NANOPARTICLE DELIVERY SYSTEMS
Nanoparticle compositions described herein comprise combinations of prodrugs of therapeutic agents that achieve enhanced therapeutic effects as compared to those observed when combinations of free forms of these therapeutic agents are administered.
1 . A pharmaceutical composition including a set of pharmaceutical compositions comprising nanoparticles wherein said nanoparticles have an average diameter of less than 80 nm and comprise:
a) at least two therapeutic agents, wherein each therapeutic agent is supplied as coupled through a linker to a hydrophobic moiety to form a prodrug, and
b) an amphiphilic stabilizer comprising a hydrophobic portion and a hydrophilic portion wherein the weight ratio of the hydrophobic portion to the hydrophilic portion is in the range of 8:5 to 12:5 and wherein the hydrophobic portion has a molecular weight of 8 kD to 15 kD, and
wherein the prodrugs of said two different therapeutic agents are contained in the same nanoparticles or are contained in separate nanoparticles.
2 . The composition of claim 1 wherein said amphiphilic stabilizer is a diblock copolymer.
3 . The composition of claim 1 wherein in said amphiphilic stabilizer, the hydrophobic portion comprises polylactic acid (PLA) or poly(lactic-co-glycolic acid (PLGA) and the hydrophilic portion comprises polyethylene glycol (PEG).
4 . The composition of claim 1 wherein said at least two therapeutic agents are included in the same nanoparticle.
5 . The composition of claim 1 wherein one therapeutic agent is a taxane and the other therapeutic agent is an HSP inhibitor or wherein one therapeutic agent is a PI3K/AKT/mTOR inhibitor and the other therapeutic agent is an RAS/RAF/MEK/ERK inhibitor.
6 . The composition of claim 1 wherein in each of said prodrugs the hydrophobic moiety is cholesterol or another natural product and/or the linker is diglycolic acid.
7 . The composition of claim 1 wherein said nanoparticles are formed by mixing an aqueous phase and an organic phase, said organic phase comprising said copolymer and said prodrug.
8 . The composition of claim 7 wherein said mixing is conducted by rapid mixing of jet streams one of which comprises the aqueous phase and the other of which comprises the organic phase.
9 . The composition of claim 1 wherein said nanoparticles have an average diameter of 20-80 nm.
10 . The composition of claim 1 which further comprises a third therapeutic agent.
11 . The composition of claim 10 wherein said third therapeutic agent is supplied as a prodrug and encapsulated in said nanoparticles.
12 . A method to administer a combination of two or more therapeutic agents which method comprises administering to a subject the composition of claim 1 .
13 . The method of claim 12 wherein said administering is by parenteral administration.
14 . The method of claim 13 wherein the subject is human or non-human mammal or avian.
15 . A method to prepare the composition of claim 1 which method comprises rapidly mixing an aqueous phase with an organic phase comprising said copolymer and said prodrug.