Biomimetic vesicles and uses thereof
The present disclosure relates to unimolecular core-shell nanoparticle, nanoclusters thereof, and platelet biomimetic nanoclusters thereof. The disclosed compositions are useful for treating a subject with a disease or condition, such as a cardiovascular disease. In a further aspect, the cardiovascular disease can be a vascular stenosis or restenosis. Also described herein are methods of making and using the unimolecular core-shell nanoparticle, nanoclusters thereof, and platelet biomimetic nanoclusters thereof. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.
1. A biomimetic nanocluster comprising
a cell membrane structure comprising a first cell membrane component; and
a core structure comprising a plurality of unimolecular core-shell nanoparticles, wherein each unimolecular core-shell nanoparticle comprises a functionalized polymer,
wherein the functionalized polymer comprises a core-forming segment and a shell-forming segment, and
wherein a first pharmaceutical agent is attached to the core-forming polymer, the shell-forming polymer, or both the core-forming polymer and the shell-forming polymer;
wherein the functionalized polymer is PAMAM-PVL-COOH; and
wherein the first pharmaceutical agent is selected from a hydrophobic pharmaceutical agent; inhibits smooth muscle cell proliferation; a bromo and extraterminal (BET) protein inhibitor; a protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor; is resveratrol, rapamycin, sirolimus, paclitaxel, halofuginone, idarubicin, a derivative thereof; a PI3K/p110α inhibitor, a CTPS1 inhibitor, a EZH2 inhibitor, a Smad3 inhibitor, a PDGFR inhibitor, a TGFBR inhibitor, a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof;
wherein the cell membrane structure is prepared from a mesenchymal stem cell, a peripheral blood mononuclear cell, a platelet, or any combination thereof.
2. The biomimetic nanocluster of claim 1 , wherein the core-forming segment is a generation 1, generation 2, generation 3, generation 4, or a generation 5 dendrimer.
3. The biomimetic nanocluster of claim 1 , wherein the functionalized polymer is functionalized with terminal negatively charged groups.
4. The biomimetic nanocluster of claim 1 , wherein the functionalized polymer is functionalized with terminal —COOH, —SO 3 H, or —OPO 3 H 2 groups, or a combination of groups thereof.
5. The biomimetic nanocluster of claim 1 , wherein the shell-forming polymer is more hydrophobic relative to the core-forming polymer.
6. The biomimetic nanocluster of claim 1 , wherein the core-forming polymer and the shell-forming polymer are hydrophobic and wherein the shell-forming polymer is more hydrophobic relative to the core-forming polymer.
7. The biomimetic nanocluster of claim 1 , wherein the bromo and extraterminal (BET) protein inhibitor is JQ1, RVX208, RO6870810, FT-1101, CPI-0610, ZEN-3694, GSK525762, MK-8628, BMS-986158, INCB054329, RVX297, a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof.
8. The biomimetic nanocluster of claim 1 , wherein the protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor is GSK2606414, GSK2656157, AMG PERK 44, a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof.
9. The biomimetic nanocluster of claim 1 , wherein the first pharmaceutical agent is UNC1999, tubstatin-A, SIS3, imatinib, SB431542, cyclopentyl cytosine, a derivative thereof, a pharmaceutically acceptable salt thereof, or any combination thereof.
10. The biomimetic nanocluster of claim 1 , further comprising a second pharmaceutical agent; and wherein the second pharmaceutical agent is an anti-inflammatory agent, an anti-thrombogenic agent, a lipid lowering agent with endothelium protection function, an anti-hypertensive agent, other epigenetic inhibitors, or any combination thereof.
11. The biomimetic nanocluster of claim 10 , wherein the anti-inflammatory agent is diflusinal, ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen, fenbufen, benoxaprofen, tiaprofenic acid, indoprofen, suprofen, etodolac, zomepirac, indomethacin, alclofenac, sulindac, fenclofenac, diclofenac, tolmetin, mefanamic acid, phenylbutazone, oxyphenbuta, azapropazone, feprazone, or piroxicam, or any combination thereof.
12. The biomimetic nanocluster of claim 1 , wherein the plurality of nanoparticles is homogeneous.
13. The biomimetic nanocluster of claim 1 , wherein the plurality of nanoparticles is heterogeneous.
14. The biomimetic nanocluster of claim 1 , wherein the diameter of the nanoclusters ranges from about 50 nm to about 200 nm.
15. The biomimetic nanocluster of claim 1 , wherein the number of unimolecular core-shell nanoparticles in the plurality of unimolecular core-shell nanoparticles can range from about 20 to about 1500.
16. The biomimetic nanocluster of claim 1 , wherein the diameter of the vesicle ranges from about 50 nm, to about 200 nm.
17. The biomimetic nanocluster of claim 1 , wherein the vesicle is capable of targeting the vascular endothelium.
18. A method for treating cardiovascular disease or injury in a subject comprising: administering to the subject the biomimetic nanocluster of claim 1 .
19. A kit comprising:
a biomimetic nanocluster of claim 1 to a subject; and
instructions to treat a subject with the unimolecular core-shell nanoparticle, the nanocluster, or
the biomimetic nanocluster.