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Researchers Submit Patent Application, "Multistage Nanoparticle Drug Delivery System for the Treatment of Solid Tumors", for Approval

July 5, 2014



By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- From Washington, D.C., NewsRx journalists report that a patent application by the inventors Wong, Cliff R. (Cambridge, MA); Bawendi, Moungi G. (Cambridge, MA); Fukumura, Dai (Newton, MA); Jain, Rakesh K. (Wellesley, MA), filed on December 10, 2013, was made available online on June 19, 2014 (see also The Massachusetts General Hospital).

The patent's assignee is The Massachusetts General Hospital.

News editors obtained the following quote from the background information supplied by the inventors: "Despite advancements made in treatment and diagnosis, cancer remains the second leading cause of mortality in the United States, superseded only by heart disease. Solid tumors account for more than 85% of cancer mortality. Currently, the primary treatment modality for solid tumors is cytoreductive surgery followed by adjuvant chemotherapy and/or radiotherapy. While this strategy has been successfully employed in a number of patients, it is accompanied by cytotoxicity to normal cells and tissues, and the development of multidrug resistance (MDR).

"Targeted cancer therapies offer the potential to improve the treatment of solid tumors. By targeting therapeutic agents to solid tumors, cytotoxicity to normal cells and tissues may be minimized. In addition, targeted therapies provide the opportunity to more rigorously control the concentration of therapeutic agent at the site of a tumor, potentially limiting the emergence of drug resistance.

"Nanoparticles (NPs) have been explored for the targeted delivery of therapeutic agents to solid tumors. The larger size of nanoparticles, as compared to conventional small molecule cancer therapeutics, allows them to preferentially accumulate in solid tumors by the enhanced permeability and retention (EPR) effect. The EPR effect is a consequence of the abnormal vasculature frequently associated with solid tumors. The vasculature of tumors is typically characterized by blood vessels containing poorly-aligned defective endothelial cells with wide fenestrations. As a result, nanoparticles with an average particle size of between about 100 nm to 200 nm can preferentially extravasate out of the leaky regions of the tumor vasculature, and accumulate within the solid tumor. In addition, the lack of lymphatics in the tumor region prevent the nanoparticles from being efficiently filtered and removed, increasing the residence time of the nanoparticles within the tumor relative to residence in normal tissue and the vasculature.

"In view of the potential of nanoparticles to passively target therapies via the EPR effect, nanoparticle formulations have been investigated for the delivery of small molecule therapeutic agents to solid tumors, including two FDA-approved nanoparticle-based therapeutics--DOXIL.RTM. (an 100 nm PEGylated liposomal form of doxorubicin) and ABRAXANE.RTM. (an 130 nm albumin-bound paclitaxel nanoparticle). While these formulations exhibit improved pharmacokinetic properties and reduced adverse effects, existing nanoparticle formulations have provided only modest survival benefits. The limited efficacy of these existing nanoparticle formulations stems from their inability to effectively deliver the therapeutic agents throughout the solid tumor.

"Systemic delivery of therapeutic agents to solid tumors is a three step process: (1) blood-borne delivery of the therapeutic agent to different regions of the tumor; (2) transport of the therapeutic agent across the vessel wall into the solid tumor; and (3) passage of the therapeutic agent from the tumor tissue adjacent to the vasculature to the tumor cells via diffusion through the interstitial space.

"Abnormalities in the tumor vasculature lead to highly heterogeneous vascular perfusion throughout solid tumors. While the microvascular density is often high at the invasive edge of tumors, the tumor center is often unperfused. As a result, diffusion through the interstitial matrix is the primary mode for drug transport to the poorly perfused tumor center and the nanoparticles are unable to effectively diffuse through the dense interstitial matrix of the solid tumor--a complex assembly of collagen, glycosaminoglycans, and proteoglycans--to reach the tumor cells within the tumor center.

"As a consequence, existing nanoparticle formulations are limited in their ability to deliver a therapeutic agent throughout the entire tumor. For example, in the case of DOXIL.RTM., upon accumulation in a solid tumor via the EPR effect, the liposomal particles are unable to diffuse through the dense interstitial matrix of the tumor and remain trapped close to the tumor vasculature. The liposomes trapped near the vasculature release doxorubicin; however, in spite of its relatively low molecular weight (approximately 400 Da), the doxorubicin cannot migrate far from the particles due to avid binding to DNA and sequestration in acidic endosomes of perivascular tumor cells.

"As a consequence, existing nanoparticle formulations tend to produce heterogeneous therapeutic effects in solid tumors. The nanoparticle formulations deliver an effective amount of the therapeutic agent near the surface of the tumor where the leaky vasculatures are located; however, effective amounts of the therapeutic agents are not delivered to the cells in the tumor center. This is particularly problematic because the hostile microenvironment of the tumor center (characterized by low pH and low pO.sub.2) often harbors the most aggressive tumor cells. As a result, the tumor will regenerate if the cells in the tumor center are not eliminated. Moreover, exposure of the tumor cells to a sublethal concentration of the therapeutic agent can facilitate the development of drug resistance in the remaining cell lines. As a result, existing nanoparticle formulations have thus far provided only modest survival benefits when used to treat solid tumors.

"Therefore, it is an object of the invention to provide improved formulations for the targeted treatment of solid tumors.

"It is also an object of the invention to provide polymer-drug conjugates capable of delivering an effective amount of one or more active agents to tumor cells throughout the solid tumor.

"It is a further object of the invention to provide improved methods of treating solid tumors, including malignant tumors."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "Polymeric nanoparticles for delivery of one or more drugs to solid tumors are provided for size-targeted, two stage delivery. Initially, the nanoparticles possess an average particle size that allows them to preferentially extravasate from the leaky regions of the tumor vasculature and accumulate within the perivascular tumor tissue via the EPR effect. Once the nanoparticles have extravasated into the tumor tissue, the nanoparticles release one or more smaller nanoparticles having an average particle size and surface chemistry which significantly lowers their diffusional hindrance in the interstitial matrix. As a result, the smaller nanoparticles are able to efficiently penetrate into the tumor parenchyma. The smaller nanoparticles contain one or more therapeutic, prophylactic or diagnostic agents that are released as the smaller nanoparticles diffuse deep into the tumor.

"The nanoparticles are formed from one or more polymer-drug conjugates. In some instances, the polymer-drug conjugate is defined by Formula I

"##STR00001##

"wherein

"A is, independently for each occurrence, a drug;

"S is absent, or is a spacer group;

"X is a hydrophilic polymer segment;

"L is absent, or is a linking group;

"Y is a hydrophobic polymer segment; and

"b is an integer between 1 and 100.

"In some embodiments of Formula I, A is a small molecule anti-neoplastic agent. The one or more drugs can optionally be connected to the hydrophilic polymer segment by means of a spacer. In some embodiments, the spacer is an alkyl group, an alkylaryl group, an oligo- or polyethylene glycol chain, or an oligo- or poly(amino acid) chain. The spacer can includes one or more heteroatoms, one or more cleavable subunits, such as an oligo- or poly(peptide) that can be enzymatically cleaved, and/or one or more hydrolysable functional groups, such as an ester or amide.

"The hydrophilic polymer segment can be any biocompatible hydrophilic homopolymer or copolymer. In some embodiments, the hydrophilic polymer segment is a graft copolymer containing a polymeric backbone functionalized by one or more hydrophilic polymeric side chains. In some embodiments, the hydrophilic polymer segment is a graft copolymer containing a poly-glutamic acid backbone functionalized by one or more poly(ethylene glycol) (PEG) side chains. In some embodiments, the poly-glutamic acid backbone is poly-L-glutamic acid. In some embodiments, the hydrophilic polymer is not gelatin.

"The hydrophobic polymer segment can be any biocompatible hydrophobic polymer or copolymer. In some embodiments, the hydrophobic polymer segment is a biodegradable aliphatic polyester. In particular embodiments, the hydrophobic polymer segment is poly(lactic acid), poly(glycolic acid), or poly(lactic acid-co-glycolic acid).

"In some embodiments, the polymer-drug conjugate is defined by Formula II

"##STR00002##

"wherein

"A is a drug;

"S is absent, or is a spacer group;

"L is absent, or is a linking group;

"D is, independently for each occurrence, O, S, or NR.sub.1;

"R.sub.1 is H or a C.sub.1-C.sub.12 alkyl group optionally containing between one and six oxygen heteroatoms;

"a, b, c, and d are each, independently, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100;

"x and y are each, independently, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100;

"z is, independently for each occurrence, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100; and

"j and k are each, independently, an integer between 1 and 1000, more preferably between 1 and 500.

"In some embodiments of Formula II, A is a small molecule anti-neoplastic agent. In some embodiments, A is an anthracycline, such as doxorubicin or daunorubicin, or a topoisomerase inhibitor, such as camptothecin.

"In some embodiments of Formula II, S is absent. In other embodiments, S is an alkyl group, an alkylaryl group, an oligo- or polyethylene glycol chain, or an oligo- or poly(amino acid) chain. S can include one or more heteroatoms and/or one or more hydrolysable functional groups, such as an ester or amide.

"In some embodiments of Formula II, D is, independently for each occurrence, O or NH. In some embodiments, D is, in every occurrence, O. In still other embodiments, D is, in every occurrence, NH.

"In some embodiments of Formula II, L is absent. In other embodiments, L is a cleavable linker which is designed to be cleaved in response to an endogenous stimulus characteristic of the tumor microenvironment, such as a change in pH or the presence of an enzyme. The linker may include one or more hydrolysable functional groups, such as an ester, amide, or glycosidic bond, which can be hydrolyzed in acidic conditions. The linker can include an oligo- or poly(peptide) sequence designed to be cleaved by a matrix metalloproteinases (MMPs), such as matrix metalloproteinase-2 (MMP-2) or matrix metalloproteinase-9 (MMP-9). The can linker also includes an oligo- or poly(peptide) sequence designed to be cleaved by a cathepsin, such as Cathepsin B. The linker can include an oligo- or poly(peptide) sequence designed to be cleaved by autotaxin.

"In other embodiments, the hydrophobic polymer segment, along with an optional linking group, is grafted onto the backbone of the hydrophilic polymer segment. In one embodiment, the polymer-drug conjugate is defined by Formula III

"##STR00003##

"wherein

"A is a drug;

"S is absent, or is a spacer group;

"L is absent, or is a linking group;

"D is, independently for each occurrence, O, S, or NR.sub.1;

"R.sub.1 is H or a C.sub.1-C.sub.12 alkyl group optionally containing between one and six oxygen heteroatoms;

"a, b, c, and d are each, independently, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100;

"x and y are each, independently, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100;

"z is, independently for each occurrence, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100; and

"j and k are each, independently, an integer between 1 and 1000, more preferably between 1 and 500.

"In some embodiments of Formula III, A is a small molecule anti-neoplastic agent. In particular embodiments, A is an anthracycline, such as doxorubicin or daunorubicin, or a topoisomerase inhibitor, such as camptothecin.

"In some embodiments of Formula III, S is absent. In other embodiments, S is an alkyl group, an alkylaryl group, an oligo- or polyethylene glycol chain, or an oligo- or poly(amino acid) chain. S can include one or more heteroatoms and/or one or more hydrolysable functional groups, such as an ester or amide.

"In some embodiments of Formula III, D is, independently for each occurrence, O or NH. In some embodiments, D is, in every occurrence, O. In still other embodiments, D is, in every occurrence, NH.

"In some embodiments of Formula III, L is absent. In other embodiments, L is a cleavable linker which is designed to be cleaved in response to an endogenous stimulus characteristic of the tumor microenvironment, such as a change in pH or the presence of an enzyme. The linker may include one or more hydrolysable functional groups, such as an ester, amide, or glycosidic bond, which can be hydrolyzed in acidic conditions. The linker can include an oligo- or poly(peptide) sequence designed to be cleaved by a matrix metalloproteinases (MMPs), such as matrix metalloproteinase-2 (MMP-2) or matrix metalloproteinase-9 (MMP-9). The can linker also includes an oligo- or poly(peptide) sequence designed to be cleaved by a cathepsin, such as Cathepsin B. The linker can include an oligo- or poly(peptide) sequence designed to be cleaved by autotaxin.

"In other embodiments, the polymer conjugate is defined by Formula IV

"##STR00004##

"wherein

"A is, independently for each occurrence, a drug;

"S is absent, or is a spacer group;

"X is a hydrophilic polymer segment;

"L is absent, or is a linking group;

"Y is a poly(alkylene oxide) or copolymer thereof; and

"b and c are, independently, integers between 1 and 100.

"In some embodiments of Formula IV, A is a small molecule anti-neoplastic agent. The one or more drugs can optionally be connected to the hydrophilic polymer segment by means of a spacer, S. In some embodiments, S is an alkyl group, an alkylaryl group, an oligo- or polyethylene glycol chain, or an oligo- or poly(amino acid) chain. S can includes one or more heteroatoms, one or more cleavable subunits, such as a oligo- or poly(peptide) that can be enzymatically cleaved, and/or one or more hydrolysable functional groups, such as an ester or amide.

"The hydrophilic polymer segment can be any biocompatible hydrophilic homopolymer or copolymer. In some embodiments, the hydrophilic polymer segment is a graft copolymer containing a polymeric backbone functionalized by one or more hydrophilic polymeric side chains. In some embodiments, the hydrophilic polymer segment is a graft copolymer containing a poly-glutamic acid backbone functionalized by one or more poly(ethylene glycol) (PEG) side chains. In some embodiments, the poly-glutamic acid backbone is poly-L-glutamic acid.

"Y can be any suitable poly(alkylene oxide) or copolymer thereof. In certain embodiments, Y is PEG, or a copolymer thereof.

"In some embodiments, the polymer-drug conjugate is defined by Formula V

"##STR00005##

"wherein

"A is a drug;

"S is absent, or is a spacer group;

"L is absent, or is a linking group;

"D is, independently for each occurrence, O, S, or NR.sub.1;

"R.sub.1 is H or a C.sub.1-C.sub.12 alkyl group optionally containing between one and six oxygen heteroatoms;

"a, b, c, and d are each, independently, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100;

"z is, independently for each occurrence, an integer between 1 and 1000, more preferably between 1 and 500, most preferably between 1 and 100; and

"k is an integer between 1 and 1000, more preferably between 1 and 500.

"In some embodiments of Formula V, A is a small molecule anti-neoplastic agent. In particular embodiments, A is an anthracycline, such as doxorubicin or daunorubicin, or a topoisomerase inhibitor, such as camptothecin.

"In some embodiments of Formula V, S is absent. In other embodiments, S is an alkyl group, an alkylaryl group, an oligo- or polyethylene glycol chain, or an oligo- or poly(amino acid) chain. S can include one or more heteroatoms and/or one or more hydrolysable functional groups, such as an ester or amide.

"In some embodiments of Formula V, D is, independently for each occurrence, O or NH. In some embodiments, D is, in every occurrence, O. In still other embodiments, D is, in every occurrence, NH.

"In some embodiments of Formula V, L is absent. In other embodiments, L is a cleavable linker which is designed to be cleaved in response to an endogenous stimulus characteristic of the tumor microenvironment, such as a change in pH or the presence of an enzyme. The linker may include one or more hydrolysable functional groups, such as an ester, amide, or glycosidic bond, which can be hydrolyzed in acidic conditions. The linker can include an oligo- or poly(peptide) sequence designed to be cleaved by a matrix metalloproteinases (MMPs), such as matrix metalloproteinase-2 (MMP-2) or matrix metalloproteinase-9 (MMP-9). The can linker also includes an oligo- or poly(peptide) sequence designed to be cleaved by a cathepsin, such as Cathepsin B. The linker can include an oligo- or poly(peptide) sequence designed to be cleaved by autotaxin.

"Nanoparticles can be formed from one or more polymer-drug conjugates using any suitable method known in the art. In some embodiments, the nanoparticles are formed by nanoprecipitation. In some instances, the nanoparticles generally contain a hydrophobic core, formed from hydrophobic polymer segments, and a hydrophilic shell composed of small nanoparticles formed from the hydrophilic polymer segments. In other instances, the nanoparticles are formed from a series of small nanoparticles joined by polymer segments to form a larger nanoparticle.

"The nanoparticles have an average particle size that causes the nanoparticles to preferentially accumulate within the perivascular tumor tissue via the EPR effect. In some embodiments, the nanoparticles have an average particle size of between about 80 nm and about 500 nm, more preferably between about 100 nm and about 250 nm, most preferably between about 100 nm and about 200 nm. In other embodiments, the nanoparticles have an average particle size of between about 10 nm and about 50 nm, more preferably between about 10 nm and about 30 nm. Preferably, the nanoparticles exhibit or present significant amounts of a hydrophilic biocompatible polymer, such as PEG, on their surface to ensure biocompatibility and sufficient circulation time in vivo.

"Once the nanoparticles have extravasated into the tumor tissue, the nanoparticles release one or more smaller nanoparticles. Preferably, the release of the one or more smaller nanoparticles is triggered by an endogenous stimulus characteristic of the tumor microenvironment, such as a change in pH and/or the presence of an enzyme such as MMP-2 which is present in elevated amounts in many tumors.

"The smaller nanoparticles possess an average particle size and surface chemistry which significantly lowers their diffusional hindrance in the interstitial matrix. In some embodiments, the smaller nanoparticles have an average particle size of between about 1 nm and about 20 nm, more preferably between about 2 nm and about 15 nm, most preferably between about 4 nm and about 8 nm.

"In some embodiments, the smaller nanoparticles contain significant amounts of a hydrophilic biocompatible polymer, such as PEG, on their surface which allows them to diffuse smoothly in the interstitial matrix, reducing the binding, sequestration, and metabolism that hinders the transport of much smaller therapeutic agents.

"Also provided are pharmaceutical formulations containing multistage nanoparticles formed from one or more polymer-drug conjugates, as well as methods of administering these pharmaceutical compositions to treat or prevent solid tumors, including benign and malignant tumors. These formulations can effectively deliver therapeutic levels of one or more drugs throughout a solid tumor in an effective amount to slow tumor growth, halt tumor growth, or decrease tumor size.

BRIEF DESCRIPTION OF THE DRAWINGS

"FIGS. 1A and 1B schematically illustrate multistage nanoparticles containing a hydrophobic core, formed from hydrophobic polymer segments, and a hydrophilic shell composed of small nanoparticles formed from hydrophilic polymer segments. FIG. 1A illustrates that multistage nanoparticles of this type can be prepared from suitable polymer-drug conjugates by nanoprecipitation. As shown in FIG. 1B, upon hydrolysis, these multistage nanoparticles release a plurality of smaller nanoparticles which can penetrate the tumor interior. The drug is released from these smaller nanoparticles within the tumor interior by hydrolysis.

"FIGS. 2A and 2B schematically illustrate multistage nanoparticles containing a hydrophobic core, formed from hydrophobic polymer segments, and a hydrophilic shell composed of small nanoparticles formed from the hydrophilic polymer segments which are connected by an enzymatically cleavable linking group. FIG. 2A illustrates that multistage nanoparticles of this type can be prepared from suitable polymer-drug conjugates containing cleavable linking groups by nanoprecipitation. As shown in FIG. 2B, upon cleavage of the linking group, such as by a suitable enzyme, these multistage nanoparticles release a plurality of smaller nanoparticles which can penetrate the tumor interior. The drug is released from these smaller nanoparticles within the tumor interior by hydrolysis.

"FIG. 3 schematically illustrates multistage nanoparticles formed from a plurality of small nanoparticles formed from hydrophilic polymer segments conjugated or joined together by poly(alkylene oxide) polymer or copolymer segments to form a larger nanoparticle or nanocluster. Once the nanoparticles have extravasated into the tumor tissue, the polymer segments joining the small nanoparticles are hydrolyzed, releasing a plurality of smaller nanoparticles, which can penetrate the tumor interior. A drug is released from these smaller nanoparticles within the tumor interior by hydrolysis.

"FIG. 4 is an overlayed plot of GFC chromatograms showing release from multistage quantum dot gelatin nanoparticles (QDGelNPs) at various times after incubation with MMP-2. The gel filtration chromatograms (GFCs) plot the fluorescence intensity (in arbitrary units) as a function of elution time (in minutes) following incubation with MMP-2 for 0 hours, 0.3 hours, 2.2 hours, 5 hours, and 12 hours (top to bottom traces at time.apprxeq.15 minutes). For comparison, the dotted trace shows the GFC of the QD control. The fluorescence signal was collected at 565 nm. Fluorescence spectrum of the peak at void volume for 2.2 hours cleaving time shows that the signal originates from QDs on the QDGelNPs.

"FIGS. 5A and 5B are plots demonstrating the kinetics of MMP-2-induced quantum dot (QD) release from multistage quantum dot gelatin nanoparticles (QDGelNPs). FIG. 5A is a plot showing the percent of QD release from QDGelNPs as a function of time (in hours) following incubation with 230 nm (0.16 .mu.M) MMP-2. FIG. 5B is a plot showing the percent of QD release from QDGelNPs as a function of MMP-2 concentration (in ng) following incubation for 12 hours."

For additional information on this patent application, see: Wong, Cliff R.; Bawendi, Moungi G.; Fukumura, Dai; Jain, Rakesh K. Multistage Nanoparticle Drug Delivery System for the Treatment of Solid Tumors. Filed December 10, 2013 and posted June 19, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3367&p=68&f=G&l=50&d=PG01&S1=20140612.PD.&OS=PD/20140612&RS=PD/20140612

Keywords for this news article include: Alkenes, Gelatin, Therapy, Oncology, Peptides, Polyenes, Chemistry, Proteomics, Camptothecin, Hydrocarbons, Legal Issues, Nanoparticle, Quantum Dots, Glutamic Acid, Solid Cancers, Nanotechnology, Scleroproteins, Drug Development, Organic Chemicals, Acidic Amino Acids, Polyethylene Glycols, Drug Delivery Systems.

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