Nanolipogel vehicles for controlled delivery of different pharmaceutical agents
A “nanolipogel” is a delivery vehicle including one or more lipid layer surrounding a hydrogel core, which may include an absorbent such as a cyclodextrin or ion-exchange resin. Nanolipogels can be constructed so as to incorporate a variety of different chemical entities that can subsequently be released in a controlled fashion. These different incorporated chemical entities can differ dramatically with respect to size and composition. Nanolipogels have been constructed to contain co-encapsulated proteins as well as small hydrophobic drugs within the interior of the lipid bilayer. Agents incorporated within nanolipogels can be released into the milieu in a controlled fashion, for example, nanolipogels provide a means of achieving simultaneous sustained release of agents that differ widely in chemical composition and molecular weight. Additionally, nanolipogels can favorably modulate biodistribution.
1. A nanolipogel comprising:
(a) a polymeric matrix core comprising a host molecule that is reversibly complexed with at least one therapeutic, diagnostic or prophylactic active agent to be delivered, such that the or each active agent can be released under in vivo conditions, and
(b) a lipid shell;
wherein the or each therapeutic, diagnostic or prophylactic active agent is a nucleic acid.
2. A nanolipogel according to claim 1 , wherein the or each nucleic acid is a DNA molecule such as a gene or cDNA molecule; or is an RNA molecule such as an inhibitory RNA, a tRNA, an rRNA, or an mRNA; or is an expression vector encoding a gene or cDNA of interest.
3. A nanolipogel according to claim 1 , wherein the polymer matrix core comprises a dendrimer core that is reversibly complexed with the or each nucleic acid.
4. A nanolipogel according to claim 3 , wherein the dendrimer is a cationic polyamidoamine (PAMAM) dendrimer.
5. A nanolipogel according to claim 4 , wherein the cationic polyamidoamine (PAMAM) dendrimer is a G5 PAMAM dendrimer.
6. A nanolipogel according to claim 1 , wherein the or each nucleic acid is reversibly complexed with a cationic polymer such as polyethyleneimine (PEI).
7. A nanolipogel according to claim 1 , further comprising one or more additional active agents which are reversibly complexed with the host molecule, and/or dispersed within the polymeric matrix, and/or dispersed in or bound to the lipid shell.
8. A nanolipogel according to claim 7 , which nanolipogel comprises two, three, four or more different active agents for simultaneous delivery to a cell, wherein the two, three, four or more different active agents are nucleic acids.
9. A nanolipogel according to claim 1 , wherein the lipid shell is composed of one or more concentric lipid layers, optionally crosslinked, wherein the lipids can be neutral, anionic or cationic lipids at physiologic pH.
10. A nanolipogel according to claim 9 , wherein the lipid is selected from the group consisting of cholesterol, phospholipids, lysolipids, lysophospholipids, and sphingolipids, and derivatives thereof.
11. A nanolipogel according to claim 9 wherein the lipid is a PEGylated derivative of a neutral, anionic, or cationic lipid.
12. A nanolipogel according to claim 1 , wherein the or each nucleic acid is an mRNA or a non-integrating expression vector which can be expressed transiently in a host cell when released into the cytoplasm of the host cell.
13. A nanolipogel as claimed in claim 1 , for use in a method of treating cancer or infectious disease in a subject, or for use in a method of vaccinating a subject to induce immunity against a disease or condition; which method comprises administering an effective amount of the nanolipogel to a subject in need thereof.