body. Metastasis involves multiple steps, including cell invasion from the primary tumor, intravasation and extravasation in the circulation system, and growth in the distant location. In such cases, early detection is preferable but is often hampered by a lack of appropriate tumor markers and clinically relevant symptoms typically associated with cancer at the primary site. Early-stage detection garners a 5-year survival rate of 92%; however, due to a lack of symptoms, late diagnoses are often a hallmark of this disease, leading to a 30% survival rate. Currently, various treatments are available for a patient to use, varying based on the state of metastasis. Although the various treatments exist, including chemotherapy, hormone therapy, surgery, and radiation therapy, there is still a lack of a targeted, minimally invasive treatment option.

Due to the heterogeneous nature of tumors and the limitation of anticancer drugs, a mono-compound treatment can usually only kill a fraction of cancer cells, sparing non-responsive cells which can continue proliferating and result in cancer recurrence. To address the inadequacy of a single drug, a drug combination (i.e., “drug cocktail”) can be utilized that includes multiple anticancer drugs of different anticancer mechanisms. Despite many promising in vitro and in vivo results achieved with a drug cocktail in cancer animal models, translation of the drug cocktail concept into a successful cancer treatment remains a challenge due to the lack of a safe and effective delivery system.

Previous research has been directed to a two-drug cocktail nanogel system by encapsulating drugs through hydrophobic interaction with a pH and redox potential dual responsive poly[(2-(pyridin-2-yldisulfanyl) ethyl acrylate)-co-[poly(ethylene glycol)]] (PDSA-PEG) polymer. It was found that the premature release of the encapsulated drugs during circulation can be reduced while significantly boosting the drugs' discharge in acidic pH or other reducing environments. Furthermore, the nano-cocktail exhibits a synergistic effect for killing cancer cells. However, the nanogel-based system could attenuate drug burst release, resulting in about 20% of the drugs being released before reaching the target tissue, which could potentially deteriorate the health condition of an already compromised cancer patient. Additionally, the ratio between the two compounds in the nano-cocktail could not be freely tuned according to their required potencies due to the constraint of their relative hydrophobicities.

To further minimize premature release-induced side effects, polymer drug conjugate-based nanoparticles, in which drug molecules are linked with a polymer carrier via covalent bonds, including hydrazone bonds, ester bonds, amide bonds, and disulfide bonds, have attracted a lot of attention. Since the loaded drug can only be released when the linker is cleaved, the systemic toxicity of the drug can be greatly reduced. Before conjugation onto a polymer, most drugs must be modified first to introduce a functional group. Consequently, after the break of the linker, the liberated molecules from the polymer are not in their original therapeutic form, which results in significantly diminished potency. Thus, the theoretic advantages of drug cocktails are locked in a catch-22 dilemma between safety and efficacy.

As such, there exists a need for a drug delivery system that can target specific cancer cells, deliver the drug safely, and provide the most effective form of treatment without initiating a toxicity response.

SUMMARY OF THE INVENTION

According to one particular embodiment of the present invention, a nanogel for use as a drug cocktail is provided. The nanogel includes a first chemotherapeutic agent, a second chemotherapeutic agent, a first targeting ligand, and a second targeting ligand.

In one embodiment, the nanogel can include a polymeric carrier, which can include a copolymer of an ethyl acrylate and an ethylene oxide. Further, the ethyl acrylate can include poly[(2-(pyridin-2-yldisulfanyl) ethyl acrylate), (pyridine-2-thiol)ethyl acrylate, (pyridine-2-thiol) ethyl methacrylate, ethyl (2-(pyridin-2-yldisulfanyl)ethyl) carbonate, N-(2-(pyridin-2-yldisulfanyl)ethyl) acrylamide, or a combination thereof. Meanwhile, the ethylene oxide can include polyethylene glycol.

In another embodiment, the first chemotherapeutic agent can be different from the second chemotherapeutic agent. Further, the first chemotherapeutic agent and the second chemotherapeutic agent can be selected from the group consisting of doxorubicin, paclitaxel, daunorubicin, valrubicin, triptolide, epirubicin, idarubicin, docetaxel, cisplatin, carboplatin, oxaliplatin, camptothecin, vincristine, vinblastine, 5-fluorouracil (5-FU), mitomycin, cyclophosphamide, methotrexate, mitoxantrone, topotecan, capecitabine, doxifluridine, irinotecan, tegafur, chlorambucil, belotecan, anastrozole, tamoxifen, GLEEVEC® (imatinib), floxuridine, leuprolide, flutamide, zoledronate, streptozocin, vinorelbine, hydroxyurea, retinoic acid, mechlorethamine, busulfan, prednisone, testosterone, aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, corticosteroid, gemcitabine, cedrol, or a combination thereof.

In yet another embodiment, the first chemotherapeutic agent can include a taxane. Further, the taxane can be paclitaxel.

In still another embodiment, the second chemotherapeutic agent can include an anthracycline. Further, the anthracycline can be doxorubicin.

In one more embodiment, the first targeting ligand can be different from the second targeting ligand. Further, the first targeting ligand and the second targeting ligand can be selected from the group consisting of 4-methoxybenzamide, Anti-ErbB2 AFFIBODY® molecule, anti-EGFR AFFIBODY® molecule, folic acid, 0-d-glucose, Asn-Gly-Arg peptide, Angiopep2, HERCEPTIN®, transferrin, arginine-glycine-aspartate peptide, lactobionic acid, or a combination thereof.

In an additional embodiment, the first targeting ligand can include 4-methoxybenazmine and the second targeting ligand can include Anti-ErbB2 AFFIBODY® molecule.

In another embodiment, the molar ratio of the first chemotherapeutic agent to the second chemotherapeutic agent can range from about 1:1 to about 1:1000.

In one more embodiment, the average particle size of the nanogel can range from about 50 nanometers to about 150 nanometers.

In still another embodiment, the nanogel can have a surface charge ranging from about −1 millivolts to about −50 millivolts.

In one more embodiment of the present invention, a method of treating a cancerous area in a mammal utilizing targeting ligands to target only cancerous cells within the cancerous area is provided. The method includes delivering a nanogel having traceless linkers to the cancerous area, wherein more than one chemotherapeutic agent is then released from the nanogel, the nanogel comprising a polymeric carrier; a first chemotherapeutic agent; a second chemotherapeutic agent that is different from the first chemotherapeutic agent, a first targeting ligand, and a second targeting ligand that is different from the first targeting ligand.

In one embodiment, the first targeting ligand can be a benzamide comprising 4-methoxybenzamide.

In still another embodiment, the second targeting ligand can be an AFFIBODY® molecule that includes Anti-ErbB2 AFFIBODY® molecule.

In yet another embodiment, the first chemotherapeutic agent and the second chemotherapeutic agent can be selected from the group consisting of doxorubicin, paclitaxel, daunorubicin, valrubicin, triptolide, epirubicin, idarubicin, docetaxel, cisplatin, carboplatin, oxaliplatin, camptothecin, vincristine, vinblastine, 5-fluorouracil(5-FU), mitomycin, cyclophosphamide, methotrexate, mitoxantrone, topotecan, capecitabine, doxifluridine, irinotecan, tegafur, chlorambucil, belotecan, anastrozole, tamoxifen, GLEEVEC® (imatinib), floxuridine, leuprolide, flutamide, zoledronate, streptozocin, vinorelbine, hydroxyurea, retinoic acid, mechlorethamine, busulfan, prednisone, testosterone, aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenyltazone, mechlorethamine, dexamethasone, prednisolone, celecoxib, valdecoxib, nimesulide, cortisone, corticosteroid, gemcitabine, cedrol, or a combination thereof.

In another embodiment, the traceless linkers can include a thiol group.

Other features and aspects of the present invention are set forth in greater detail below.

