WO2020217231A2 - Nanosystème magnétique et procédé de production du nanosystème - Google Patents

Nanosystème magnétique et procédé de production du nanosystème Download PDF

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WO2020217231A2
WO2020217231A2 PCT/IB2020/053947 IB2020053947W WO2020217231A2 WO 2020217231 A2 WO2020217231 A2 WO 2020217231A2 IB 2020053947 W IB2020053947 W IB 2020053947W WO 2020217231 A2 WO2020217231 A2 WO 2020217231A2
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magnetic
nanosystem
nanoparticles
lipid
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WO2020217231A3 (fr
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Ana Rita OLIVEIRA RODRIGUES
Daniela Sofia MARQUES PEREIRA
Beatriz DIAS CARDOSO
Elisabete Maria DOS SANTOS CASTANHEIRA COUTINHO
Paulo José GOMES COUTINHO
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Universidade do Minho
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • the present application relates to a magnetic nanosystem and method to produce the nanosystem.
  • cancer is one of the main causes of death in the world, with an estimated 7.6 million deaths per year and a predicted increase to 13.1 million by 2030 (Singh, 2008) .
  • the main obstacles in the fight against cancer include (i) the absence of effective biomarkers in diagnosis and prognosis; (ii) invasive diagnostic and treatment methods; (iii) reduced epigenetic profile; (iv) lack of individualized treatments; (v) limitations associated with existing chemotherapeutic agents and (vi) the occurrence of metastases.
  • Such systems can improve the properties of the therapeutic drug molecules and their pharmacokinetics by increase half time circulation (acting as a stealth nanocarrier to the immune system) and to overcome certain biological barriers, such as the blood-brain barrier (Pradhan, 2010; Caban, 2014) .
  • the application of these nanomaterials in the treatment of cancer has already shown to improve drugs behavior.
  • the first success in nanomedicine research was the approval of liposomal doxorubicin for clinical use (Doxil ® approved in 1995) .
  • liposome-based products have been approved for cancer therapy, such as DaunoXome ® approved in 1996, Depocyt ® approved in 1999, Myocet ® approved in 2000, Mepact ® approved in 2004, Marqibo ® approved in 2012 and OnivydeTM approved in 2015.
  • liposome-based products have shown an improvement in therapeutic drug molecules pharmacokinetics
  • active targeting approaches has been exploited in order to enhance a specific interaction with cancer cells. Consequently, specific ligands and surface moieties have been investigated for the efficient nanocarriers internalization by active targeting, namely, folate or transferrin receptors, glycoproteins, EGFR (epidermal growth factor receptor) and ssDNA or RNA aptamers (single-stranded nucleic acid oligonucleotides which bind to their targets with high specificity and affinity) .
  • active targeting namely, folate or transferrin receptors, glycoproteins, EGFR (epidermal growth factor receptor) and ssDNA or RNA aptamers (single-stranded nucleic acid oligonucleotides which bind to their targets with high specificity and affinity) .
  • active targeting namely, folate or transferrin receptors, glycoproteins, EGFR (epidermal growth factor
  • Magnetic nanoparticles location can be controlled by the use of an external magnetic field gradient and heat can be produced by these nanoparticles under an alternate magnetic field.
  • nanoparticles with superparamagnetic behavior are of major interest because they only present magnetization in the presence of an external magnetic field. The fact that they do not present permanent magnetism shows itself as an added value, since it prevents their aggregation (in the absence of a magnetic field) . Based on this, magnetic nanoparticles are very desirable for target drug delivery and hyperthermia.
  • Magnetic fluid hyperthermia is a therapeutic approach in which the patient is subjected to electromagnetic waves with frequencies in the order of 100 to 1000 kHz and fields between 150 and 250 Gauss.
  • This stimulus incites the heat production by the nanoparticles and increase tumor tissue temperature (between 43 ° C and 46 ° C) in order to interrupt the processes of regulation and growth of tumor cells. At these temperatures, heat causes structural damage to tumor cells leading to apoptosis. In addition to direct cell damage, hyperthermia may induce a synergistic effect with chemotherapy and radiotherapy, as cells become more sensitive to these treatments.
  • the FDA approved magnetic nanoparticles are mainly for magnetic resonance imaging (Feridex ® and Lumirem ® ) and chronic kidney disease (Venofer ® , Ferrlecit ® , INFeD ® and Dexlron ® ) .
  • the Nanotherm ® therapy was the first magnetic nanoparticle-based therapy approved (2010) and uses biocompatible aminosilane-coated superparamagnetic iron oxide nanoparticles in for Glioblastoma treatment. Magnetic nanoparticles present some issues related to their accumulation, degradation and clearance.
  • magneto-sensitive liposomes In order to overcome the problems of liposomes and magnetic nanoparticles, magneto-sensitive liposomes have been proposed, combining the advantages of both. Magnetoliposomes are known for their potential in the field of cancer diagnosis and therapy.
  • Therapeutic drug molecules can be encapsulated into liposomes by either passive loading or active loading. In passive loading the drugs are encapsulated during the formation of liposomes, in which lipophilic drugs are entrapped in the lipid bilayer and hydrophilic drugs in the aqueous compartment. In active loading, drug molecules are loaded into preformed liposomes.
  • This process is driven by an electrochemical potential created by the pH or ion gradients established across the lipid bilayer of the liposomes, which are created during liposomes preparation by using a buffer of specified pH and ion concentration.
  • This nanosystem has the capacity to encapsulate, transport and release drugs due to its ability to generate heat (when subjected to an alternating magnetic field) combined with the thermo-sensibility of lipid bilayer composition.
  • magnetoliposomes offer several advantages in oncology, such as guiding capabilities (using a permanent magnetic field) , magnetic stimulus controlled release and hyperthermia.
  • magnetoliposomes promote improved release of the drug in a tissue of interest, offer the possibility of combined therapy (chemotherapy and hyperthermia) and deeper intracellular penetration of drugs in the tumor environment.
  • chemotherapy and hyperthermia combined therapy
  • the major drawback regarding this type of nanosystems remains on the final magnetic behavior of the magnetoliposomes. This occurs since the ratio between the magnetic and the non magnetic components decrease (after magnetic nanoparticle encapsulation into the liposomes), compromising the magnetic nanosystems overall magnetic behavior.
  • This product is based on ferrite and mixed ferrite nanoparticles of alkaline earth metals (magnesium, calcium and strontium, ) , being strong, highly biocompatible candidates due to their decreased oxidation rate and, consequently, less radical oxygen species (ROS) production.
  • alkaline earth metals magnesium, calcium and strontium,
  • magnetoliposomes are not simple or expedite and the resulting insufficient magnetic properties compromise their therapeutic efficacy.
  • New approaches in which coating occurs only after nanoparticles synthesis, have been drawn to improve the magnetism of the magnetoliposomes.
  • these routes are either long in time or complex. For instance, a dialysis procedure can take up to two days and does not have the proper control of magnetoliposomes diameters and size distribution. Thin film hydration has been one of the most used protocols, however, it is reported that it can form multilamellar structures, display low drug encapsulation efficiency and cannot control the diameter and size distribution of the synthesized structures.
  • nanoparticles synthesis and lipid bilayer are formed at the same time.
  • the calcination step an additional procedure that improve magnetic properties of nanoparticles
  • the nanoparticles used in this type of nanosystem typically possess a spherical structure.
  • non-spherical structures e.g. prisms, rods, cubes
  • the present solution describes a route for the synthesis of a new generation of magnetoliposomes for better therapeutic effect.
  • the synthesized magnetic nanoparticles present, preferably, inherent higher shape anisotropy, which translate in a better magnetic response and heating capabilities.
  • the calcination step is independent of nanoparticles encapsulation into liposomes, the nanosystems overall magnetic behavior is ensured by this additional procedure.
  • the present solution for nanoparticles encapsulation ensure that the final product possess a well- defined morphology, size distribution and that the magnetic behavior is similar to net nanoparticles, by increasing the ratio between the magnetic and non-magnetic components of the final structure.
  • lipid bilayer comprising dipalmitoylphosphatidylcholine lipids, surrounding an
  • the magnetoliposomes have a size between 100 and 200 nm.
  • the inner magnetic core comprises superparamagnetic nanoparticles with particle sizes between 1 and 100 nm.
  • the superparamagnetic nanoparticles have a spherical shape, cubic shape or flower shape. In yet another embodiment the superparamagnetic nanoparticles are made of metal oxide composed by alkaline earth metals.
  • the superparamagnetic nanoparticles are ferrite magnetic particles composed by the metals of magnesium and calcium.
  • the ferrite magnetic nanoparticles further comprise alkaline earth metals of strontium (Sr), Calcium (Ca) and Magnesium (Mg), alone or in combination.
  • the lipid bilayer is composed by a lipid formulation with transition temperatures between 40 and 45°C .
  • the lipid bilayer formulation further comprises phospholipid molecules such as phosphatidylcholine, phosphatidylethanolamine , phosphatidylserine , phosphatidylglycerol , phosphatidic acid, phosphatidylinositol , sphingomyelin, alone or in combination.
  • phospholipid molecules such as phosphatidylcholine, phosphatidylethanolamine , phosphatidylserine , phosphatidylglycerol , phosphatidic acid, phosphatidylinositol , sphingomyelin, alone or in combination.
  • the lipid bilayer formulation further comprises cholesterol.
  • the lipid bilayer formulation further comprises pH sensitive lipids such as cholesteryl hemisuccinate, N- ( 4-carboxybenzyl ) -N, N-dimethyl-2 , 3- bis (oleoyloxy) propan-l-aminium, 1, 2-dipalmitoyl-sn-glycero- 3-succinate, 1 , 2-dioleoyl-sn-glycero-3-succinate and N- palmitoyl homocysteine.
  • the surface of the lipid bilayer is functionalized with polyethylene glycol.
  • the surface of the lipid bilayer is further functionalized with permeability inducing ligands such as bradykinin, vascular permeability factor/endothelial growth factor, Prostaglandins, Collagenase, Peroxynitrite, Tumor necrosis factor-a.
  • permeability inducing ligands such as bradykinin, vascular permeability factor/endothelial growth factor, Prostaglandins, Collagenase, Peroxynitrite, Tumor necrosis factor-a.
  • the therapeutic drug molecules are located inside the lipid bilayer if the drug molecules are hydrophobic .
  • the therapeutic drug molecules are located in the hydrophilic compartment of the magnetoliposome if the drug molecules are hydrophilic.
  • the surface of the lipid bilayer is functionalized with active targeting molecules.
  • the present application further relates to a method of producing the magnetic nanosystem, comprising the following steps :
  • the superparamagnetic nanoparticles are added to the lipid formulation, in an iron concentration between 20 mg/ml and 180 mg/ml;
  • the solution is ultrasonicated for a time between 15 min and 60 min;
  • the resulting magnetoliposomes are washed and purified with ultrapure water by magnetic decantation.
  • the superparamagnetic nanoparticles are added to the lipid formulation in a concentration between 5xlCh 4 M and 2xlCh 5 M with a percentage of water between 0.005% and 1 % .
  • the superparamagnetic nanoparticles are added to the lipid formulation in a concentration between 5xl0 4 M and 2xl0 5 M with a percentage of water between 1 and 5% .
  • the surfactant is selected from Triton X-100, AOT , SDS and CTAB .
  • the nonpolar solvent is selected from hexane, heptane, octane, decane, dodecane, chloroform, cyclohexane, toluene, benzene.
  • the first lipid formulation has a concentration between 0.01 mg/mL and 10 mg/mL.
  • the second lipid formulation has a concentration between 0.05 mM and 1.5 mM.
  • cholesterol and/or active targeting molecules and/or polyethylene glycol are added to the lipid formulations .
  • the present application further relates to a method to prepare cubic shaped superparamagnetic nanoparticles of the nanosystem, comprising the following steps:
  • the present application also relates to a method to prepare flower shaped superpara agnetic nanoparticles of the nanosystem, comprising the following steps:
  • the mixture is heated to 90°C for a time range between 2 and 4 h;
  • the final product is washed with a basic solution of 1 M sodium hydroxide, by several cycles of centrifugation, aqueous redispersion and magnetic decantation;
  • the nanoparticles are calcined preferably between 300°C and 800°C for a time range between 1 h and 4 h.
  • the present application relates to a magnetic nanosystem comprising :
  • lipid bilayer that can be sensitive to temperature, pH, among other properties
  • an inner magnetic core comprising nanoparticles of alkaline earth metal mixed ferrite, either composed of a magnetic fluid or a nanoparticle cluster;
  • Magnetoliposomes are nanocarriers based on liposomes entrapping magnetic nanoparticles. They consist of an inner magnetic nanoparticles part, either a cluster of nanoparticles or a magnetic fluid, covered by a lipid bilayer. Lipid composition can be manipulated according to the cancer family type and microenvironment specific requirements.
  • aqueous magnetoliposomes consist in an aqueous magnetic nanoparticles solution entrapped in the liposomes hydrophilic compartment, which result from self-assembling, an inherent behaviour of the phospholipids when in contact with nanoparticles aqueous solutions.
  • AMLs are especially useful to encapsulate hydrophilic drug molecules.
  • AML's are produced when the inner core of the magnetoliposomes is formed by magnetic nanoparticles and a high percentage of water, between 1% and 5%.
  • solid magnetoliposomes consist in a magnetic nanoparticles cluster covered with a lipid bilayer, as a result of the interaction of the polar head group of the phospholipids with the magnetic nanoparticles cluster. This interaction can either be covalent bonding, electrostatic attraction, Van der Waals interactions or by the balance between the hydrophilic and hydrophobic forces. SMLs present a pronounced magnetic behaviour and a better therapeutic effect. They are more easily guided, present a higher temperature range, provide more drug release and better hyperthermia effect. SMLs are produced when the inner core of the magnetoliposomes is formed by magnetic nanoparticles and a reduced percentage of water, between 0.005% and 1%, or no presence of water.
  • Magnetoliposomes can be loaded with one type, or more than one type of molecules, particularly therapeutic drugs, including but not limited to chemotherapeutic drugs, prodrugs, DNA, proteins, antibiotics, anti-inflammatory and inflammatory agents, diagnostic and theranostic compounds.
  • the nanosystem Upon administration, the nanosystem has the ability to protect the encapsulated drugs, preserving their bioactive action. Also, it improves the pharmacokinetics and enables magnetic guidance to the site of interest through a magnetic field gradient (physical active targeting) .
  • the surface of the nanosystem can be functionalized in order to mask it from the reticuloendothelial system (RES) for increased circulation time and make the nanosystem sensitive to trigger release.
  • RES reticuloendothelial system
  • the nanosystem After reaching the target area, the nanosystem interacts with the cancer cells, by specific ligand-receptor interaction, it is internalized through endocytosis or membrane fusion.
  • the tumor microenvironment physiological conditions such as acidic pH
  • the thermo-sensibility of the nanosystems destabilize the nanosystem lipid bilayer leading to the controlled payload release, thus increasing drug concentration on target site.
  • Figure 1 illustrates four representations of the nanosystem of the present technology, wherein the reference numbers mean: A - Magnetic nanosystem comprising a lipid formulation, encapsulating a therapeutic drug molecule;
  • B- Magnetic nanosystem comprising a lipid formulation based with cholesterol, encapsulating a therapeutic drug molecule
  • C- Magnetic nanosystem comprising a lipid formulation with cholesterol and PEG-lipid conjugates, encapsulating a therapeutic drug molecule and functionalized with an active targeting ligand;
  • D- Magnetic nanosystem comprising a lipid formulation with cholesterol, encapsulating a therapeutic drug molecule and functionalized with an active targeting ligand;
  • reference numbers are: 1 - Inner magnetic core; 2 - Therapeutic drug molecule; 3 - Lipid; 4 - Cholesterol molecule; 5 - pH-sensitive lipid; 6 - Active targeting molecule; 7 - PEG-lipid conjugates.
  • Figure 2 illustrates a solid magnetoliposome with flower-like nanoparticles .
  • Figure 3 illustrates a solid magnetoliposome with cubic nanoparticles .
  • the present application describes a magnetic nanosystem based on superparamagnetic nanoparticles and the method to produce the nanosystems.
  • High shape-anisotropic superparamagnetic nanoparticles which is the preferred magnetic component of the magnetic nanosystems, have an improved magnetic response and heating capabilities compared with conventional spherical ones.
  • This method ensures that the superpara agnetic nanoparticles incorporation does not affect the nanosystems overall magnetic behavior, keeping it slightly the same as the net superparamagnetic nanoparticles. It also guarantees the synthesis of magnetic nanosystems with a size range between 100 and 200 nanometers and a reduced polydispersity index .
  • thermo-sensible magnetoliposomes are a very promising multifunctional nanosystem. Additionally to the magnetic guidance ability, the superparamagnetic nanoparticles heating capabilities induces drug release and synergistic cytotoxic effect in cancer cells (combined chemotherapy and hyperthermia) .
  • the present application relates to a nanosystem comprising:
  • an inner magnetic core (1) composed by a cluster of superparamagnetic nanoparticles, regarding SMLs, or an aqueous magnetic solution of superparamagnetic nanoparticles, regarding AMLs;
  • thermo-sensible lipid bilayer (3) composed by a lipid formulation with transition temperatures between 40°C and 45°C, preferably between 41°C and 43°C, that surrounds the magnetic core in both AMLs or SMLs;
  • thermo-sensible lipid bilayer formulation can optionally include pH-sensitive lipids (5), in order to make pH-sensitive nanosystems that are stable at physiological pH but are destabilized at acidic cancer microenvironment, inducing the release of drugs in situ;
  • encapsulated therapeutic drug molecules (2) that can be located inside the lipid bilayer (if the drug molecules are hydrophobic) or in the hydrophilic component of the nanosystem (if the drug molecules are hydrophilic);
  • the surface is functionalized with active targeting molecules (6);
  • the surface is functionalized with polyethylene glycol (PEG) molecules in a process in which PEG molecules are covalently attached to the surface of preformed magnetoliposomes or by including PEG-lipid conjugates (7) in the mixture of lipids in magnetoliposomes preparation.
  • PEG polyethylene glycol
  • the terms “payload” means the segment of content localized in the lipid bilayer of the nanosystem.
  • drug designates a polymeric or non-polymeric organic chemical, a nucleic acid or an oligonucleotide, a peptide or a peptidomimetic or a protein, antibody, growth fragment or a fragment thereof presenting a linear or cyclic conformation, or a non-naturally occurring compound.
  • ligand designate molecules that are attached to the lipid bilayer surface in order to promote the effective active targeting to a specific subset cell tissue.
  • tumor tissue
  • cancer cancer
  • neoplasia are generic terms that define a broad range of diseases characterized by the uncontrolled proliferation of cells of a given tissue or organ as a result of genetic or epigenetic changes in somatic cells.
  • nanosystem represents the combination of the single components (liposomes and superparamagnetic nanoparticles) in an integrated whole that can interact with the target tissue.
  • the intrinsic guiding capabilities of the present technology rely on the active physical targeting (magnetic) due to the presence of the magnetic nanoparticles and on the passive targeting because of the enhanced retention and permeability (EPR) effect. Therefore, the absence of chemical active targeting molecules does not compromise guiding capabilities. Yet, optionally, these active targeting molecules can be linked through covalent bonding to the lipid bilayer surface in order to improve the therapeutic effect in specific microenvironments .
  • lipid formulations can be used, alone or in combination, including but not limited to, phospholipid molecules such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl serine (PS), phosphatidylglycerol (PG) , phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SPM) .
  • phospholipid molecules such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl serine (PS), phosphatidylglycerol (PG) , phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SPM) .
  • the phospholipids can be either synthetic or derived from natural sources such as egg or soy.
  • the liposome formulations comprise dipalmitoylphosphatidylcholine (DPPC) , which has an ideal transition temperature for physical drug release.
  • DPPC dipalmitoylphosphatidylcholine
  • lipids are added to the liposome formulation in order to modulate, for instance, content release, prolong circulation time, etc.
  • thermo-sensitive liposome formulations are originally composed by dipalmitoylphosphatidylcholine (DPPC) and 1 , 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), in a molar ratio of 3:1.
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC 2-distearoyl-sn-glycero-3-phosphocholine
  • the lipid bilayer formulation is preferably composed by a lipid or a lipid mixture with a global lipid formulation transition temperature between 40 and 45°C.
  • DPPC is used as a major lipid component in thermo-sensitive liposome formulations.
  • DPPC lipid presence is ubiquitous in all possible lipid-mixture formulations, as its transition temperature is above body temperature.
  • a slightly increase in liposomes transition temperature (which can be necessary to avoid unwanted drug leakage at body temperature) can be achieved by mixing small percentages of other phospholipids with higher transition temperatures, as the final transition temperature of the formulation depends on the composition of miscible phospholipids .
  • This mixture can include phospholipids such as 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC) , Hydrogenated soybean phosphatidylcholine (HSPC) , l-tetradecanoyl-2- octadecanoyl-sn-glycero-3-phosphocholine (MSPC) , 1,2- dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG) , among others .
  • phospholipids such as 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC) , Hydrogenated soybean phosphatidylcholine (HSPC) , l-tetradecanoyl-2- octadecanoyl-sn-glycero-3-phosphocholine (MSPC) , 1,2- dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG
  • DPPC phosphatidylcholine
  • phospholipids containing choline groups are the most abundant class in eukaryotic cells.
  • DPPC presents a transition temperature at 41.3°C, being in a solid-like gel state at a temperature between 20 to 25°C, when the heating generation by the superparamagnetic nanoparticles reaches higher temperatures, above 41.3°C, DPPC behaves in a fluid like liquid crystalline state because the hydrophobic interaction between the lipid chains decreases.
  • thermo-sensitive nanocarriers should retain the drug at the biological temperature, approximately 37°C, and release it when the tumor environment warms to temperatures between 40- 42 °C.
  • the transition temperature of the nanosystem itself and, as such, to model its permeability.
  • thermo-sensitive nanosystems are thermo-sensitive nanosystems and can be used as thermo- responsive drug delivery systems, that is a process dependent on the transition temperature of the lipids that make up the lipid formulation of the nanosystem.
  • Supplementation of DPPC-based liposomes with other lipids and molecules has an effect in the response of the magnetic nanosystems in the amount and rate of drug release at specific microenvironments, temperature conditions and drug molecules bioavailability .
  • the inclusion of molecules such as cholesterol and polyethylene glycol into the DPPC-based lipid bilayer, can prolong the inherent circulation time of the nanosystems and enhance the controlled drug molecules release upon heating.
  • the inclusion of cholesterol (4) as shown in Figures 1 to 3, in magnetoliposomes lipid formulation improves the nanosystems resistance to aggregation, makes them more rigid by decreasing their fluidity, protecting the magnetoliposomes in severe shear stress. It also reduces bilayer permeability to non-electrolyte and electrolyte solutes.
  • the formulation is composed by DPPC and cholesterol in the molar ratio preferably between 7:3 and 9:1, more preferably of 8:2, respectively.
  • PEG molecules can be added by either covalent attachment to the surface of preformed magnetoliposomes or by including ligand-PEG lipids in the mixture of lipids in the magnetoliposomes preparation.
  • Magnetoliposomes surface can also be functionalized with ligands that aim permeability enhancement, including, but not limited to: bradykinin, vascular permeability factor/endothelial growth factor (VPF / VEGF) , Prostaglandins, Collagenase, Peroxynitrite , Tumor necrosis factor (TNF) -a.
  • ligands that aim permeability enhancement including, but not limited to: bradykinin, vascular permeability factor/endothelial growth factor (VPF / VEGF) , Prostaglandins, Collagenase, Peroxynitrite , Tumor necrosis factor (TNF) -a.
  • the formulation is composed by DPPC, cholesterol and 1, 2 Distearoyl-sn-glycero-3- phosphoethanolamine-Polyethylene glycol (DSPE-PEG) in a molar ratio of 55:15:2.
  • DPPC distearoyl-sn-glycero-3- phosphoethanolamine-Polyethylene glycol
  • DPPC-based nanosystems may include pH-sensitive lipids, resulting in pH-responsive drug delivery systems with combination of the thermo-sensitive response. These formulations are designed to trigger drug molecules release into the cytoplasm of cells, via the endocytotic pathway, as a response to the pH change. Drug molecules are specifically released in tumors microenvironments since the proton concentration in pathological conditions are enhanced (acidic pH) comparably to the normal physiological conditions, as a result of higher endosome processing, eschemia, tumor growth and inflammation.
  • the lipid formulations include pH-sensitive lipids such as cholesteryl hemisuccinate (CHEMS), N-(4- carboxybenzyl ) -N, N-dimethyl-2 , 3-bis (oleoyloxy) propan- 1- aminium (DOBAQ) , 1 , 2-dipalmitoyl-sn-glycero-3-succinate
  • pH-sensitive lipids such as cholesteryl hemisuccinate (CHEMS), N-(4- carboxybenzyl ) -N, N-dimethyl-2 , 3-bis (oleoyloxy) propan- 1- aminium (DOBAQ) , 1 , 2-dipalmitoyl-sn-glycero-3-succinate
  • the formulation is composed by a mixture of DPPC, CHEMS and DSPE-PEG in a molar ratio of 6:3:1, respectively. More preferably, by a mixture of DPPC cholesterol and CHEMS in the molar ratio of 6:3:1, respectively .
  • the magnetic nanoparticles (MNPs) in the present nanosystem are metal oxide nanoparticles composed by alkaline earth metals, localized in the hydrophilic compartment of the liposome.
  • ferrite magnetic nanoparticles are composed by the metals of magnesium and calcium (Ca x Mgi- x Fe 2 C> 4 , where x is preferably between 0.1 and 0.9, more preferably between 0.3 and 0.7) .
  • ferrite magnetic nanoparticles could comprise, single or in combination, other alkaline earth metals of calcium (Ca) strontium (Sr) and Magnesium (Mg) .
  • D S PM superparamagnetic diameter
  • Nanoparticles ideal size diameter should be between 1 and 100 nm, preferably between 5 and 70 nm and more preferably 10 and 50 nm, making sure that they are suitable for biomedical applications and possess superparamagnetic behavior.
  • the nanoparticles used in the magnetoliposomes formulations consist on a single domain structure, consequently, heat production per unit mass is much higher than larger multi- domain ferrite particles of similar composition.
  • the magnetization disappears once the external magnetic field is removed, avoiding particle agglomeration and hence the possible embolization of the capillary vessels. They also exhibit remarkable magnetic heating properties that can be finely tuned by adjusting the composition, mean size, structure and magnetic anisotropy.
  • Heating mechanisms of superparamagnetic nanoparticles are based on Neel and Brownian losses. Low amplitudes of alternating magnetic fields, almost “transparent" to the human body, are being extremely useful in hyperthermia treatment methods.
  • Superparamagnetic nanoparticles should exhibit high specific absorption rate (SAR) in order to reach temperatures with therapeutic effect with minimal particle concentration. SAR values are highly dependent on the particle mean size, the alternating magnetic field amplitude (Hmax) and frequency (f), saturation magnetization (M s ) and magnetic anisotropy (K) . Magnetic anisotropy can be controlled by changing nanoparticles shape.
  • Cubic nanoparticles possess higher hyperthermia performance as a result of higher surface magnetic anisotropy and the facilitated tendency towards aggregation into nano-chains by the cubic shape.
  • Flower-like nanoparticles architectures are associated with higher SAR values since these particles magneto-structures are composed of highly ordered nanocrystals that do not behave like isolated grains.
  • EPR effect The process that allows passive bioaccumulation of drug nanosystems into solid tumors is known as EPR effect.
  • This effect results from the accelerated angiogenesis associated with tumors as they reach about 2-3 mm as a result of the increase of nutritional and oxygen necessity.
  • the newly generated vasculature presents irregular shape and with wide fenestrations, making it permeable to macromolecules and nanometric systems such as liposomes, magnetoliposomes and polymeric micelles.
  • the increased permeability in the tumor is the result of the absence of an efficient lymphatic drainage that allows the retention of these nanosystems in the tumor.
  • the EPR effect is currently the clinical base of nanosystem functioning and delivery of existing drugs, it presents limitations that need to be rethought when formulating new approaches.
  • the pore diameter of the tumor vasculature varies between 100 and 1200 nm and the diameter of the magnetoliposomes being around 100-200 nm, it is possible to preferentially accumulate these nanosystems in tumor tissues without affecting healthy tissues by the EPR effect (passive targeting) .
  • nanoparticles heat generation can be used in order to increase the permeability of the tumor vasculature.
  • the duration and respective bioaccumulation of magnetoliposomes in the tumor can be increased by the use of an external magnetic field gradient, in a process known as physical active targeting.
  • the surface of the magnetoliposomes with specific active targeting molecules for cancer cell surface receptors, included but not limited to folate, transferrin and EGFR receptors.
  • the magnetoliposomes thermo sensitivity is exploited. Under the action of an external alternate magnetic field, temperature gradients are generated and the thermo-sensible lipid bilayer is destabilized becoming more permeable for therapeutic drug molecules release .
  • the chemotherapy drugs According to the chemical structure presented by the chemotherapy drugs and their interaction with other types of drugs, they can be classified into different types, including but not limited to alkylating agents, antimetabolites, anti tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors and corticosteroids.
  • chemotherapeutic drugs which can be encapsulated into magnetoliposomes, include but are not limited to: Revlimid®, Avastin®, Herceptin®, Rituxan®, Opdivo®, Gleevec®, Imbruvica®, Velcade®, Zytiga®, Xtandi®, Alimta®, Gardasil®, Ibrance®, Perj eta®, Tasigna®, Xgeva®, Afinitor®, Jakafi®, Tarceva®, Keytruda®, Sutent®, Yervoy®, Cytoxan®, Gemzar®, Nexavar®, Zoladex®, Erbitux®, Darzalex®, Xeloda®, Gazyva®, Venclexta® and Tecentriq®.
  • the administration route of the magnetoliposomes depends on the intended use.
  • the administration of the systems may be carried out in several ways ( intravascularly, intralymphatically, parenterally, subcutaneously, intramuscularly, intranasally, intrarectally, intraperitoneally, interstitially, into the airways via nebulizer, hyperbarically, orally, topically, or intratumorly) , using different dosages.
  • the preferred route of administration is intravascularly, where the delivery system is generally injected intravenously, but may be injected intra arterially as well.
  • the magnetoliposomes may also be injected interstitially or into any body cavity.
  • a new route for the synthesis of magnetoliposomes with better magnetic properties is here presented. This method was developed taking into account the problems that compromise the therapeutic effect of previously developed magnetoliposomes, which include: (i) nanoparticles biocompatibility; (ii) nanoparticles magnetic behavior and heating efficiency; (iii) drugs and nanoparticles encapsulation efficiency; (iv) magnetoliposomes magnetic behavior and heating efficiency; and (v) magnetoliposomes size polydispersity index.
  • the approach for the encapsulation of the nanoparticles into the liposomes was carefully thought to keep almost the same magnetic properties as net nanoparticles, one of the main drawbacks of the current magnetic based nanosystem solutions. It was also investigated a new approach that ensures optimal size and size distribution. Furthermore, the liposomal component of the magnetoliposomes was designed to ensure a sensitive composition that supports a safe encapsulation and transport of the encapsulated drugs with a trigger release at the target site.
  • the MNPs of the present technology present a spherical shape, a cubic shape, such as represented in Figure 2, flower-like, such as represented in Figure 3, and a combination between them.
  • the magnetic nanoparticles of the present technology are shape-anisotropic, such as cubic shaped or flower shaped.
  • spherical mixed ferrite nanoparticles can be prepared by the coprecipitation method. First, an aqueous solution containing 50 mmol of alkaline earth metals precursors, 53 mmol of iron (II) sulphate heptahydrate and a 10% sulfuric acid solution are heated at 75°C, under magnetic stirring, until a clear solution is obtained. Then, 55 mmol of potassium oxalate monohydrate is dissolved in warm deionized water. The two solutions are then mixed, under vigorous stirring, at 90°C. After 15 min, the solution is cooled to temperature between 20 and 25°C. The precipitated nanoparticles are washed by several cycles of centrifugation and redispersion in water. Finally, the nanoparticles are calcined preferably between 300°C and 800°C, more preferably between 400°C and 600°C for a time range between 1 h and 4 h.
  • shape-anisotropic cubic superparamagnetic nanoparticles of magnesium and calcium mixed ferrites can be synthetized by co-precipitation method.
  • 50 mmol of octadecylamine is heated until reaching its melting point (50-52°C) in continuously magnetic stirring.
  • a solution containing 0.5 mmol of magnesium acetate tetrahydrate , 0.5 mmol of calcium acetate hydrate, 2 mmol of iron (iii) citrate tribasic monohydrate and 3.1 mmol of oleic acid is added to the pre-heated 50 mmol octadecylamine solution.
  • nanoparticles are washed with an ethanol solution, by several cycles of centrifugation and aqueous redispersion. Finally, the nanoparticles are calcined preferably between 300°C and 800°C, more preferably between 400°C and 600°C for a time range between 1 h and 4 h.
  • a solution (solution A) containing 0.05 mol of potassium oxalate, 0.05 mol of sodium hydroxide and 2.5 mmol of agarose is added to 25 mL of ultrapure water (Milli-Q grade) under nitrogen flow and magnetic stirring.
  • a solution containing 2.5 mmol of iron (iii) citrate tribasic monohydrate is added drop by drop to solution A.
  • the mixture is heated to 90 °C for a time range between 2 and 4 h, resulting in the precipitation of Fe(OH)2.
  • nanoparticles are calcined preferably between 300°C and 800°C, more preferably between 400°C and 600°C for a time range between 1 h and 4 h.
  • lipid and/or surfactant included but not limited the lipids DPPC, DOPG, DPPE, Egg-PC, soy lecithin and the surfactants Triton X-100, aerosol-OT (AOT), sodium dodecyl sulphate (SDS) and cetyl trimethylammonium bromide (CTAB), of concentration above critical micelle concentration, preferably between 0.01 mM and 2 mM and ideally between 0.05 mM and 1.5 mM, was prepared under nitrogen flow.
  • a lipid and/or surfactant included but not limited the lipids DPPC, DOPG, DPPE, Egg-PC, soy lecithin and the surfactants Triton X-100, aerosol-OT (AOT), sodium dodecyl sulphate (SDS) and cetyl trimethylammonium bromide (CTAB), of concentration above critical micelle concentration, preferably between 0.01 mM and 2 mM and ideally between 0.05 mM and 1.5
  • a nonpolar solvent such as, but not limited to hexane, heptane, octane, decane, dodecane, chloroform, cyclohexane, toluene, benzene, was pre-heated at 41°C and 48°C, preferably between 43°C and 46°C, added to the thin film and ultrasonicated at a power range between 180 W and 220 W, preferably between 185 W and 200W, for a time interval between of 15 min and 60 min, preferably between 25 min and 45 min.
  • the superparamagnetic nanoparticles are added to the lipid formulation prepared previously in a total lipid concentration preferably of 0.01 mM and 2 mM and ideally between 0.05 mM and 1.5 mM.
  • the concentration of magnetic nanoparticles is added in aqueous solution in a molar concentration between 5xl0 4 M and 2xl0 5 M, and ideally between lxl0 4 and lxl0 5 M, with a percentage of water between l%-5% (v/v) .
  • the concentration of magnetic nanoparticles is added in aqueous solution in a molar concentration between 5xlCh 4 M and 2xlCh 5 M, and ideally between lxlCh 4 M and lxlCh 5 M, with a percentage of water between 0.005%-l% (v/v) .
  • the solution is ultrasonicated at a power range between 180 W and 220 W, preferably between 185 W and 200 W, for a time interval between of 15 min and 60 min, preferably between 25 min and 45 min.
  • Magnetic decantation was used to purify the solution containing the reversed micelles with the magnetic nanoparticles.
  • a second lipid layer is prepared according to the same steps for the first lipid layer, in a total lipid concentration preferably of 0.01 mM and 2 mM and ideally between 0.05 mM and 1.5 mM, and is added to the aqueous solution prepared previously which is at a temperature range between 41°C and 48°C, preferably between 43°C and 46°C.
  • the total DPPC lipid formulation can include cholesterol in a DPPC : cholesterol molar ratio of 8:2, respectively.
  • lipid formulation containing DPPC :CHEMS: PEG, CHEM-lipid conjugates and PEG-Lipid conjugates are included in the total lipid concentration in a molar ratio of 6:3:1, respectively.
  • lipid formulation containing DPPC : Choi : CHEMS cholesterol and CHEM-lipid conjugates are included in the total lipid concentration in a molar ratio of 6:3:1, respectively, for co-ethanolic injection.
  • Magnetoliposomes functionalization with specific molecules for active targeting is done by the incorporation of a ligand, for instance, lipid-ligand conjugate into the liposome formulation step, at a ligand/total lipid molar ratio ranging between 1:1000 and 1:100.
  • a ligand for instance, lipid-ligand conjugate into the liposome formulation step
  • the therapeutic drug molecules are added in an ethanolic solution for passive loading into magnetoliposomes, in a preferably concentration between lxlCh 6 M and 5xlCh 5 M.
  • the resulting magnetoliposomes were then washed and purified with ultrapure water by magnetic decantation.
  • magnetoliposomes comprise a lipid bilayer of DPPC and cholesterol, in a molar ratio of 8:2, encapsulating drug molecules of Methotrexate as a chemotherapeutic agent for cancer therapy.
  • the magnetic component is composed of high anisotropic cubic shaped mixed ferrites of magnesium and calcium (Cao.5Mgo.5Fe204) .

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Abstract

La présente invention concerne un nanosystème magnétique comprenant des magnétoliposomes et un procédé pour produire les magnétoliposomes. Les magnétoliposomes sont des nanovecteurs basés sur des liposomes piégeant des nanoparticules magnétiques. Ils sont constitués d'un noyau magnétique interne, soit d'un groupe de nanoparticules, soit d'un fluide magnétique, recouvert d'une bicouche lipidique. Les magnétoliposomes peuvent être chargés avec un type ou plus d'un type de molécules, en particulier des médicaments thérapeutiques qui seront libérés selon la cible de maladie spécifique, en particulier un cancer. En ce sens, la composition lipidique de la bicouche peut être manipulée selon le type de la famille du cancer à traiter et les exigences spécifiques au microenvironnement.
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CN113975248A (zh) * 2021-10-09 2022-01-28 广东省人民医院 肿瘤靶向诊疗一体化的纳米颗粒及其应用
CN118892454A (zh) * 2024-07-10 2024-11-05 北京航空航天大学 一种用于神经修复的磁性载药脂质体及其制备方法

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