Massachusetts Institute of Technology

The Penn State Research Foundation

Other

The Pennsylvania Research Corporation

Smadar Cohen

Robert Samuel Langer

Harry R Allcock

Karyn B Visscher

Carmen Bano

Alexander K Andrianov

Margaret Alison Wheatley

Marie B Chow

Junichi Okada

Tae G Park

Polymerized liposomes, methods of preparing the polymerized liposomes and incorporating biologically active substances within the polymerized liposomes, and methods of administering polymerized liposomes containing a biologically active substance to be delivered to a patient are disclosed. The polymerized liposomes are prepared by polymerizing double bond-containing liposomes. The polymerization can be initiated with a source of radiation and/or a free radical initiator. Biologically active substances can be incorporated into both the hydrophilic and hydrophobic layers of the liposomes, either during or after polymerization. The polymerized liposomes can be administered orally to a patient in need of the biologically active substance to be delivered. Examples demonstrate enhanced stability.

Oral delivery of vaccines using polymerized liposomes

Compositions, methods for preparing and methods of using contrast agent-filled polymeric microparticles for imaging are disclosed. In a preferred embodiment, air-encapsulating microparticles are formed by ionotropically gelling synthetic polyelectrolytes such as poly(carboxylatophenoxy)phosphazene, poly(acrylic acid), poly(methacrylic acid) and methacrylic acid copolymers (Eudragit's) by contact with multivalent ions such as calcium ions. In the preferred embodiment, the average size of the microparticles is less than seven .mu.m so that they are suitable for injection intravenously. The polymeric microparticles are stable to imaging and display high echogenicity, both in vitro and in vivo. Due to their in vivo stability their potential application is extended beyond vascular imaging to liver and renal diseases, fallopian tube diseases, detecting and characterizing tumor masses and tissues, and measuring peripheral blood velocity. The microparticles can optionally be linked with ligands that minimize tissue adhesion or that target the microparticles to specific regions.

Polymeric microparticles containing agents for imaging

A method for encapsulating biologically-labile materials such as proteins, liposomes, bacteria and eucaryotic cells within a synthetic polymeric capsule, and the product thereof, are disclosed. The method is based on the use of a water-soluble polymer with charged side chains that are crosslinked with multivalent ions of the opposite charge to form a gel encapsulating biological material, that is optionally further stabilized by interactions with multivalent polyions of the same charge as those used to form the gel. In the preferred embodiment, hydrolytically stable polyphosphazenes are formed of monomers having carboxylic acid side groups that are crosslinked by divalent or trivalent cations such as Ca.sup.2+ or Al.sup.3+, then stabilized with a polycation such as poly-L-lysine. A variety of different compositions can be formed from the crosslinked polymer. In a preferred embodiment, microcapsules are made by spraying an aqueous solution of polyphosphazene and material to be encapsulated into a calcium chloride solution.

Ionically cross-linked polymeric microcapsules

Compositions, methods for preparing and methods of using air-filled polymeric microcapsules for ultrasound imaging are disclosed. Air-encapsulating microcapsules are formed by ionotropically gelling synthetic polyelectrolytes such as poly(carboxylatophenoxy)phosphazene, poly(acrylic acid), poly(methacrylic acid) and methacrylic acid copolymers (Eudragit's) by contact with multivalent ions such as calcium ions. In the preferred embodiment, the average size of the microcapsules is less than seven .mu.m so that they are suitable for injection intravenously. The polymeric microcapsules are stable to imaging and display high echogenicity, both in vitro and in vivo. Due to their in vivo stability their potential application is extended beyond vascular imaging to liver and renal diseases, fallopian tube diseases, detecting and characterizing tumor masses and tissues, and measuring peripheral blood velocity. The microcapsules can optionally be linked with ligands that minimize tissue adhesion or that target the microcapsules to specific regions.

Gas-filled polymeric microbubbles for ultrasound imaging

A new series of degradable polymeric matrices were prepared by blending polymers that degrade by hydrolysis such as poly(L-lactic acid)(PLA), and nonionic Pluronic.TM. surfactants, block copolymers of polyethyleneoxide (PEO) and polypropyleneoxide (PPO). The water content of the polymer blend films was controlled by mixing different types of block copolymers and by adjusting their amount. In aqueous solution, the blends revealed the typical liquid-crystalline phase transition of Pluronic.TM. polymers, suggesting the formation of a gel-like structure within the polymer skeleton. Poly(lactic acid) degradation rates were not affected by the blending procedure, although the hydration degree in these matrices was higher. When used as drug-releasing matrices, these blends extended protein release and minimized the initial protein burst, as compared to the pure polymer.

Controlled drug delivery using polymer/pluronic blends

A method for encapsulating biologically-labile materials such as proteins, liposomes, bacteria and eucaryotic cells within a synthetic polymeric capsule, and the product thereof, are disclosed. The method is based on the use of a water-soluble polymer with charged side chains that are crosslinked with multivalent ions of the opposite charge to form a gel encapsulating biological material, that is optionally further stabilized by interactions with multivalent polyions of the same charge as those used to form the gel. In the preferred embodiment, hydrolytically stable polyphosphazenes are formed of monomers having carboxylic acid side groups that are crosslinked by divalent or trivalent cations such as Ca.sup.2+ or Al.sup.3+, then stabilized with a polycation such as poly-L-lysine. A variety of different compositions can be formed from the crosslinked polymer. In a preferred embodiment, microcapsules are made by spraying an aqueous solution of polyphosphazene and material to be encapsulated into a calcium chloride solution. A semi-permeable membrane is formed on the microspheres by complexation of the surface carboxylate groups with poly(L-lysine).

A method for encapsulating biologically-labile materials such as proteins, liposomes, bacteria and eucaryotic cells within a synthetic polymeric capsule, and the product thereof, are disclosed. The method is based on the use of a water-soluble polymer with charged side chains that are crosslinked with multivalent ions of the opposite charge to form a gel encapsulating biological material, that is optionally further stabilized by interactions with multivalent polyions of the same charge as those used to form the gel. In the preferred embodiment, hydrolytically stable polyphosphazenes are formed of monomers having carboxylic acid side groups that are crosslinked by divalent or trivalent cations such as Ca.sup.2+ or Al.sup.3+, then stabilized with a polycation such as poly-L-lysine. A variety of different compositions can be formed from the crosslinked polymer. In a preferred embodiment, microcapsules are made by spraying an aqueous solution of polyphosphazene and material to be encapsulated into a calcium chloride solution. A semipermeable membrane is formed on the microspheres by complexation of the surface carboxylate groups with poly(L-lysine).

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Petach-Tickva, Israel

Smadar Cohen