Poly(vinyl alcohol) nanocarriers
The present invention provides a nanoparticle including at least one poly(vinyl alcohol) (PVA) having a molecular weight of from about 10 kDa to about 200 kDa, substituted with one or more moieties selected from: a therapeutic agent having a boronic acid moiety, wherein the therapeutic agent is covalently linked to the PVA via a boronate ester bond; a crosslinking group having a disulfide moiety, wherein the crosslinking group is covalently linked to the PVA, and a porphyrin, wherein the porphyrin is covalently linked to the PVA. Use of the nanoparticles for tumor detection and the treatment of diseases, including methods for photodynamic therapy and photothermal therapy, are also described.
1. A nanoparticle comprising:
at least one poly(vinyl alcohol) (PVA) having a molecular weight of from about 10 kDa to about 200 kDa, substituted with one or more moieties of
a therapeutic agent having a boronic acid moiety, wherein the therapeutic agent is covalently linked to the PVA via a boronate ester bond,
wherein the PVA has a structure according to formula I:
wherein:
each R′ is independently selected from the group consisting of H and a moiety according to formula Ia:
wherein L is a linking moiety and R 1a is a therapeutic moiety,
provided that at least one R′ is H and at least one R′ is other than H;
each R 2 is independently selected from the group consisting of —OH, a cellular targeting moiety, and an imaging moiety, or any two adjacent R 2 moieties are taken together to form a cellular targeting moiety or an imaging moiety;
subscript x is an integer of from about 1 to about 1200, and
subscript y is an integer of from 0 to about 3800, wherein
the sum of x and y is an integer of from about 200 to about 5000, and the x and y repeating units are randomly distributed in the PVA.
2. The nanoparticle of claim 1 , wherein the therapeutic agent moiety is selected from the group consisting of a proteasome inhibitor, a serine protease inhibitor, a β-lactamase inhibitor, and an arginase inhibitor.
3. The nanoparticle of claim 1 , wherein each R 1a is independently selected from the group consisting of:
4. The nanoparticle of claim 1 , further comprising a drug encapsulated in the nanoparticle.
5. The nanoparticle of claim 1 , wherein each R 2 is a moiety according to formula IVa
or
any two adjacent R 2 moieties are taken together to form a moiety according to formula IVb
wherein each R 2a is independently selected from the group consisting of a cellular targeting moiety and an imaging moiety.
6. The nanoparticle of claim 5 , wherein each cellular targeting moiety is independently selected from the group consisting of an antibody, a peptidomimetic moiety, a folic acid moiety, and a peptide.
7. The nanoparticle of claim 5 , wherein each cellular targeting moiety is independently selected from the group consisting of LLP2A, bombesin, LXY1, LXY3, LXY4, LXY30, LXW7, O A02, luteinizing-hormone-releasing hormone (LHRH), a melanocyte-stimulating hormone (MSH), folic acid, prostate-specific membrane antigen (PSMA)-targeted ligand, and a PSMA-targeted antibody.
8. The nanoparticle of claim 5 , wherein the imaging moiety comprises a fluorophore.
9. The nanoparticle of claim 1 , further comprising a branched polymeric crosslinker having from 2 to 4 branches and one boronic acid moiety per branch.
10. A method of treating a disease via photodynamic or photothermal therapy, comprising administering to a subject in need thereof a therapeutically effective amount of a nanoparticle of claim 1 , and exposing the subject to radiation, thereby treating the disease via photodynamic or photothermal therapy.
11. A method of detecting a tumor in a subject, comprising:
administering to the subject an effective amount of a nanoparticle of claim 1 ; and
detecting the tumor using an imaging modality selected from the group consisting of fluorescence imaging, magnetic resonance imaging, and positron emission tomography.