Nanoparticles for cytoplasmic drug delivery to cancer cells
The invention is a nanoparticle that contains an anticancer drug that is released in cancer cells when administered to a subject. The nanoparticles have a core including the anticancer drug and polymer chains that are soluble at the pH of the cancer cell. The core is surrounded by a layer of polymer chains that are insoluble at the pH of healthy tissue but soluble at the pH of the cancer interstitium. An outside layer is made of water-soluble polymer chains to shield the nanoparticle from RES recognition and give the nanoparticle a long circulation time in the bloodstream of the subject. The outside layer may also include folic acid moieties that bind folic acid receptors on the surface of the cancer cell.
1. A layered nanoparticle that, when administered to a subject, releases an anticancer drug within a cancer cell, the layered nanoparticle comprising:
a block copolymer micelle, comprising poly[2-(N,N-dimethylamino)ethyl methacrylatel](PDMA) and poly[2-(N,N-diethylamino)ethyl methacrylatel](PDEA);
(a) an outer layer of water-soluble polymer chain moieties;
(b) an inner core layer containing the anticancer drug and polymer chains that dissolve in the cancer cell; and
(c) an intermediate layer between the outer layer and the inner core layer, the intermediate layer being insoluble at a pH of about 7.4 but soluble at the pH of a cancer interstitium, wherein the pH of said cancer interstitium is between 5.6 and 6.4.
2. A layered nanoparticle as defined in claim 1 , further comprising folate moieties in the outer layer.
3. A layered nanoparticle as defined in claim 1 , wherein the water-soluble polymer chain moieties are selected from the group consisting of PEG, PEO, PDMA, PVA (polyvinyl alcohol) and co-polymers of thereof.
4. A layered nanoparticle as defined in claim 1 , wherein the anticancer drug is selected from the group consisting of 6-mercaptopurine, ara-CMP, bleomycin, busulfan, camptothecin sodium salt, carboplatin, carmustine, chlorambucil, chlorodeoxyadenosine, cisplatin, cyclophosphamide, cytarabine, dacarbazin, dactinomycin, daunorubicin, docetaxel, doxorubicin, etoposide, floxuridine, fludarabine phosphate, fluorouracil, gemcitabine, hexamethyl melamine, hydroxyurea, idarubicin, iphosphamide, irinotecan, lomustine, mechlorethamine, melphalan, methotrexate, mithramycin, mitomycin, mitotane, mitoxantrone, navelbine, paclitaxel, pentostatin, pipobroman, procarbazine, streptozocin, teniposide, thioguanine, thiotepa, topotecan, triethylene melamine, trimetrexate, uracil nitrogen mustard, vinblastine, and vincristine.
5. A layered nanoparticle as defined in claim 1 , wherein the size of the nanoparticle is limited to the range of between 10 and 500 nm.
6. A layered nanoparticle as defined in claim 1 , wherein the outer layer is insoluble in healthy tissue above a pH of about 6.7.
7. A layered nanoparticle as defined in claim 1 , wherein the inner core is soluble in the cancer cell, below a pH of 5.3.