IP Library Granted Patent US 12,383,499
Granted Patent B2
US 12,383,499 · App. 16/235,950 · Granted Aug 12, 2025

Scale up synthesis of silicasome nanocarriers

Inventors: Andre E. Nel (Sherman Oaks, CA); Huan Meng (Los Angeles, CA); Xiangsheng Liu (Los Angeles, CA)
Assignee: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
A61K9/1271A61K9/1277A61K9/5115A61K9/5192A61K31/4745A61P35/00
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Quick Facts
Patent No.
US 12,383,499
App. No.
16/235,950
Granted
Aug 12, 2025
Kind
B2
Abstract

In order to facilitate the approval and commercialization of silicasome drug delivery systems (e.g. irinotecan silicasomes) it is necessary to scale up synthesis of the drug-loaded silicasomes. In this regard, it was discovered that the synthesis protocols used for laboratory synthesis of drug-loaded silicasomes (e.g., 500 mg/batch) do not scale to large scale silicasome production, because the resulting products were too heterogeneous for use as pharmaceuticals. Accordingly, new methods are provided herein that effectively afford the large-scale production of mesoporous silica nanoparticles (MSNPs) and lipid bilayer coated MSNPs (silicasomes).

Claims (53)

1. A method for large-scale preparation of mesoporous silica nanoparticles suitable for use in pharmaceuticals, said method comprising:

providing a cationic surfactant in water at a concentration greater than a critical micellar concentration (CMC) of said cationic surfactant to form an aqueous mixture of micelles, where said cationic surfactant comprises cetyltrimethylammonium chloride (CTAC) or cetyltrimethylammonium bromide (CTAB);

adding triethanolamine (TEA) and tetraethylorthosilicate (TEOS) to said aqueous mixture of micelles at a molar ratio of water: cationic surfactant: TEA:TEOS ranging from 100 to 150 water: 0.06 to 0.10 cationic surfactant:0.04 to 0.08 TEA: 0.08 to 1.2 TEOS; and

stirring or agitating said aqueous mixture of micelles to allow said cationic surfactant, said TEA, and said TEOS in said aqueous mixture of micelles to react to form a population of mesoporous silica nanoparticles (MSNPs), wherein said method produces at least 30 grams of mesoporous silica nanoparticles in a single batch, and

wherein the providing of the cationic surfactant at the concentration greater than the CMC maintains a size of MSNPs in presence of said TEA.

2. The method of claim 1 , wherein said cationic surfactant is CTAC.

3. The method of claim 1 , wherein said method further comprises adding ethanol to said aqueous mixture of micelles after said population of MSNPs is formed to precipitate said population of MSNPs.

4. The method of claim 1 , wherein the molar ratio of water:cationic surfactant:TEA:TEOS is 125:0.08:0.06:1.

5. The method of claim 1 , wherein said reaction proceeds until at least one of the following: 1) a hydrodynamic size of said population of MSNPs is constant or 2) a yield of said population of MSNPs is constant.

6. The method of claim 1 , wherein said method produces said population of MSNPs characterized by at least one of the following features:

a monotonic size distribution;

a size distribution having a coefficient of variation of less than 0.10;

said population of MSNPs having an average diameter ranging from 40 nm up to 100 nm; and

an average pore size ranging from 2.2 to 3.4 nm.

7. The method of claim 1 , wherein said method further comprises:

providing a plurality of lipids in a polar solvent forming a dispersion of lipid in a solvent;

introducing said population of MSNPs into said dispersion to form a dispersion containing said population of MSNPs; and

sonicating or homogenizing said dispersion containing said population of MSNPs to provide a population of MSNPs encased in a lipid bilayer.

8. The method of claim 7 , wherein said polar solvent comprises a solvent selected from the group consisting of ethanol, methanol, ethanol containing an aqueous solvent with the organic phase greater than 30%, methanol containing the aqueous solvent with an organic phase greater than 30%, pure acetone, and acetone aqueous solution with acetone concentration of 50% or greater.

9. The method of claim 7 , wherein the ratio of the population of MSNPs to the lipid ranges from 1:0.5 to 1:5 w/w.

10. The method of claim 7 , wherein said sonication proceeds at an energy and duration sufficient to provide a clear suspension of said population of MSNPs encased in said lipid bilayer.

11. The method of claim 7 , wherein:

said plurality of lipids comprise a phospholipid, cholesterol (CHOL), and an mPEG phospholipid and said lipid bilayer encapsulating said population of MSNPs comprises said phospholipid, cholesterol (CHOL), and mPEG phospholipid; or

said lipid bilayer comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG (DSPE-PEG); or

said lipid bilayer comprises DPPC/Chol/DSPE-PEG or DSPC/Chol/DSPE-PEG; or said lipid bilayer comprises a phospholipid, cholesterol, and mPEG phospholipid at a ratio of 50-90 mol % phospholipid:10-50 mol % CHOL:1-10 mol % mPEG phospholipid.

12. The method of claim 7 , wherein said lipid bilayer forms a continuous uniform and intact bilayer encompassing an entire nanoparticle within the population of MSNPs.

13. The method of claim 7 , wherein said providing said population of MSNPs comprises providing said population of MSNPs loaded with a protonating agent and wherein said population of MSNPs encased in said lipid bilayer formed by said method contain said protonating agent.

14. The method of claim 13 , wherein said protonating agent is selected from the group consisting of triethylammmonium sucrose octasulfate (TEA8SOS), proton-generating dissociable salts, a trimethylammonium salt, a triethylammonium salt, an acidic buffer, a metal salt, and calcium acetate.

15. The method of claim 13 , wherein said method comprises remote loading said population of MSNPs encased in said lipid bilayer with a drug by incubating said population of MSNPs encased in said lipid bilayer containing said protonating agent with one or more drugs comprising at least one weakly basic group capable of being protonated.

16. The method of claim 15 , wherein said drug comprises one or more of the following:

at least one weakly basic group capable of being protonated, and the protonating agent

comprises at least one anionic group;

a pKa greater than 7 and less than 11;

a primary, secondary, or tertiary amine; a water solubility index of 2 to 25 mg/mL;

an octanol/water partition coefficient or log P value of −3.0 to 3.0; or

a size smaller than the average or median size of the pores of the silica nanoparticle.

17. The method of claim 16 , wherein: said drug comprises an anticancer drug; or said drug comprises irinotecan, a substantially pure D isomer of irinotecan, or a substantially pure L isomer of irinotecan; or said drug comprises one or more drugs independently selected from the group consisting of a topoisomerase inhibitor, an antitumor anthracycline antibiotic, a mitotic inhibitor, an alkaloid, an alkaline alkylating agent, a purine or pyrimidine derivative, and a protein kinase inhibitor; or said drug comprises a drug selected from the group consisting of topotecan, 10-hydroxycamptothecin, belotecan, rubitecan, vinorelbine, LAQ824, doxorubicin, mitoxantrone, vinblastine, vinorelbine, cyclophosphamide, mechlorethamine, temozolomide, 5-fluorouracil, 5′-deoxy-5-fluorouridine, gemcitabine, imatinib, osimertinib and sunitinib pazopanib, enzastaurin, vandetanib, erlotinib, dasatinib, nilotinib, abemaciclib, palbociclib, and ribociclib.

18. The method of claim 16 , wherein said drug comprises irinotecan, a pure D isomer of irinotecan, or a pure L isomer of irinotecan.

19. The method of claim 15 , wherein:

said population of MSNPs encased in said lipid bilayer have a drug loading capacity of at least 5% w/w, or at least 10% w/w, or at least 20% w/w, or at least 30% w/w, or greater than 40% w/w, or greater than 50% w/w, or greater than 60% w/w, or greater than 70% w/w, or greater than 80% w/w; and/or

said lipid bilayer comprises a hydrophobic drug that is introduced into said lipid bilayer before encapsulation of said population of MSNPs; and/or

said lipid bilayer comprises a hydrophobic drug that is introduced into said lipid bilayer before encapsulation of said population of MSNPs where said lipid bilayer comprises a hydrophobic drug selected from the group consisting of paclitaxel, ellipticine, camptothecan, SN-38, and a lipid prodrug.

20. The method of claim 7 , wherein said population of MSNPs encased in said lipid bilayer are each conjugated to a moiety selected from the group consisting of a targeting moiety, a fusogenic peptide, and a transport peptide.

21. The method of claim 7 , wherein said method produces said population of MSNPs encased in said lipid bilayer in suspension that comprises one or more of the following properties:

is stable for at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months when stored at 4° C.;

shows a size distribution having a full width half maximum of less than 30 nm, or less than 20 nm, or less than 10 nm, or less than 5 nm, or less than 3 nm, or less than 2 nm;

shows a unimodal size distribution;

shows a PDI less than 0.2, or less than 0.1; and shows a coefficient of variation in size less than 0.1 or less than 0.05, or less than 1.7/120.

22. The method of claim 1 , wherein the molar ratio of water:cationic surfactant:_TEA:TEOS is 125:0.08:0.06:0.33.

23. The method of claim 22 , wherein said method produces greater than 100 grams of mesoporous silica nanoparticles in a single batch.

24. The method of claim 23 , wherein said method produces about 120 grams to about 140 grams of mesoporous silica nanoparticles in a single batch.

25. The method of claim 1 , wherein said method produces at least 60 grams of mesoporous silica nanoparticles in a single batch.

26. The method of claim 1 , wherein said method has a yield of greater than about 80%.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 1, 2019
From: NEL, ANDRE E.; MENG, HUAN; LIU, XIANGSHENG
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 048759/0215 →
Continuity (2)
Provisional Application 62612671 · Jan 1, 2018
Related Publication 20190216736A1 · Jul 18, 2019
References Cited (265)
US 4737323A · Martin et al. · 1988 [cited by applicant]
US 5670631A · Bayerl et al. · 1997 [cited by applicant]
US 6296870B1 · Needham et al. · 2001 [cited by applicant]
US 6868343B1 · Bayerl et al. · 2005 [cited by applicant]
US 8734816B2 · Liu et al. · 2014 [cited by applicant]
US 8758811B2 · Ho et al. · 2014 [cited by applicant]
US 8992984B1 · Brinker et al. · 2015 [cited by applicant]
US 9532949B2 · Zeinelden et al. · 2017 [cited by applicant]
US 9579283B2 · Brinker et al. · 2017 [cited by applicant]
US 10143660B2 · Nel et al. · 2018 [cited by applicant]
US 10343903B2 · Zink et al. · 2019 [cited by applicant]
US 10765636B2 · Nel et al. · 2020 [cited by applicant]
US 10828255B2 · Nel et al. · 2020 [cited by applicant]
US 11096900B2 · Nel et al. · 2021 [cited by applicant]
US 20030035842A1 · Kazakov et al. · 2003 [cited by applicant]
US 20040005352A1 · Lopez et al. · 2004 [cited by applicant]
US 20050249795A1 · Zhang et al. · 2005 [cited by applicant]
US 20060154069A1 · Lin et al. · 2006 [cited by applicant]
US 20070116753A1 · Hong et al. · 2007 [cited by applicant]
US 20080175992A1 · Plieth et al. · 2008 [cited by applicant]
US 20100255103A1 · Liong et al. · 2010 [cited by applicant]
US 20100284924A1 · Zink et al. · 2010 [cited by applicant]
US 20100310465A1 · Zink et al. · 2010 [cited by applicant]
US 20110104073A1 · Zeng et al. · 2011 [cited by applicant]
US 20110123601A1 · Ho et al. · 2011 [cited by applicant]
US 20110268791A1 · Liu et al. · 2011 [cited by applicant]
US 20120021034A1 · Zink et al. · 2012 [cited by applicant]
US 20120207795A1 · Zink et al. · 2012 [cited by applicant]
US 20130046274A1 · Zink et al. · 2013 [cited by applicant]
US 20130195963A1 · Serda et al. · 2013 [cited by applicant]
US 20140079774A1 · Brinker et al. · 2014 [cited by applicant]
US 20140138278A1 · Kennedy · 2014 [cited by applicant]
US 20140301951A1 · Liu et al. · 2014 [cited by applicant]
US 20150272885A1 · Ashley et al. · 2015 [cited by applicant]
US 20160008283A1 · Nel et al. · 2016 [cited by applicant]
US 20170095418A1 · Zink et al. · 2017 [cited by applicant]
US 20170173169A1 · Yantasee et al. · 2017 [cited by applicant]
US 20180098945A1 · Nel et al. · 2018 [cited by applicant]
US 20190160015A1 · Nel et al. · 2019 [cited by applicant]
US 20200383929A1 · Nel et al. · 2020 [cited by applicant]
US 20210077397A1 · Nel et al. · 2021 [cited by applicant]
US 20220160644A1 · Nel et al. · 2022 [cited by applicant]
AU 2017206077B2 · 2021 [cited by applicant]
EP 2964201A1 · 2016 [cited by applicant]
WO WO2006015757A1 · 2006 [cited by applicant]
WO WO2006032136A1 · 2006 [cited by applicant]
WO WO2010078569A2 · 2010 [cited by applicant]
WO WO2012009448A2 · 2012 [cited by applicant]
WO WO2012149376A2 · 2012 [cited by applicant]
WO WO2013012891A1 · 2013 [cited by applicant]
WO WO2014138278A1 · 2014 [cited by applicant]
WO WO2017013250A1 · 2017 [cited by applicant]
WO WO2017120537A1 · 2017 [cited by applicant]
WO WO2019133884A1 · 2019 [cited by applicant]
US Office Action (Restriction Requirement), dated Feb. 3, 2017, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Office Action dated Jun. 2, 2017, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Final Office Action dated Feb. 20, 2018, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Advisory Action dated Jun. 1, 2018, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Office Action dated Aug. 7, 2018, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Final Office Action dated Apr. 1, 2019, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Office Action dated Nov. 27, 2019, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Office Action dated Jan. 31, 2018 issued in U.S. Appl. No. 15/798,287. [cited by applicant]
US Office Action dated May 29, 2018 issued in U.S. Appl. No. 15/798,287. [cited by applicant]
US Notice of Allowance dated Jul. 19, 2018 issued in U.S. Appl. No. 15/798,287. [cited by applicant]
US Office Action dated Sep. 4, 2019 issued in U.S. Appl. No. 16/164,030. [cited by applicant]
US Miscellaneous Communication dated Apr. 22, 2020 issued in U.S. Appl. No. 16/164,030. [cited by applicant]
US Examiner Initiated Interview Summary dated Apr. 23, 2020 issued in U.S. Appl. No. 16/164,030. [cited by applicant]
U.S. Appl. No. 14/253,030 Office Action dated Dec. 9, 2016. [cited by applicant]
U.S. Appl. No. 14/253,030 Response as filed on May 9, 2017. [cited by applicant]
PCT International Search Report and Written Opinion dated Jun. 24, 2014 issued in PCT/US2014/020857. [cited by applicant]
PCT International Report on Patentability and Written Opinion dated Sep. 17, 2015 issued in PCT/US2014/020857. [cited by applicant]
European Extended Search Report dated Jul. 27, 2016 issued in Application No. EP 14 760 467.2. [cited by applicant]
European Office Action dated Aug. 23, 2018 issued in Application No. EP 14 760 467.2. [cited by applicant]
PCT International Search Report and Written Opinion dated Apr. 18, 2017 issued in PCT/US2017/012625. [cited by applicant]
PCT International Preliminary Report on Patentability and Written Opinion dated Jul. 10, 2018 issued in PCT/US2017/012625. [cited by applicant]
European Extended Search Report dated Aug. 7, 2019 issued in Application No. EP 17736481.7. [cited by applicant]
PCT International Search Report and Written Opinion dated Mar. 27, 2019 issued in PCT/US18/67970. [cited by applicant]
Abigerges et al. (1995) “Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.” [cited by applicant]
Al Shamsi et al. (2010) “Biocompatibility of calcined mesoporous silica particles with cellular bioenergetics in murine tissues.” [cited by applicant]
Angelos et al. (2007) “Mesostructured silica supports for functional materials and molecular machines.” [cited by applicant]
Argyo, et al. (2013) “Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery.” [cited by applicant]
Arruebo et al. (2006) “Development of Magnetic Nanostructured Silica-Based Materials as Potential Vectors for Drug-Delivery Applications.” [cited by applicant]
Arruebo et al. (Published Jul. 18, 2006) “Sustained release of doxorubicin from zeolite-magnetite nanocomposited prepared by mechanical activation.” [cited by applicant]
Aryal, et al. (2011) “Polymeric Nanoparticles with Precise Ratiometric Control over Drug Loading for Combination Therapy.” [cited by applicant]
Ashley et al. (2011) “The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.” [cited by applicant]
Ashley et al. (2012) “Delivery of Small Interfering RNA by Peptide-Targeted Mesoporous Silica Nanoparticle-Supported Lipid Bilayers.” [cited by applicant]
Awasthi et al. (2013) “Comparative Benefits of Nab-Paclitaxel over Gemcitabine or Polysor-bate-Based Docetaxel in Experimental Pancreatic Cancer.” [cited by applicant]
Bagwe et al. (Apr. 25, 2006) “Surface Modification of Silica Nanoparticles to Reduce Aggregation and Nonspecific Binding.” [cited by applicant]
Baker et al. (2008) “Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin.” [cited by applicant]
Barbe et al. (2004) “Silica particles: A novel drug-delivery system.” [cited by applicant]
Bardelle (1993) “Membrane binding kinetics of factor VIII indicate a complex binding process.” [cited by applicant]
Bayerl, et al. (1990) “Physical Properties of Single Phospholipid Bilayers Adsorbed to Micro Glass Beads. A New Vesicular Model System Studied by 2H-Nuclear Magnetic Resonance.” [cited by applicant]
Bourzac, K. (2012) “Nanotechnology: Carrying Drugs.” [cited by applicant]
Brigger et al. (2002) “Nanoparticles in cancer therapy and diagnosis.” [cited by applicant]
Brumm et al. (1996) “The effect of increasing membrane curvature on the phase transition and mixing behavior of a dimyristoyl-sn-glycero-3-phosphatidylcholine/distearoyl-sn-glycero-3-phosphatidylcholine lipid mixture as… [cited by applicant]
Buck et al. (2004) “Engineering Lipobeads: Properties of the Hydrogel Core and the Lipid Bilayer Shell” [cited by applicant]
Buranda et al. (2003) “Biomimetic Molecular Assemblies on Glass and Mesoporous Silica Microbeads for Biotechnology” [cited by applicant]
Carmona-Ribeiro (2003) “Bilayer-forming synthetic lipids: drugs or carriers?” [cited by applicant]
Cauda et al. (2010) “Colchicine-Loaded Lipid Bilayer-Coated 50 nm Mesoporous Nanoparticles Efficiently Induce Microtubule Depolymerization upon Cell Uptake” [cited by applicant]
Celano et al. (2004) “Cytotoxic effects of Gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells,” [cited by applicant]
“CHEBI:53581—cetyttrimethylammonium chloride”, Retrieved from the Internet: URL https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:53581, Sep. 11, 2013 (Sep. 11, 2013), Section “Synonyms”. [cited by applicant]
Chemburu et al. (2010) “Biomimetic Silica Microspheres in Biosensing” [cited by applicant]
Chen et al. (2009) “Co-delivery of Doxorubicin and Bcl-2 siRNA by Mesoporous Silica Nanoparticles Enhances the Efficacy of Chemotherapy in Multidrug Resistant Cancer Cells.” [cited by applicant]
Chen, et al. (2014) “Antitumor efficacy of irinotecan-loaded galactosyl modified lipid bilayer-coated mesoporous silica nanoparticles against hepatocellular carcinoma cells.” [cited by applicant]
Cho et al. (2008) “Therapeutic nanoparticles for drug delivery in cancer.” [cited by applicant]
Chou et al. (2003) “Effect of Composition on the stability of liposomal irinotecan prepared by a pH gradient method.” [cited by applicant]
Cosco et al. (2009) “In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer” [cited by applicant]
Davis et al. (2008) “Nanoparticle therapeutics: an emerging treatment modality for cancer.” [cited by applicant]
Davis, M. E., (2009) “The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic.” [cited by applicant]
Dengler et al. (2013) “Mesoporous Silica-Supported Lipid Bilayers (Protocells) for DNA Cargo Delivery to the Spinal Cord.” [cited by applicant]
Dolainsky et al. (1993) “Transverse relaxation in supported and nonsupported phospholipid model membranes and the influence of ultraslow motions: A 31P-NMR study” [cited by applicant]
Drummond et al. (2006) “Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy.” [cited by applicant]
Duncan et al. (2005) “Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer.” [cited by applicant]
Eschwege et al. (1996) “Detection of bilayer phospholipid-binding antibodies using flow cytometry” [cited by applicant]
Federico et al. (2012) “Gemcitabine-Loaded Liposomes: Rationale, Potentialities and Future Perspectives.” [cited by applicant]
Ferrari, M. (2005) “Cancer Nanotechnology: Opportunities and Challenges.” [cited by applicant]
Frese et al. (2012) “Nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer.” [cited by applicant]
Fritze et al. (2006) “Remote loading of doxorubicin into liposomes driven by transmembrane phosphate gradient,” [cited by applicant]
Fuchs et al. (2006) “Irinotecan in the treatment of colorectal cancer.” [cited by applicant]
Gahlyan et al. (2014) “Oral Controlled Release Drug Delivery System—A Review” [cited by applicant]
Gilbert et al. (1992) “Specificity of phosphatidylserine-containing membrane binding sites for factor VIII. Studies with model membranes supported by glass microspheres (lipospheres).” [cited by applicant]
Gorelikov et al. (2008) “Single-step coating of mesoporous silica on cetyltrimethyl ammonium bromide-capped nanoparticles.” [cited by applicant]
Grün et al. (1997) “The Synthesis of Micrometer- and Submicrometer-Size Spheres of Ordered Mesoporous Oxide MCM-41.” [cited by applicant]
Guiotto et al. (2004) “Synthesis, Characterization, and Preliminary in Vivo Tests of New Poly(ethylene glycol) Conjugates of the Antitumor Agent 10-Amino-7-ethylcamptothecin.” [cited by applicant]
Haran et al. (1993) “Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases.” [cited by applicant]
He et al. (2011) “In vivo biodistribution and urinary excretion of mesoporous silica nanoparticles: effects of particle size and PEGylation.” [cited by applicant]
Hetzer et al. (1998) “Asymmetric Molecular Friction in Supported Phospholipid Bilayers Revealed by NMR Measurements of Lipid Diffusion” [cited by applicant]
Jabr-Milane et al. (2008) “Multi-functional nanocarriers to overcome tumor drug resistance.” [cited by applicant]
Jin et al. (1996) “Lipobeads: a hydrogen anchored lipid vesicle system” [cited by applicant]
Junglas et al. (2003) “Molecular Order Parameter Profiles and Diffusion Coefficients of Cationic Lipid Bilayers on a Solid Support” [cited by applicant]
Kasbauer et al. (1999) “Effect of cationic lipids in the formation of asymmetries in supported bilayers.” [cited by applicant]
Katiyar et al. (2006) “Synthesis of ordered large pore SBA-15 spherical particles for adsorption of biomolecules.” [cited by applicant]
Kiser et al. (1998) “A synthetic mimic of the secretory granule for drug delivery” [cited by applicant]
Kiser et al. (2000) “Lipid-coated microgels for the triggered release of doxorubicin” J. Control Release, 68: 9-22. [cited by applicant]
Kneuer et al. (2000) “A nonviral DNA delivery system based on surface modified silica-nanoparticles can efficiently transfect cells in vitro.” [cited by applicant]
Kochy & Bayerl (1993) “Lateral diffusion coefficients of phospholipids in spherical bilayers on a solid support measured by resonance relaxation” [cited by applicant]
Lammers et al. (2010) “Nanomedicine Formulations for Combination Therapies.” [cited by applicant]
Lee et al. (2008) “Synthesis and characterization of positive-charge functionalized mesoporous silica nanoparticles for oral drug delivery of an anti-inflammatory drug.” [cited by applicant]
Li et al. (2012) “Mesoporous silica nanoparticles in biomedical applications.” [cited by applicant]
Li et al. (2013) “Preliminary study on pH-sensitive lipid bilayer-coated mesoporous silica nanoparticles as a novel drug carrier for antitumor drug.” [cited by applicant]
Li et al. (2015) “Multiple Layer-by-Layer Lipid-Polymer Hybrid Nanoparticles for Improved FOLFIRINOX Chemotherapy in Pancreatic Tumor Models.” [cited by applicant]
Lin et al. (2009) “Synthesis and Characterization of Biocompatible and Size-Tunable Multifunctional Porous Silica Nanoparticles.” [cited by applicant]
Linseisen et al. (1996) “2H-NMR and DSC study of DPPC-DODAB mixtures” [cited by applicant]
Linseisen et al. (1997) “Differences in the Physical Properties of Lipid Monolayers and Bilayers on a Spherical Solid Support.” [cited by applicant]
Liong et al. (2008) “Multifunctional inorganic nanoparticles for imaging, targeting and drug delivery.” [cited by applicant]
Liong et al. (2009) “Mesostructured Multifunctional Nanoparticles for Imaging and Drug Delivery.” [cited by applicant]
Liu et al. (2009) “Electrostatically Mediated Liposome Fusion and Lipid Exchange with a Nanoparticle-Supported Bilayer for Control of Surface Charge, Drug Containment, and Delivery.” [cited by applicant]
Liu et al. (2009) “Porous Nanoparticle Supported Lipid Bilayers (Protocells) as Delivery Vehicles,” [cited by applicant]
Liu et al. (2012) “Delivering hydrophilic and hydrophobic chemotherapeutics simultaneously by magnetic mesoporous silica nanoparticles to inhibit cancer cells” [cited by applicant]
Liu et al. (2016) “Irinotecan delivery by lipid-coated mesoporous silica nanoparticles shows improved efficacy and safety over liposomes for pancreatic cancer.” [cited by applicant]
Liu et al. (2016) “Irinotecan delivery by lipid-coated mesoporous silica nanoparticles shows improved efficacy and safety over liposomes for pancreatic cancer.” [cited by applicant]
Loidl-Stahlhofen et al. (2001) “Multilamellar liposomes and solid-supported lipid membranes (TRANSIL): screening of lipid-water partitioning toward a high-throughput scale” [cited by applicant]
Loidl-Stahlhofen et al. (2001) “Solid-Supported Biomolecules on Modified Silica Surfaces—A Tool for Fast Physicochemical Characterization and High-Throughput Screening” [cited by applicant]
Loidl-Stahlhofen et al. (2001) “Solid-supported lipid membranes as a tool for determination of membrane affinity: High-throughput screening of a physicochemical parameter.” [cited by applicant]
Loidl-Stahlhofen et al. (1996) “The thermodynamic control of protein binding to lipid bilayers for protein chromatography” [cited by applicant]
Lu et al. (2007) “Mesoporous silica nanoparticles as a delivery system for hydrophobic anticancer drugs.” [cited by applicant]
Ma et al. (2013) “Nanoparticles for Combination Drug Therapy.” [cited by applicant]
Mackowiak et al. (2013) “Targeted Drug Delivery in Cancer Cells with Red-Light Photoactivated Mesoporous Silica Nanoparticles.” [cited by applicant]
Mai et al. (2013) “Mesoporous Silica Nanoparticles: A Multifunctional Nano Therapeutic System.” [cited by applicant]
Mayer et al. (2007) “Optimizing Combination Chemotherapy by Controlling Drug Ratios.” [cited by applicant]
Meng et al. (2006) “A Family of Highly Ordered Mesoporous Polymer Resin and Carbon Structures from Organic-Organic Self-Assembly.” [cited by applicant]
Meng et al. (2010) “Autonomous in Vitro Anticancer Drug Release from Mesoporous Silica Nanoparticles by pH-Sensitive Nanovalves.” [cited by applicant]
Meng et al. (2010) “Engineered Design of Mesoporous Silica Nanoparticles to Deliver Doxorubicin and P-Glycoprotein siRNA to Overcome Drug Resistance in a Cancer Cell Line,” [cited by applicant]
Meng et al. (2010) “Potent Angiogenesis Inhibition by the Particulate Form of Fullerene Derivatives.” [cited by applicant]
Meng et al. (2011) “Aspect Ratio Determines the Quantity of Mesoporous Silica Nanoparticle Uptake by a Small GTPase-Dependent Macropinocytosis Mechanism,” [cited by applicant]
Meng et al. (2011) “Use of Size and a Copolymer Design Feature To Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin Loaded Mesoporous Silica Nanoparticles in a Murine Xenograf… [cited by applicant]
Meng et al. (2012) “Development of Pharmaceutically Adapted Mesoporous Silica Nanoparticles Platform.” [cited by applicant]
Meng et al. (2013) “Codelivery of an Optimal Drug/siRNA Combination Using Mesoporous Silica Nano-particles To Overcome Drug Resistance in Breast Cancer in Vitro and in Vivo.” [cited by applicant]
Meng et al. (2013) “Two-Wave Nanotherapy to Target the Stroma and Optimize Gemcitabine Delivery to a Human Pancreatic Cancer Model in Mice,” [cited by applicant]
Meng et al. (2015) “Use of a Lipid-Coated Mesoporous Silica Nanoparticle Platform for Synergistic Gemcitabine and Paclitaxel Delivery to Human Pancreatic Cancer in Mice” [cited by applicant]
Messerer et al. (2004) “Liposomal Irinotecan: Formulation Development and Therapeutic Assessment in Murine Xenograft Models of Colorectal Cancer.” [cited by applicant]
Miao et al. (2014) “Nanoparticles with Precise Ratiometric Co-loading and Co-delivery of Gemcitabine Monophosphate and Cisplatin for Treatment of Bladder Cancer.” [cited by applicant]
Moore et al. (2007) “Erlotinib Plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group.” [cited by applicant]
Mornet, et al. (2005) “The Formation of Supported Lipid Bilayers on Silica Nanoparticles Revealed by Cryoelectron Microscopy.” [cited by applicant]
Moura & Carmona-Ribeiro (2003) “Cationic Bilayer Fragments on Silica at Low Ionic Strength: Competitive Adsorption and Colloid Stability” [cited by applicant]
Moura & Carmona-Ribeiro (2005) “Biomimetic Particles: Optimization of Phospholipid Bilayer Coverage on Silica and Colloid Stabilization” [cited by applicant]
Naumann et al. (1992) “Phase transition behavior of single phosphatidylcholine bilayers on a solid spherical support studied by DSC, NMR and FT-IR” [cited by applicant]
Ng et al. (2001) “One-Step Synthesis of a Fluorescent Phospholipid-Hydrogel Conjugate for Driving Self-Assembly of Supported Lipid Membranes” [cited by applicant]
Ng et al. (2004) “Properties of a Self-Assembled Phospholipid Membrane Supported on Lipobeads” [cited by applicant]
Nordlund et al. (2009) “Formation of supported lipid bilayers on silica particles studied using flow cytometry.” [cited by applicant]
Obringer et al.(1995) Antiphospholipid antibody binding to bilayer-coated glass microspheres [cited by applicant]
Onishi et al. (2003) “Antitumor Properties of Irinotecan-Containing Nanoparticles Prepared Using Poly(DL-lactic acid) and Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol).” [cited by applicant]
Onivyde (irinotecan liposome injection)—Highlights of Prescribing Information—Reference ID: 3836766; 18 pages [accessed Oct. 23, 2015]. Retrieved from the Internet, URL: https://www.accessdata.fda.gov/drugsatfda_docs/la… [cited by applicant]
Park et al. (2004) “Characterization of radioligand binding to a transmembrane receptor reconstituted into Lipobeads” [cited by applicant]
Pasqua et al. (Published online Feb. 3, 2007) “Preparation of bifunctional hybrid mesoporous silica potentially useful for drug targeting.” [cited by applicant]
Patil et al. (2010) “Use of nanoparticle mediated gene silencing and drug delivery to overcome tumor drug resistance.” Biomaterials 31:358-365. [cited by applicant]
Pearse et al. (1987) “Structure and assembly of coated vesicles.” [cited by applicant]
Peer, et al. (2007) “Nanocarriers as an Emerging Platform for Cancer Therapy.” [cited by applicant]
Piyasena et al. (2008) “Biosensors based on release of compounds upon disruption of lipid bilayers supported on porous microspheres.” [cited by applicant]
Ramsay et al. (2008) “A novel liposomal irinotecan formulation with significant anti-tumour activity: Use of the divalent cation ionophore A23187 and copper-containing liposomes to improve drug retention.” [cited by applicant]
Rapuano & Carmona-Ribeiro (1997) “Physical Adsorption of Bilayer Membranes on Silica” [cited by applicant]
Rapuano & Carmona-Ribeiro (2000) “Supported Bilayers On Silica” [cited by applicant]
Reinl & Bayerl (1993) “Interaction of myelin basic protein with single bilayers on a solid support: an NMR, DSC and polarized infrared ATR study” [cited by applicant]
Reinl & Bayerl (1994) “Lipid Transfer between Small Unilamellar Vesicles and Single Bilayers on a Solid Support: Self-Assembly of Supported Bilayers with Asymmetric Lipid Distribution” [cited by applicant]
Roggers et al. (2012) “Chemically Reducible Lipid Bilayer Coated Mesoporous Silica Nano-particles Demonstrating Controlled Release and HeLa and Normal Mouse Liver Cell Biocompatibility and Cellular Internalization.” [cited by applicant]
Roiter et al. (2008) “Interaction of Nanoparticles with Liquid Membrane.” [cited by applicant]
Saad et al. (2008) “Co-delivery of siRNA and an anticancer drug for treatment of multi-drug resistant cancer.” [cited by applicant]
Sachae et al. (2017) “Surfactant-Templating of Zeolites: From Design to Application” [cited by applicant]
Sackmann, E. (1996) “Supported Membranes: Scientific and Prac-tical Applications.” [cited by applicant]
Sadzuka et al. (1998) “Effect of liposomalization on the antitumor activity, side-effects and tissue distribution of CPT-11.” [cited by applicant]
Santos et al. (2009) “The Power of Ultrasound”, [cited by applicant]
Schmitt et al. (2001) “Polymer Cushions in Supported Phospholipid Bilayers Reduce Significantly the Frictional Drag between Bilayer and Solid Surface” [cited by applicant]
Schmitz et al. (1999) “Interactions of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS)-Related Protein with a Novel Solid-Supported Lipid Membrane System (TRANSIL)” [cited by applicant]
Schuhmacher et al. (2004) “High-throughput determination of the free fraction of drugs strongly bound to plasma proteins.” [cited by applicant]
Sharma et al. (2004) “Bacteriorhodopsin conjugates as anchors for supported membranes.” [cited by applicant]
Shidhaye et al. (2008) “Nanogel Engineered Polymeric Micelles for Drug Delivery.” [cited by applicant]
Singh et al. (2008) “Nanoengineering artificial lipid envelopes around adenovirus by self-assembly.” [cited by applicant]
Slowing et al. (2008) “Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers.” [cited by applicant]
Sommerwerk et al. (2011) “Lipid Coated Chitosan Micro-particles as Protein Carriers.” [cited by applicant]
Sugahara et al. (2010) “Coadministration of a tumor-penetrating peptiden enhances the efficacy fo cancer drugs.” [cited by applicant]
Szakacs et al. (2006) “Targeting multidrug resistance in cancer.” [cited by applicant]
Tamanoi “Nanodelivery: Towards controlled release of anti-cancer drugs.” Oral Presentation on Dec. 6, 2006 (see NanoBio-Tokyo 2006 Program), 7 pages. Abstract provided in Proceedings of UT Symposium on NanoBio Integrati… [cited by applicant]
Tang et al. (2012) “Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery.” [cited by applicant]
Tardi et al. (2009) “In Vivo Maintenance of Synergistic Cytarabine: Daunorubicin Ratios Greatly Enhances Therapeutic Efficacy.” [cited by applicant]
Tarn et al. (2013) “Mesoporous Silica Nanoparticle Nanocarriers: Biofunctionality and Biocompatibility.” [cited by applicant]
Thorolfsson et al. (2002) “The binding of tyrosine hydroxylase to negatively charged lipid bilayers involves the N-terminal region of the enzyme.” [cited by applicant]
Torney et al. (2007) “Mesoporous silica nanoparticles deliver DNA and chemicals into plants.” [cited by applicant]
Troutier & Lada Viere (2007) “An overview of lipid membrane supported by colloidal particles.” [cited by applicant]
Valencia et al. (2013) “Synergistic cytotoxicity of irinotecan and cisplatin in dual-drug targeted polymeric nanoparticles.” [cited by applicant]
Van Schooneveld et al. (2008) “Improved Biocompatibility and Pharmacokinetics of Silica Nanoparticles by Means of a Lipid Coating: A Multimodality Investigation.” [cited by applicant]
Van Vlerken et al. (2007) “Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer.” [cited by applicant]
Von Hoff et al. (2011) “Gemcitabine Plus Nab-Paclitaxel Is an Active Regimen in Patients with Advanced Pancreatic Cancer: A Phase I/II Trial.” [cited by applicant]
Von Hoff et al. (2013) “Increased Survival in Pancreatic Cancer with Nab-Paclitaxel Plus Gemcitabine.” [cited by applicant]
Wu et al. (2007) “Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil.” [cited by applicant]
Xia et al. (2009) “Polyethyleneimine Coating Enhances the Cellular Uptake of Mesoporous Silica Nanoparticles and Allows Safe Delivery of siRNA and DNA Constructs.” [cited by applicant]
Xu et al. (2013) “Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice.” [cited by applicant]
Yang et al. (2010) “Lipid Coated Mesoporous Silica Nanoparticles as Photosensitive Drug Carriers.” [cited by applicant]
Yezhelyev et al. (2008) “Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging.” [cited by applicant]
Zhang et al. (2011) “Synergistic Antitumor Activity of Gemcitabine and ABT-737 in Vitro and in Vivo through Disrupting the Interaction of USP9X and Mcl-1.” [cited by applicant]
Zhang et al. (2013) “Facile Large-Scale Synthesis of Monodisperse Mesoporous Silica Nanospheres with Tunable Pore Structure” [cited by applicant]
Zhang et al. (2014) “Biofunctionalized polymer-lipid supported mesoporous silica nanoparticles for release of chemotherapeutics in multidrug resistant cancer cells.” [cited by applicant]
Zhu et al. (2004) “Poly(L-lysine)-modified silican nanoparticles for the delivery of anitsense oligonucleotides.” [cited by applicant]
Zucker et al. (2009) “Liposome drugs' loading efficiency: A working model based on loading conditions and drug's physicochemical properties.” [cited by applicant]
US Notice of Allowance dated Jun. 22, 2020, issued in U.S. Appl. No. 14/772,740. [cited by applicant]
US Notice of Allowance dated May 6, 2020, issued in U.S. Appl. No. 16/164,030. [cited by applicant]
European 2nd Office Action dated May 26, 2020 issued in Application No. EP 14 760 467.2. [cited by applicant]
PCT International Preliminary Report on Patentability and Written Opinion dated Jul. 7, 2020 issued in PCT/US18/67970. [cited by applicant]
Chen, et al. (2014) “Antitumor efficacy of irinotecan-loaded galactosyl modified lipid bilayer-coated mesoporous silica nanoparticles against hepatocellular carcinoma cells.” [cited by applicant]
Li et al. (2013) “Preliminary study on pH-sensitive lipid bilayer-coated mesoporous silica nanoparticles as a novel drug carrier for antitumor drug.” [cited by applicant]
U.S. Appl. No. 16/947,539, filed Aug. 5, 2020, Nel et al. [cited by applicant]
U.S. Appl. No. 16/948,498, filed Sep. 21, 2020, Nel et al. [cited by applicant]
US Office Action dated Sep. 9, 2020, issued in U.S. Appl. No. 16/947,539. [cited by applicant]
US Notice of Allowance dated Apr. 21, 2021 issued in U.S. Appl. No. 16/947,539. [cited by applicant]
Australian Office Action dated Dec. 17, 2020 issued in AU 2017206077. [cited by applicant]
Chinese Office Action dated Aug. 14, 2020 issued in CN 201780010248.8. [cited by applicant]
Chinese 2nd Office Action dated May 17, 2021 issued in CN 201780010248.8. [cited by applicant]
Japanese Office Action dated Oct. 5, 2020 issued in JP 2018-535362. [cited by applicant]
Korean Office Action dated May 18, 2021 issued in KR 10-2018-7022622. [cited by applicant]
CN Office Action dated Jan. 30, 2022, in Application No. CN201780010248.8 with English translation. [cited by applicant]
Co-pending U.S. Appl. No. 17/384,214, filed Jul. 23, 2021. [cited by applicant]
Daqing Li., et al., “Critical Micelle Concentrations of Cetyltrimethylammonium Chloride and Their Influence on the Periodic Structure of Mesoporous Silica”, Colloid Journal of The Russian Academy of Science—Kolloidnyyie… [cited by applicant]
EP Partial Supplemental Search Report dated Nov. 11, 2021 in EP Application No. 18897783.9. [cited by applicant]
European 3rd Office Action dated Sep. 2, 2021 issued in Application No. EP 14 760 467.2. [cited by applicant]
Extended European Search Report dated Mar. 15, 2022, in Application No. 18897783.9. [cited by applicant]
Japanese 2nd Office Action dated Aug. 2, 2021 issued in JP 2018-535362. [cited by applicant]
AU Office action dated May 22, 2023, in AU Application No. AU2022200881. [cited by applicant]
CA Office Action dated Oct. 24, 2023, in Application No. CA3010711. [cited by applicant]
EP Extended European Search Report dated Jul. 11, 2023, in Application No. 23158990.4. [cited by applicant]
JP Office Action dated Apr. 17, 2023 in Application No. JP2022-72344 with English translation. [cited by applicant]
JP Office Action dated Oct. 16, 2023 in Application No. JP2022-72344 with English translation. [cited by applicant]
KR Office Action dated Mar. 22, 2023 in Application No. KR10-2022-7019372 with English translation. [cited by applicant]
KR Office Action dated Sep. 25, 2023 in Application No. KR10-2022-7019372 with English translation. [cited by applicant]
U.S. Non-Final Office Action dated Aug. 22, 2023, in U.S. Appl. No. 16/948,498. [cited by applicant]
U.S. Non-Final Office Action dated Jul. 24, 2023, in U.S. Appl. No. 17/384,214. [cited by applicant]
U.S. Notice of Allowance dated Nov. 17, 2023 in U.S. Appl. No. 16/948,498. [cited by applicant]