WO2018134268A1 - Hydrogels injectables et utilisations correspondantes - Google Patents

Hydrogels injectables et utilisations correspondantes Download PDF

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Publication number
WO2018134268A1
WO2018134268A1 PCT/EP2018/051130 EP2018051130W WO2018134268A1 WO 2018134268 A1 WO2018134268 A1 WO 2018134268A1 EP 2018051130 W EP2018051130 W EP 2018051130W WO 2018134268 A1 WO2018134268 A1 WO 2018134268A1
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Prior art keywords
moiety
6alkyl
hydrogel
optionally substituted
occurrence
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PCT/EP2018/051130
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English (en)
Inventor
Luisa De Cola
Giuseppe ALONCI
Silvana Perretta
Pietro RIVA
Federica FIORINI
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Université De Strasbourg
Centre National De La Recherche Scientifique
Ihu Strasbourg - Institut Hospitalo-Universitaire De Strasbourg
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Priority to US16/478,500 priority Critical patent/US20200138711A1/en
Publication of WO2018134268A1 publication Critical patent/WO2018134268A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/001—Macromolecular compounds containing organic and inorganic sequences, e.g. organic polymers grafted onto silica
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/62—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 non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/62—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 non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/641—Branched, dendritic or hypercomb peptides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0246—Polyamines containing other atoms than carbon, hydrogen, nitrogen or oxygen in the main chain
    • C08G73/0253—Polyamines containing sulfur in the main chain
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/028—Polyamidoamines
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels

Definitions

  • the invention relates to a hydrogel, in particular degradable or non degradable, comprising monomers of formula (I) and organosilica particles or porous silicon particles covalently bound thereto, optionally with non covalently bound organosilica particles and/or silicon particles mixed therewith, in particular degradable organosilica nanoparticles or core- shell nanocapsules; pharmaceutical, veterinary or cosmetic compositions thereof; and uses thereof as a medicament.
  • a hydrogel in particular degradable or non degradable, comprising monomers of formula (I) and organosilica particles or porous silicon particles covalently bound thereto, optionally with non covalently bound organosilica particles and/or silicon particles mixed therewith, in particular degradable organosilica nanoparticles or core- shell nanocapsules; pharmaceutical, veterinary or cosmetic compositions thereof; and uses thereof as a medicament.
  • the present invention finds applications in the therapeutic and diagnostic medical technical fields and also in cosmetic and veterinary technical fields.
  • Biocompatible soft materials and in particular hydrogels and liquids that can form interlayers between tissues, have been recently used in surgery to facilitate resection of tumors.
  • ESD endoscopic submucosal dissection
  • NS normal saline solution
  • hyaluronic acid solution is one of the best options, [12] it has been shown to induce a serious side effect which corresponds to a stimulation of the growth of residual tumors proliferation in animal models.
  • hyaluronic acid is necessary to create a SFC and its use is associated with high costs (US $550.58/g) and a general lack of availability.
  • UV light for the photoinitiated radical polymerization may be difficult in hard-to-reach areas and resulted somehow inconvenient as performed by the authors: was irradiated with UV light for a total of 5 min (30 s each at 10 different places by using an UV light-fiber through the endoscopic accessory channel and UV lamp system). Moreover, the authors mentioned that UV irradiation may be associated with inflammation of the residual tissue.
  • thermoresponsive polymers have been investigated as well for ESD applications, such as the recently proposed water solution of a PEG/PLGA-based temperature-sensitive polymer.
  • many of these materials have been shown to clog inside long delivery tools at normal body temperature.
  • Biocompatible soft materials, and in particular hydrogels have been also proposed as dressing for example for topical wound.
  • hydrogels are particularly useful on superficial and deep chronic wounds, ulcers, leg ulcers, restorative and reconstructive surgery, sluggish wounds, dermabrasion, severe sunburn, superficial and deep burns of the second degree.
  • Such dressings are commercially available, for example, Askina Gel sold by B Braun, Duoderm Hydrogel sold by Convatec, Hydrosorb sold by Hartmann, IntraSite Gel marketed by Smith & Nephew, Normgel sold by Molnlycke, Purilon sold by Coloplas and Urgo hydrogel sold by Urgo.
  • known hydrogels have limited spectra of uses and are particularly designed to fit to specific wound and/or to be used in particular environments.
  • known hydrogels are most of the time roughly applied onto the surface of the wound and cannot be injected at the wound and/or lesion site.
  • the known hydrogels can, most of the time, not be used due to their rheo logical and/or biocompatible properties.
  • most of the known hydrogels used as wound dressing are not biocompatible and/or biodegradable in-situ.
  • the known hydrogels are reticulated previously to their use and thus cannot be injected, for example with a needle, due to their viscosity.
  • the terms “a,” “an,” “the,” and/or “said” means one or more.
  • the words “a,” “an,” “the,” and/or “said” may mean one or more than one.
  • the terms “having,” “has,” “is,” “have,” “including,” “includes,” and/or “include” has the same meaning as “comprising,” “comprises,” and “comprise.”
  • another may mean at least a second or more.
  • a combination thereof a mixture thereof and such like following a listing, the use of "and/or” as part of a listing, a listing in a table, the use of "etc” as part of a listing, the phrase “such as,” and/or a listing within brackets with “e.g.,” or i.e., refers to any combination (e.g., any sub-set) of a set of listed components, and combinations and/or mixtures of related species and/or embodiments described herein though not directly placed in such a listing are also contemplated.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • substituents may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • alkyl refers to straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms.
  • Illustrative alkyl groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert- pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • Ci- X alkylenyl refers to a linear or branched saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to x carbon atoms, having a free valence "-" at both ends of the radical.
  • Ci_ xheteroalkylenyl refers to a linear or branched saturated divalent Ci_ x alkylenyl radical as defined above, comprising at least one heteroatom selected from O, N, or S, and having a free valence "-" at both ends of the radical.
  • Ci- X alkylenyl or Ci_ xheteroalkylenyl is optionally substituted, at least one of the H atoms may be replaced by a substituent such as halogen or -OR where R may represent Cl-6alkyl.
  • a substituent such as halogen or -OR where R may represent Cl-6alkyl.
  • aromatic moiety refers to stable substituted or unsubstituted unsaturated mono- or polycyclic hydrocarbon moieties having preferably 3-14 carbon atoms, comprising at least one ring satisfying the Hackle rule for aromaticity.
  • aromatic moieties include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and anthracyl.
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • template or “supramolecular template” refers to a self- aggregation of ionic or non-ionic molecules or polymers that have a structure directing function for another molecule or polymer.
  • the term “about” can refer to a variation of ⁇ 5%, ⁇ 10%, ⁇ 20%, or ⁇ 25%, of the value specified. For example, “about 50" percent can in some embodiments carry a variation from 45 to 55 percent.
  • the term “about” can include one or two integers greater than and/or less than a recited integer. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percents, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment.
  • ranges recited herein also encompass any and all possible subranges and combinations of subranges thereof, as well as the individual values making up the range, particularly integer values.
  • a recited range e.g., weight percents or carbon groups
  • Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • an “effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
  • an amount effective can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons of ordinary skill in the art.
  • the term "effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
  • an “effective amount” generally means an amount that provides the desired effect.
  • treating include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
  • the terms “treat”, “treatment”, and “treating” extend to prophylaxis and include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated.
  • treatment includes medical, therapeutic, and/or prophylactic administration, as appropriate.
  • responsively disintegratable when referring to the shell of the nanocapsule system according to the invention, refers to the property of a material or particle that undergoes degradation (i.e., breakdown of the structural integrity of the material or particle) triggered by a particular signal.
  • the signal can be, for example, a change in pH (either an increase or decrease), a change in redox potential, the presence of reduction or oxidation agent, the presence of UV, visible or near infrared light, ultrasounds, electromagnetic radiation, an enzymatic cleavage, a change in temperature, etc.
  • responsively cleavable when referring to a chemical bond, polymer fragment or linking group, refers to a covalent bond, polymer fragment or linking group that is cleaved upon application of one of the aforementioned particular signals.
  • a responsively cleavable bond, polymer fragment or linker moiety within a siliconoxide nanocapsule shell of the invention confers to the nanocapsule shell its disintegratable properties (the property of structurally breaking down upon application of a specific signal/stimulus, akin to "self-destructive" behavior).
  • stable covalent bond refers to a covalent bond that is not cleaved in the environment to which it is exposed and/or upon application of one of the aforementioned particular signals. In that sense, the term “stable covalent bond” may be used interchangeably with “non-responsively cleavable covalent bond”.
  • hydrogel refers to polymers comprising a solid polymer lattice and an interstitial aqueous phase.
  • the term "degradable hydrogel” refers to hydrogels comprising at least one crosslinker within its structure, which can be cleaved upon application of a suitable signal/stimulus, or by biodegradation of the linker, resulting in the breakdown of the hydrogel crosslinked structure.
  • the hydrogel may comprise a redox-responsive crosslinker, such as cystamine crosslinker, which can be cleaved in response to a change in the redox potential of the environment.
  • cystamine crosslinker may cleave in response to a variation in glutathione concentration in the surrounding environment.
  • the hydrogel may comprise a pH-responsive crosslinker, such as an imine- bond containing crosslinker, which can be cleaved in response to a change in pH of the environment.
  • the hydrogel may be said to be biodegradable when the environment is a physiological environment, and/or when the hydrogel contains at least one crosslinker which can undergo cleavage by biological means (bacteria, enzymes, etc.).
  • degradable linkers being sugars, hyaluronic acid derivatives, aminoacids and peptides.
  • biopolymer refers to polymers produced by living organisms, or synthetic mimics of those.
  • biopolymers There are three main classes of biopolymers, classified according to the monomeric units used and the structure of the biopolymer formed: polynucleotides (RNA and DNA), which are long polymers composed of 4 or more, for example 13 or more nucleotide monomers; polypeptides, which are short polymers of amino acids; and polysaccharides, which are often linear bonded polymeric carbohydrate structures.
  • RNA and DNA polynucleotides
  • polypeptides which are short polymers of amino acids
  • polysaccharides which are often linear bonded polymeric carbohydrate structures.
  • biodegradable polymer refers to natural or synthetic polymers, which can undergo chemical dissolution by biological means (bacteria, enzymes, etc.)
  • surfactant refers to an ordered supramolecular assembly of surfactant or block copolymer molecule micelles, with translation symmetry between about 2 and about 50 nm.
  • the term "cleavable” refers both to the reversible/biodegradable nature of linkers such as '"'-R'-Li-R 2 -* and #-R 3 -L 2 -R 4 -#, as defined herein, triggering the decomposition/disintegration of the hydrogel framework material and/or degradable organosilica material (nanoparticles/nanocapsules) that may be bound to the hydrogel polymer network.
  • the linker may contain a dynamic covalent bond.
  • dynamic covalent bond refers to any covalent chemical bond possessing the capacity to be formed and broken under equilibrium control. In this sense, they can be intended as “reversible” covalent bonds.
  • a “bioactive macromolecule” refers to a macromolecular bio molecule in an undenatured state, which still shows a conformation suited to carry on its supposed biological activity.
  • a “biomolecule” refers to a naturally-occurring molecule (e.g., a compound) comprising of one or more chemical moiety(s) ["specie(s),” “group(s),” “functionality(s),” “functional group(s)”], including but not limited to, polynucleotides (RNA and DNA), which are long polymers composed of 4 or more, for example 13 or more nucleotide monomers; polypeptides, which are short polymers of amino acids; proteins; and polysaccharides, which are often linear bonded polymeric carbohydrate structures, or a combination thereof.
  • RNA and DNA polynucleotides
  • polypeptides which are short polymers of amino acids
  • proteins proteins
  • polysaccharides which are often linear bonded polymeric carbohydrate structures, or a combination thereof.
  • Examples of a macromolecule includes, an enzyme, an antibody, a receptor, a transport protein, structural protein, a prion, an antibiological proteinaceous molecule (e.g., an antimicrobial proteinaceous molecule, an antifungal proteinaceous molecule), or a combination thereof.
  • an antibiological proteinaceous molecule e.g., an antimicrobial proteinaceous molecule, an antifungal proteinaceous molecule
  • peptidic agent comprises a polymer formed from an amino acid, such as a peptide (i.e., about 3 to about 100 amino acids), a polypeptide (i.e., about 101 or more amino acids, such as about 50,000 or more amino acids), and/or a protein.
  • a “protein” comprises a proteinaceous molecule comprising a contiguous molecular sequence of three amino acids or greater in length, matching the length of a biologically produced proteinaceous molecule encoded by the genome of an organism. Examples of a proteinaceous molecule include an enzyme, an antibody, a receptor, a transport protein, a structural protein, or a combination thereof.
  • a peptide e.g., an inhibitory peptide, an antifungal peptide
  • a peptidic agent and/or proteinaceous molecule may comprise a mixture of such peptide(s) (e.g., an aliquot of a peptide library), polypeptide(s) and/or protein(s), and may also include materials such as any associated stabilizer(s), carrier(s), and/or inactive peptide(s), polypeptide(s), and/or protein(s).
  • hydrogel comprising monomers of formula (I):
  • n is an integer representing the number of monomers (I) in the hydrogel polymer; for each occurrence of the bracketed structure n, Y independently represents:
  • a molecular crosslinker for connecting at least a monomer of formula (I) in the framework to at least another monomer of formula (I) in another framework through a linker having the following structure:
  • each occurrence of '"'-R'-Li-R 2 -* independently represents a responsively cleavable moiety or a non-cleavable moiety; each occurrence of * denotes a point of attachment of the linker to a monomer of formula (I) in the hydrogel's framework;
  • each occurrence of Li independently represents a responsively cleavable covalent bond, a moiety containing a responsively cleavable covalent bond and/or a stable covalent bond;
  • R 1 and R 2 for each occurrence, independently represent an optionally substituted CI -20 alkylenyl moiety, an optionally substituted CI -20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety, wherein the CI -20 alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or CI -6 alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N0 2 , -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl- 6alkyl;
  • '"'-R'-Li-R 2 -* may independently comprise sugar derivatives such as glucose, lactose or mannose derivatives, hyaluronic acid derivatives, collagene, aminoacids or peptides;
  • R 7 represents N
  • R 8 represents an optionally substituted CI -20 alkyl, Cl-20alkenyl or Cl-20alkynyl moiety, a CI -20 alkyl optionally substituted with carboxyl moiety, an optionally substituted Cl-20heteroalkyl moiety, an optionally substituted Cl-20alkylphenyl moiety or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20alkenyl, Cl-20alkynyl, Cl-20heteroalkyl or Cl-20alkylphenyl moieties may bear one or more substituents selected from halogen, -OR, -CO2R or -N(Rp)2; where R may represent H or Cl-6alkyl and each occurrence of Rp may independently represent H or Cl-6alkyl; and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -NO2, -CN, isocyano, -
  • a hyaluronic acid alginic acid, peptide, cellulose, amino acid, sugar (for example glucose, lactose or mannose derivatives), or oligonucleotide moiety;
  • Rio independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl- 6alkyl;
  • X independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl.
  • n bracketed structures may be the same or different.
  • the hydrogel polymer may be composed of a succession of repeat units of formula I (no other monomer is used to make up the hydrogel polymer structure).
  • R 10 may independently represent CH or CH-CH2, preferably CH.
  • the hyaluronic acid, alginic acid, peptide, cellulose, amino acid, sugar (for example glucose, lactose or mannose derivatives), or oligonucleotide moiety may be incorporated via an amino group (NH 2 ) naturally present on the hyaluronic acid, alginic acid, peptide, cellulose, amino acid, sugar, or oligonucleotide moiety.
  • the hyaluronic acid, alginic acid, peptide, cellulose, amino acid, sugar, or oligonucleotide moiety may be chemically modified to bear an amino group, prior to incorporation in the hydrogel polymer structure, as variable Y.
  • At least one occurrence of Y in the hydrogel polymer bears or comprises an organosilica particle (organosilica nanoparticle or core-shell nanocapsule, wherein the organosilica matrix may be porous (preferably mesoporous) and may contain responsively cleavable bonds within the organosilica framework (in other words, the organosilica nanoparticle or core-shell nanocapsule may be degradable upon application of an external stimulus, or may be non-degradable)), as further described infra.
  • at least a subset of occurrences of Y in the hydrogel polymer bears or comprises an organosilica particle, as defined immediately above.
  • the organosilica particles may be functionalized so as to allow crosslinking between the hydrogel polymers (in other words, the organosilica particles allow connecting at least a monomer of formula (I) in the framework to at least another monomer of formula (I) in another framework).
  • the hydrogel polymer may be terminated by appropriate termination groups, as dictated by the chemical synthesis and reaction conditions used.
  • the hydrogel polymer may be terminated independently at each end with H, or a starting material used in the synthesis (one of the building blocks used to make up the monomer of formula (I)) ⁇
  • n the number of monomers (I), can be such that the mass of said hydrogel polymer may be greater than about 100 kilodaltons.
  • the number of monomers, "n" can be such that the mass of the hydrogel polymer of formula (I) is less than about 1000 daltons.
  • the mass of the hydrogel polymer of formula (I) may range from about 300 daltons to infinite, for example from about 500 daltons to infinite.
  • the molecular mass of the hydrogel can be considered to be infinite, on account that the hydrpgel network may be completely crosslinked.
  • n may be an integer between 2 and 10000, for example between 2 and
  • Advantageously Rio may independently represent a CI -20 alkylenyl moiety, for example a CI -6 alkylenyl moiety, for example -CH 2 - or -CH2-CH2-, advantageously -CH 2 - .
  • Rl 1 and R12 may independently represent H or C1-C6 alkyl.
  • Rn and R12 may independently represent H, a CI -20 alkyl, Cl- 20alkenyl or Cl-20alkynyl moiety, a Cl-20heteroalkyl— moiety, or a phenyl moiety.
  • Advantageously Rn and R12 may independently represent H or C1-C6 alkyl.
  • Advantageously Rn and R12 may be identical.
  • Advantageously Rn and R12 may represent H.
  • X may independently represent a CI -20 alkylenyl moiety, for example a CI -6 alkylenyl moiety, for example -CH 2 - or -CH2-CH2-, advantageously -CH2-.
  • each occurrence of R 1 and R 2 may be identical.
  • R 1 and R 2 may independently represent CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, or phenyl.
  • R 1 and R 2 may be identical and may each represent -CH2-, -(CH 2 ) 2 - , -(CH 2 ) 3 -, -(CH 2 ) 4 -, or phenyl.
  • the substituent(s) on R 1 and R 2 may be suitably selected to facilitate the cleavage of the responsively cleavable linker Li when an external signal/stimulus is applied (e.g., a change in pH (either an increase or decrease), a change in redox potential, the presence of reduction or oxidation agent, the presence of UV light or near infrared light, an enzymatic cleavage, a change in temperature, etc.).
  • the substituent(s) on R 1 and R 2 may be selected based on their electron-withdrawing or -donating properties, to facilitate the cleavage of the linker moiety.
  • L may be an imine bond and Ri and/or R2 may be a phenyl group
  • the phenyl group may bear a nitro group to make the imine bond more reactive (i.e., more responsive to cleavage upon application of a suitable stimulus).
  • Li may represent independently a responsively cleavable covalent bond selected from
  • Li may independently represent or comprise a disulfide, ester, imine or hydrazone bond, preferably a disulfide bond.
  • '"'-R'-Li-R 2 -* may preferably be a di-imine linker conjugated with an aromatic group such as phenyl. More preferably, '"'-R'-Li-R 2 -* may comprise a para di-imino phenyl moiety.
  • '"'-R'-Li-R 2 -* may independently comprise sugar derivatives such as mannose, hyaluronic acid derivatives, collagene, aminoacids or peptides; all of which may serve as degradable crosslinker.
  • '"'-R'-Li-R 2 -* may represent independently a responsively pH cleavable moiety of formula (III) :
  • each occurrence of q independently represents an integer, for example q may be an integer from 1 to 6,
  • D independently represents for each occurrence a C1-C3 alkylenyl moiety, or -N(Rz)- wherein Rz represents H or Cl-6alkyl.
  • '"'-R'-Li-R 2 -* may contain more than one responsively cleavable covalent bond.
  • '"'-R'-Li-R 2 -* contains two responsively pH cleavable covalent bond (two imine bonds).
  • the responsively pH cleavable moiety of formula (III) may be bound on either side to a monomer of formula (I) via a nitrogen atom (in other words, Y may be a molecular crosslinker having the structure
  • -R'-Li-R 2 -* may have formula (III) as defined above, and * denotes the point of attachment of the molecular crosslinker to another monomer of formula (I) in the hydrogel polymer network.
  • '"'-R'-Li-R 2 -* may represent independently a responsively pH cleavable moiety of formula Ilia, Ilia' or Illb :
  • the responsively pH cleavable moiety of formula (Ilia), (Ilia') or (Illb) may be bound on either side to a monomer of formula (I) via a nitrogen atom (in other words, Y may be a molecular crosslinker having the structure
  • -R'-Li-R 2 -* may have formula (Ilia), (Ilia') or (Illb) as defined above, and * denotes the point of attachment of the molecular crosslinker to another monomer of formula (I) in the hydrogel polymer network.
  • Li or -R'-Li-R 2 -* may represent independently a light responsively cleavable group and/or a photo-responsive cleavable group.
  • the light-responsively cleavable group and/or photo -responsive cleavable group may be any suitable light responsively cleavable group and/or photo -responsive cleavable group known from the person of ordinary skill in the art.
  • -R'-Li-R 2 -* may represent a light-induced cleavable linker having formula:
  • ql and q2 independently represent an integer from 1 to 6, preferably from 1 to 3.
  • the light-sensitive linker (V) may be cleaved by irradiation with light produced by a Hg lamp.
  • the light-sensitive cleavable moiety of formula (V) may be bound on either side to a monomer of formula (I) via a nitrogen atom (in other words, Y may be a molecular crosslinker having the structure
  • -R'-Li-R 2 -* may have formula (V) as defined above, and * denotes the point of attachment of the molecular crosslinker to another monomer of formula (I) in the hydrogel polymer network.
  • '"'-R'-Li-R 2 -* may represent independently a responsively cleavable moiety selected from:
  • Li and '"'-R'-Li-R 2 -* may independently be a stable covalent bond or moiety, respectively (i.e., which is not cleaved under the conditions in which it is used/intended), for example it may be any stable bond or moiety known to the person of ordinary skill in the art and adapted to cross-link monomer and/or polymer frameworks. It may be for example a CI -20 alkylenyl moiety or CI -20 heteroalkylenyl moiety, for example a Cl-6 alkylenyl or Cl-6 heteroalkylenyl moiety, polyglycols, or lipids.
  • '"'-R 1 - Li-R 2 -* represent a stable covalent bond or moiety
  • the hydrogel is said to be n -degradable.
  • '"'-R'-Li-R 2 -* may represent:
  • R 7 may be N and R 8 may represent an optionally substituted CI -20 alkyl moiety, a CI -20 alkyl optionally substituted with carboxyl moiety, an optionally substituted Cl-20heteroalkyl moiety, an optionally substituted Cl-20alkylphenyl moiety or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, C l-20heteroalkyl or Cl-20alkylphenyl moieties may bear one or more substituents selected from halogen, -OR, -CO2R or -N(Rp)2 where R may represent H or C l-6alkyl, and each occurrence of Rp may independently represent H or C l- 6alkyl; and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano,
  • Y may represent a group of formula *-N(R 8 )-*, wherein R 8 may represent the residue of the corresponding amino acid H2NR 8 .
  • R 8 may represent the residue of the corresponding amino acid H2NR 8 .
  • gamma- aminobutyric acid may be used, and Y may represent *-N[(CH2)3C02H]-*.
  • R 7 may be N and R 8 may represent a C1-C6 alkyl substituted with a carboxyl moiety, a C1-C6 alkyl substituted with one or more hydroxyl groups, C1-C6 alkoxy, C 1-C6 alkyl substituted with -N(Rp)2 wherein each occurrence of Rp independently represents a C 1 -6alkyl.
  • R 8 may represent a C1-C6 alkyl substituted with -N(Rp)2 wherein each occurrence of Rp independently represents a Cl- 6alkyl; for example a C1-C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a Cl-2alkyl.
  • R 8 may represent a C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a CI alkyl.
  • R 8 mar represent -(CH 2 )NMe2.
  • R 7 may be N and R 8 may represent R 8 may represent a C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a CI alkyl.
  • R 8 mar represent -(CH2)NMe2.
  • R 7 may be may be N, and R 8 may represent independently from other occurrences of R8 a Cl-20alkylphenyl moiety optionally substituted with one or more -OR wherein R may represent H or C l-6alkyl.
  • R may represent independently from other occurrences of R8 a Cl-6alkylphenyl moiety optionally substituted with one or more -OR wherein R may represent H or C l-6alkyl.
  • R 8 may represent independently from other occurrences of R8 a Cl-6alkyl moiety bearing a catechol moiety.
  • R 7 may be may be N, and R 8 may be independently a group of following formula:
  • the hydrogels of the invention may carry biologicals molecules.
  • Y may advantageously represent a moiety selected from hyaluronic acid, alginic acid, amino acid, peptide, cellulose, sugar (for example glucose, lactose or mannose derivatives) and oligonucleotide moieties.
  • the hyaluronic acid derivatives may be any hyaluronic acid derivatives known to the person of ordinary skill in the art. It may be for example any commercially available hyaluronic acid derivatives, for example a hyaluronic acid derivative disclosed in Voigt J et al. "Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials.” Wound Repair Regen. 2012 May- Jun;20(3):317-31 [30].
  • the alginic acid derivatives may be any alginic acid derivatives known to the person of ordinary skill in the art.
  • alginic acid or alginic acid sodium salt from different sources and of any available molecular weight, such as alginic acid sodium salt derived from brown algae, including Laminaria hyperborea, Laminaria digitata, Laminaria japonica, Ascophyllum nodosum, and Macrocystis pyrifera, or obtained from genetic engineered bacteria. It may be chemically modified to improve adhesion or biocompatibility, for example through oxidation, functionalization or conjugation with small molecules, for example Dodecylamine, or with biomolecules, such as peptides, cellulose or sugars, as disclosed for example in K.J. Lee, D.J. Mooney, "Alginate: properties and biomedical applications", Prog Polym Sci., 2012 Jan; 37(1) 106-126. [31]
  • Y represents an amino acid it may be any amino acid known to the person of ordinary skill in the art. It may be for example D or L amino acid. It may be for example amino acid selected from the group comprising alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. It may also be gamma aminobutyric acid.
  • Y represents a peptide moiety
  • it may be peptide moiety comprising for 3 to 20 amino acids, for example 3 to 5 amino acids.
  • Y represents a sugar moiety (carbohydrate moiety)
  • it may be any sugar known to the person of ordinary skill in the art and adapted to be linked to a polymer framework. It may be for example a sugar selected from the group comprising Arabinose, Fructose, Galactose, Glucose, Lactose, Inositol, Mannose, Ribose, Trehalose and Xylose, preferably glucose, lactose or mannose.
  • these sugars may be functionalized with an amino-containing moiety, for proper incorporation of the sugar moiety as Y into the monomer of formula (I).
  • Y represents an oligonucleotide moiety it may be derived from any oligonucleotide known to the person of ordinary skill in the art and adapted to be linked to a polymer framework. It may be for example an oligonucleotide moiety comprising from 2 to 25 Deoxyribonucleic acid and/or Ribonucleic acid.
  • the oligonucleotide moiety may be functionalized with an amino-containing moiety, for proper incorporation of the oligonucleotide moiety as Y into the monomer of formula (I).
  • the hydrogels according to the invention may be advantageously functionalized, for example with organosilica material for example in the form of particles (organosilica nanoparticles or core-shell nanocapsules), wherein the organosilica matrix may be porous (preferably mesoporous) and may contain responsively cleavable bonds L 2 or responsively cleavable linkers #-R 3 -L 2 -R 4 -# within the organosilica framework (in other words, the organosilica nanoparticles or core-shell nanocapsules may be degradable upon application of an external stimulus, or may be non-degradable)), as further described infra.
  • organosilica material for example in the form of particles (organosilica nanoparticles or core-shell nanocapsules)
  • organosilica matrix may be porous (preferably mesoporous) and may contain responsively cleavable bonds L 2 or responsively cleavable linkers #-R 3 -L 2 -R 4
  • At least a subset of occurrences of Y in the hydrogel polymer may represent *-N(R 8 )-* wherein R 8 represents a Cl-20alkyl or Cl-20heteroalkyl moiety, preferably Cl-6alkyl or Cl-6heteroalkyl, most preferably Cl-6alkyl, bearing an organosilica nanoparticle, preferably the organosilica matrix may be porous, most preferably mesoporous, and may contain responsively cleavable bonds L 2 or responsively cleavable linkers #-R 3 -L 2 - R 4 -# within the organosilica framework (R3, R 4 and L 2 are as defined below).
  • R 8 comprises an organosilica particle, preferably an organosilica nanoparticle, it may be bound on either side to a monomer of formula (I) via a nitrogen atom (in other words, Y may be a molecular rosslinker having the structure
  • R 8A and R 8B independently represent a Cl-lOalkyl or Cl-lOheteroalkyl moiety, preferably Cl-6alkyl or Cl-6heteroalkyl;
  • NP denotes an organosilica nanoparticle; and * denotes the point of attachment of the molecular crosslinker to another monomer of formula (I) in the hydrogel polymer network).
  • Organosilica materials are well known, as well as method for preparing them, such as sol gel chemistry-based methods.
  • the organosilica material optionally in the form of nanoparticles, may preferably be degradable as described in WO 2015/107087, the entire contents of which are hereby incorporated by reference herein. The reader may refer to the teachings of this document for guidance as to how to prepare such degradable/disintegratable organosilica materials.
  • At least a subset of occurrences of Y in the hydrogel polymer may represent *-N(R 8 )-* wherein R 8 represents a Cl-20alkyl or Cl-20heteroalkyl moiety, preferably Cl-6alkyl or Cl-6heteroalkyl, most preferably Cl-6alkyl, bearing an organosilica core/shell nanocapsule, preferably the organosilica matrix may be porous, most preferably mesoporous, and may contain responsively cleavable bonds L 2 or responsively cleavable linkers #-R 3 -L 2 -R 4 -# within the organosilica framework (R3, R 4 and L 2 are as defined below).
  • the organosilica core/shell nanocapsule may be degradable/disintegratable in that its shell framework contains Si adjacent sites covalently bound via a responsively cleavable linker, as described in WO 2015/189402, the entire contents ofwhich are hereby incorporated by reference herein.
  • the organosilica core/shell nanocapsule may encapsulate a bioactive macromolecule or bioactive macromolecule cluster, and/or another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity.
  • the bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule may be in active conformation (i.e., in a biologically active form).
  • the reader may refer to the teachings of WO 2015/189402 for guidance as to how to prepare such degradable/disintegratable organosilica nanocapsules. Briefly, such nanocapsules may be prepared by a method comprising steps of:
  • a water-in-oil emulsion from (i) a solution of a suitable surfactant and alcohol in a suitable organic solvent, and (ii) an aqueous solution of a bioactive macromolecule or bioactive macromolecule clusters and/or another molecule of interest, a silane precursor Si(Z A ) 4 and a selected precursor having the structure (Z) 3 Si-R 3 -L2-R 4 -Si(Z) 3 ;
  • step II Stirring the water-in-oil emulsion obtained in step I) under alkaline conditions; thereby coating the bioactive macromolecule or bioactive macromolecule clusters with an organosilica sol-gel mixture obtained by hydrolysis- condensation of silicon alkoxide; and
  • each occurrence of Z and Z A independently represents a hydrolysable or nonhydrolyzable group, provided that on each occurrence of Si of the precursor (Z) 3 Si- R 3 -L2-R 4 -Si(Z) 3 , at least one occurrence of Z represents a hydrolysable group, and at least two occurrences of Z A in the the precursor Si(Z A ) 4 independently represent a hydrolysable group; wherein (i) when Z or Z A represents a nonhydrolyzable group, it may be selected from an optionally substituted Cl-20alkyl, C2-20alkenyl or C2- 20alkynyl moiety, an optionally substituted Cl-20heteroalkyl, C2-20heteroalkynyl or C2-20heteroalkynyl moiety, or an optionally substituted phenyl moiety, wherein the substituents on the phenyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkeny
  • R 3 , R 4 , L 2 and # are as defined generally and in any variants herein.
  • R 8 comprises an organosilica core/shell nanocapsule
  • it may be bound on either side to a monomer of formula (I) via a nitrogen atom (in other words, Y may be a molecular crosslink r having the structure
  • R 8A and R 8B independently represent a Cl-lOalkyl or Cl-lOheteroalkyl moiety, preferably Cl-6alkyl or Cl-6heteroalkyl;
  • NP denotes an organosilica core/shell nanocapsule; and * denotes the point of attachment of the molecular crosslinker to another monomer of formula (I) in the hydrogel polymer network).
  • the aforementioned organosilica material for example in the form of particles (organosilica nanoparticles or core-shell nanocapsules), may be chemically modified to bear amino-containing tether groups at the outer surface, prior to incorporation in the hydrogel polymer structure, as variable Y (cf. crosslinker *-R -NP-R - mentioned above).
  • Such functionalization may be effected by any suitable ways known in the art.
  • such functionalization may be carried out by reacting organosilica material for example in the form of particles (e.g., organosilica nanoparticles or core-shell nanocapsules), with a silylated starting material (W)3Si-R 8 -N(Rp) 2 ; each occurrence of W independently represents a hydro lysable group selected from a CI -6 alkoxy, CI -6 acyloxy, halogen or an amino moiety; R 8 represents an optionally substituted CI -20 alkyl, C2-20 alkenyl or C2-20 alkynyl moiety, an optionally substituted CI -20 heteroalkyl, C2-20 heteroalkynyl or C2-20 heteroalkynyl moiety, or an optionally substituted phenyl moiety, wherein the substituents on the phenyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl moieties may be
  • each occurrence of W may independently represent CI, -OMe, -OEt, -Oz ' Pr or -OtBu.
  • R 8 may represent a Cl-20alkyl or Cl-20heteroalkyl moiety, preferably Cl-6alkyl or Cl-6heteroalkyl, most preferably Cl- 6alkyl.
  • organosilica material for example in the form of particles (organosilica nanoparticles or core-shell nanocapsules), with a silylated starting material (W)3Si-R 8 -N(Rp) 2 as defined above, under conventional sol gel chemistry conditions.
  • organosilica material for example in the form of particles (organosilica nanoparticles or core-shell nanocapsules) bearing -R 8 -N(Rp) 2 tethers at the outer surface
  • organosilica material for example in the form of particles (organosilica nanoparticles or core-shell nanocapsules) bearing -R 8 -N(Rp) 2 tethers at the outer surface
  • the -R 8 -N(Rp) 2 tethers may be first deprotected to yield -R 8 -NH 2 tethers prior to proceeding with the functionalization of the organosilica material.
  • At least a subset of occurrences of Y may further comprise a core/shell nanocapsule, advantageously an organosilica core/shell nanocapsule, preferably the shell organosilica matrix may be porous, most preferably mesoporous, preferably the shell matrix may additionally degradable/disintegratable, with a bioactive macromolecule or bioactive macromolecule cluster encapsulated within said nanocapsule.
  • the nanocapsule may alternatively or additionally contain another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity.
  • At least a subset of occurrences of Y may comprise a nanoencapsulated molecule or bioactive macromolecule or bio macro molecule cluster comprising
  • nanocapsule having a core/shell structure
  • b a molecule of interest or bioactive macromolecule or bioactive macromolecule cluster encapsulated within said nanocapsule.
  • the shell of said nanocapsule may be made of hybrid organosilica material comprising a three-dimensional framework of Si-0 bonds, wherein at least a subset of Si atoms in the material's framework are connected to at least another Si atom in the framework through a linker having the following structure:
  • each occurrence of # denotes a point of attachment to a Si atom in the hybrid organosilica material's framework
  • L 2 represents a responsively cleavable covalent bond or a stable bridging ligand; preferably a responsively cleavable covalent bond;
  • R 3 and R 4 independently represent an optionally substituted CI -20 alkylenyl moiety, an optionally substituted CI -20 heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety, wherein the Cl-20alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N0 2 , -CN, isocyano, -OR p , -N(R P ) 2 wherein each occurrence of R p independently represents H or Cl-6alkyl.
  • L 2 may be any moiety that contains a responsively cleavable covalent bond, which can be cleaved upon exposure to a determined stimulus.
  • L 2 may represent a responsively cleavable covalent bond selected from:
  • #-R 3 -L 2 -R 4 -# may represent independently a responsively pH cleavable moiety of formula (III) :
  • D independently represents for each occurrence a C1-C3 alkylenyl moiety, or -N(Rz)- wherein Rz represents H or Cl-6alkyl.
  • *-R 3 -L 2 -R 4 -* may contain more than one responsively cleavable covalent bond.
  • *-R 3 -L 2 -R 4 -* contains two responsively pH cleavable covalent bond (two imine bonds).
  • #-R 3 -L 2 -R 4 -# may represent independently a responsively pH cleavable moiety of formula Ilia, Ilia' or Illb :
  • L 2 or #-R 3 -L 2 -R 4 -# may represent independently a light responsively cleavable group and/or a photo-responsive cleavable group.
  • the light-responsively cleavable group and/or photo -responsive cleavable group may be any suitable light responsively cleavable group and/or photo-responsive cleavable group known from a person of ordinary skill in the art.
  • #-R 3 -L 2 -R 4 -# may represent a light-sensitive linker having formula:
  • ql and q2 independently represent an integer from 1 to 6, preferably from 1 to 3.
  • the light-sensitive linker (V) may be cleaved by irradiation with light produced by a Hg lamp.
  • #-R 3 -L 2 -R 4 -# may represent independently a responsively cleavable moiety selected from
  • L 2 may represent a responsively cleavable covalent bond selected from disulfide, diselenides, imine, amide, ester, urea, hydrazone or thiourea; preferably disulfide, imine (preferably #-R 3 -L 2 -R 4 -# may comprise a para di-imino phenyl moiety), ester, or hydrazone; more preferably disulfide.
  • bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule may be in active conformation (i.e., in a biologically active form).
  • bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule may be in a undenatured state.
  • the bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule may remain in a folded position and retain an active conformation.
  • each occurrence of R 3 and R 4 may be identical.
  • R 3 and R 4 may be any organic radical from any commercially available silylated derivative suitable for sol-gel chemistry.
  • R 3 and R 4 may independently represent-CH 2 -, -(CH 2 ) 2 -, -(CH 2 )3-, -(CH 2 )4-, or phenyl.
  • the substituent(s) on R 3 and R 4 may be suitably selected to facilitate the cleavage of the responsively cleavable linker #-R 3 -L 2 -R 4 -# when an external signal/stimulus is applied (e.g., a change in pH (either an increase or decrease), a change in redox potential, the presence of reduction or oxidation agent, the presence of UV light or near infrared light, an enzymatic cleavage, a change in temperature, etc.).
  • the substituent(s) on R 3 and R 4 may be selected based on their electron- withdrawing or -donating properties, to facilitate the cleavage of the linker moiety.
  • L 2 may be an imine bond and R 3 and/or R 4 may be a phenyl group
  • the phenyl group may bear a nitro group to make the imine bond more reactive (i.e., more responsive to cleavage upon application of a suitable stimulus).
  • each occurrence of # denotes a point of attachment to a Si atom at the outer surface of the hybrid organosilica material's framework
  • each occurrence of R 5 independently represents an optionally substituted Cl- 20alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety, wherein the Cl-20alkylenyl, Cl-20heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl; and each occurrence of R 6 independently represents represents -OR, -SR or -N(Rf)2; preferably -N(Rf)
  • R 5 may represent a CI -20 alkyl moiety, for example a Cl-6alkyl, for example CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -.
  • R 6 represents an amino group, preferably -N(Rf) 2 wherein each occurrence of Rf independently represents H or Cl-6alkyl, for example R 6 may represent - NH 2 .
  • the core-shell nanocapsules may be in the form of nanoparticles.
  • core-shell nanocapsules according to the invention may have a diameter from 1 to 999 nanometers, preferably from 1 to 500 nm, more preferably from 1 to 250 nm and most particularly from 1 to 100 nm.
  • core-shell nanocapsules according to the invention may have a diameter from 25 to 500 nm, preferably from 25 to 200 nm, preferably from 40 to 90 nm, preferably from 40 to 80 nm, preferably from 50 to 70nm.
  • the shape of the organosilica particles may be tuned to obtain mostly particles of a specific shape (spherical, rice- shape, etc%) according to known methods.
  • the particle shape may in turn have an effect on the mechanical properties of the hydrogel.
  • the molecule of interest may be selected from proteins, enzymes, oligonucleotides, antibodies, peptides, PNA, DNA, RNA, gene fragments and small molecules with or without pharmaceutical or cosmetic activity.
  • the proteins may be fluorescence protein family such as GFP, RFP; Cytotoxic proteins such as: TRAIL/ APO-2L, Onconase, Ricin, Parasporin; Therapeutic proteins: Insulin Family, Angiopoietin family, Coagulation factor proteins, Dystrophin, HIV antigen, Hepatitis C antigen.
  • the protein may be proteins for cosmetic for example Botulinum toxin protein family, Elastin, Collagen, Keratin, Calcitonin, Silk proteins.
  • the enzymes may be RNAase, Hyaluronidase, Lysosomal enzyme acid alpha-glucosidase, Galactosidase, Glucocerebrosidase, Streptokinase, Urokinase, Altepase, Thymidine kinase, cytosine deaminase.
  • the oligonucleotides may be DNA (Deoxyribonucleic acid), RNA(Ribo Nucleic acid), PNA(Peptide Nucleic acid), LNA (Locked Nucleic Acid).
  • the antibodies may be selected from the group comprising Trastuzumab, Bevacizumab, Cetuximab, Mylotarg, Alemtuzumab, Rituximab, Brentuximab.
  • the small molecules with or without pharmaceutical activity may be for example sugars and/or polypeptide.
  • the nanoencapsulated biomolecule may be selected from proteins, enzymes, oligonucleotides, antibodies, peptides, PNA, DNA, RNA, and gene fragments.
  • the hybrid organosilica nanocapsule shell may be in the form of nanoparticles.
  • the hybrid organosilica nanocapsule shell according to the invention may have a diameter from 1 to 999 nanometers, preferably from 1 to 500 nm, more preferably from 1 to 250 nm and most particularly from 1 to 100 nm.
  • the hybrid organosilica nanocapsule shell according to the invention may have a diameter from 25 to 500 nm, preferably from 25 to 200 nm, preferably from 40 to 90 nm, preferably from 40 to 80 nm.
  • the cleavage/degradation of the linker '"'-R'-Li-R 2 -* and/or #-R 3 -L 2 - R 4 -# may be independently triggered by any suitable means.
  • it may be a change in pH (either an increase or a decrease), a change in redox potential, the presence of reduction or oxidation agent, application of UV, visible or near infrared light, ultrasounds, electromagnetic radiation, a change in temperature, enzymatic cleavage, DNA binding, etc...
  • Table 1 gives examples of cleavage/degradation triggering means for each of the aforementioned types of responsively cleavable linkers :
  • Diselenide Reducing agents e.g. thiols, metal complexes
  • the degradation of the hydrogel network may be controlled/effected independently from the degradation of the organosilica material (degradable nanoparticles or core/shell nanocapsules) that may be covalently bound to the hydrogel framework.
  • This new class of materials includes polymer framework systems whose framework is formed from precursors having one of the following structures:
  • At least one bivalent molecular crosslinker precursor having the structure A- wherein each occurrence of A independently represents a hydro lysable or nonhydrolyzable group, provided that at least one occurrence of A represents a hydrolysable group, wherein (i) when A represents a nonhydrolyzable group, it may be selected from an optionally substituted Cl-20alkyl, C2-20alkenyl or C2-20alkynyl moiety, an optionally substituted Cl-20heteroalkyl, C2-20heteroalkynyl or C2- 20heteroalkynyl moiety, or an optionally substituted phenyl moiety, wherein the substituents on the phenyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl moieties may be independently selected from halogen, -N0 2 , -CN, isocyano, Cl-6alkoxy, an oxirane/epoxy
  • Li independently represents a stable or responsively cleavable covalent bond
  • R 1 and R 2 independently represent an optionally substituted Cl-20alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety
  • the Cl- 20alkylenyl, Cl-20heteroalkylenyl or ethylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N0 2 , -CN, isocyano, -OR p , -N(R P ) 2 wherein each occurrence of R p independently represents H or Cl-6alkyl,
  • Rio independently represents an optionally substituted CI -20 alkylenyl moiety
  • Ri i and R12 independently represent H, an optionally substituted CI -20 alkyl moiety, an optionally substituted CI -20 alkylenyl moiety, an optionally substituted Cl- 20heteroalkylenyl moiety, an optionally substituted ethylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety
  • the Cl-20alkylenyl, Cl- 20heteroalkylenyl or ethylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, - N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6al
  • X independently represents an optionally substituted CI -20 alkyl moiety.
  • each occurrence of A may independently represent a nucleophilic moiety, preferably one that can undergo a Michael-type nucleophilic addition onto the double bond of the monomer precursor (IV).
  • each occurrence of A may independently represent -N(Rf) 2 wherein each occurrence of Rf may represent H or Cl-6alkyl.
  • L 1 , R 1 , R 2 , R 10 , R 11 , R 12 and X are independently as defined generally and in any variants above.
  • a method of preparing a hydrogel by covalently introducing a preselected precursor (general structure: monomer precursor of formula (IV)) with a molecular crosslinker precursor (general structure: as defined herein, in the framework of the hydrogel material itself.
  • the hydrogels present controlled self-destructive behavior in the environment where it is intended to perform its activity.
  • the controlled self-destructive behavior is a property that provides numerous avenues of important applications for such hydrogel, ranging from medical to cosmetics.
  • the method may comprise steps of:
  • disintegratable organosilica nanoparticles bearing amino- containing tether groups at the outer surface bearing amino- containing tether groups at the outer surface; or disintegratable organosilica core/shell nanocapsules bearing amino-containing tether groups at the outer surface and encapsulating a bioactive macromolecule or bioactive macro molecule cluster, and/or another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity; wherein the bioactive macromolecule or bioactive macromolecule cluster encapsulated within the nanocapsule is preferably in active conformation, and
  • a selected precursor of formula B-R 8 b) Stirring the solution obtained in step a), at any appropriate temperature, thereby allowing the polymerization carried out to form the hydrogel,
  • each occurrence of A or B independently represents a hydro lysable or nonhydrolyzable group, provided that at least one occurrence of A represents a hydrolysable group, wherein (i) when A or B independently represents a nonhydrolyzable group, it may be selected from an optionally substituted Cl-20alkyl, C2-20alkenyl or C2-20alkynyl moiety, an optionally substituted Cl-20heteroalkyl, C2-20heteroalkynyl or C2- 20heteroalkynyl moiety, or an optionally substituted phenyl moiety, wherein the substituents on the phenyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl moieties may be independently selected from halogen, -NO2, -CN, isocyano, Cl-6alkoxy, an oxirane/epoxyde moiety, -N(R) 2 wherein each occurrence of
  • Li independently represents a responsively cleavable covalent bond, a moiety containing a responsively cleavable covalent bond or a stable covalent bond; and R 1 and R 2 independently represent an optionally substituted CI -20 alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety, wherein the Cl- 20 alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or CI -6 alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -NO2, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently
  • Rio independently represents an optionally substituted CI -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl; Ri i and R12 independently represent an optionally substituted CI -20 alkyl, Cl- 20alkenyl or C l-20alkynyl moiety, an optionally substituted C l-20heteroalkyl moiety, or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20alkenyl, Cl-20alkynyl or Cl-20heteroalkyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -NO2, -CN, isocyano, -ORp,
  • X independently represents an optionally substituted C I -20 alkylenyl moiety, wherein the CI -20 alkylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl.
  • each occurrence of A may independently represent a nucleophilic moiety, preferably one that can undergo a Michael-type nucleophilic addition onto the double bond of the monomer precursor (IV).
  • each occurrence of A may independently represent -N(Rf) 2 wherein each occurrence of Rf may represent H or Cl-6alkyl.
  • At least two different molecular crosslinker precursors A-R 1 -Li-R 2 -A are used, wherein in one molecular crosslinker precursor Li represents a responsively cleavable covalent bond or a moiety containing a responsively cleavable covalent bond as described generally and in any variant herein, and in the other Li represents a stable covalent bond.
  • Ri , R 2 , Rio, R11, R12, Li, and X may be as described generally and in any variant above, and in any combination.
  • the monomer precursor may be of formula (IVa)
  • the amount and/or concentration of monomer precursor dissolved in solution of step a) may range anywhere from 0.1% to 100% w/v.
  • it may be from 2%o to 30%o w/v, for example from 4% to 30%> w/v, preferably from 9% to 18% w/v.
  • the molecular crosslinker precursor may be any organic radical
  • the amount and/or concentration of molecular crosslinker precursor dissolved in solution of step a) may range anywhere from 0.1% to 100% w/v.
  • it may be from 0.5 % to 20% w/v, for example from 1% to 20% w/v, preferably from 2% to 8% w/v.
  • B when the process comprises in step a) selected precursor of formula B-R 8 , B may independently represent a hydrolysable or nonhydrolyzable group, wherein (i) when B represents a nonhydrolyzable group, it may be selected from an optionally substituted Cl-20alkyl, C2-20alkenyl or C2-20alkynyl moiety, an optionally substituted Cl- 20heteroalkyl, C2-20heteroalkynyl or C2-20heteroalkynyl moiety, or an optionally substituted phenyl moiety, wherein the substituents on the phenyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl moieties may be independently selected from halogen, -N0 2 , -OH, -CN, isocyano, Cl-6alkoxy, an oxirane/epoxyde moiety, -N(R) 2 wherein each
  • B may independently represent a nucleophilic moiety, preferably one that can undergo a Michael-type nucleophilic addition onto the double bond of the monomer precursor (IV).
  • each occurrence of A may independently represent -N(Rf) 2 wherein each occurrence of Rf may represent H or Cl-6alkyl.
  • R 8 may be as described generally and in any variant above.
  • R may represent an optionally substituted CI -20 alkyl moiety, a CI -20 alkyl optionally substituted with carboxyl moiety, an optionally substituted Cl- 20heteroalkyl moiety, an optionally substituted Cl-20alkylphenyl moiety or an optionally substituted phenyl moiety, wherein each of the foregoing CI -20 alkyl, Cl-20heteroalkyl or Cl-20alkylphenyl moieties may bear one or more substituents selected from halogen, -OR, -CO2R or -N(Rp)2 where R may represent H or Cl- 6alkyl, and each occurrence of Rp may independently represent H or Cl-6alkyl; and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H, Cl-6
  • R 8 may represent the residue of the corresponding amino acid H2NR 8 ;
  • R 8 may represent a C1-C6 alkyl substituted with a carboxyl moiety, a C1-C6 alkyl substituted with one or more hydroxyl groups, C1-C6 alkoxy, C1-C6 alkyl substituted with -N(Rp)2 wherein each occurrence of Rp independently represents a Cl-6alkyl;
  • R 8 may represent a C1-C6 alkyl substituted with -N(Rp)2 wherein each occurrence of Rp independently represents a Cl-6alkyl; for example a C1-C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a Cl-2alkyl.
  • R 8 may represent a C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a C 1 alkyl.
  • R 8 mar represent -(CH 2 )NMe 2 ;
  • R 8 may represent a C2 alkyl substituted with-N(Rp)2 wherein each occurrence of Rp independently represents a CI alkyl.
  • R 8 mar represent -(CH 2 )NMe 2 ;
  • R 8 may represent independently from other occurrences of R8 a Cl-20alkylphenyl moiety optionally substituted with one or more -OR wherein R may represent H or Cl-6alkyl.
  • R 8 may represent independently from other occurrences of R8 a Cl-6alkylphenyl moiety optionally substituted with one or more -OR wherein R may represent H or Cl-6alkyl.
  • R 8 may represent independently from other occurrences of R8 a Cl-6alkyl moiety bearing a catechol moiety;
  • R 8 may be independently a group of following formula:
  • R may be independently a hyaluronic acid, alginic acid, peptide, cellulose, amino acid, sugar (for example glucose, lactose or mannose derivatives), or oligonucleotide moiety;
  • R 8 may be independently a C 1 -20alkyl or C 1 -20heteroalkyl moiety, preferably C 1 - 6alkyl or Cl-6heteroalkyl, most preferably Cl-6alkyl, bearing an organosilica core/shell nanocapsule, preferably the organosilica matrix may be porous, most preferably mesoporous.
  • the organosilica core/shell nanocapsule may be degradable/disintegratable in that its shell framework contains Si adjacent sites covalently bound via a responsively cleavable linker, as described in WO 2015/189402.
  • the organosilica core/shell nanocapsule may encapsulate a bioactive macromolecule or bioactive macromolecule cluster, and/or another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity.
  • a selected precursor of general formula B-R 8 it may be selected from the group comprising:
  • the amount and/or concentration of precursor (general formula B- R 8 ) dissolved in solution of step a) may range anywhere from 0.1 % to 100% w/v.
  • it may be from 1% to 10% w/v, preferably from 1% to 5% w/v.
  • the process comprises in step a) the addition of nanoencapsulated molecules or bioactive macromolecules or bio macro molecule cluster, it advantageously allows to prepare hydrogels comprising nanoencapsulated molecules or bioactive macromolecules or bio macro molecule cluster.
  • the nanoencapsulated molecules or bioactive macromolecules or bio macro molecule cluster is as mentioned above, generally and in any variant described above, and in any combination.
  • the shell of said nanocapsule may be made of hybrid organosilica material comprising a three-dimensional framework of Si-0 bonds, wherein at least a subset of Si atoms in the material's framework are connected to at least another Si atom in the framework through a linker having the following structure:
  • each occurrence of # denotes a point of attachment to a Si atom in the hybrid organosilica material's framework
  • L 2 independently represents a responsively cleavable covalent bond or a stable bridging ligand; preferably a responsively cleavable covalent bond;
  • R 3 and R 4 independently represent an optionally substituted CI -20 alkylenyl moiety, an optionally substituted CI -20 heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety, wherein the Cl-20alkylenyl, CI -20 heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N0 2 , -CN, isocyano, -OR p , -N(R P )2 wherein each occurrence of R p independently represents H or Cl-6alkyl,
  • the nanocapsule outer surface may comprise a group of formula
  • each occurrence of # denotes a point of attachment to a Si atom in the hybrid organosilica material's framework
  • R 5 independently represents an optionally substituted Cl-20alkylenyl moiety, an optionally substituted Cl-20heteroalkylenyl moiety, an optionally substituted ethenylenyl moiety, -C ⁇ C- or an optionally substituted phenyl moiety, wherein the Cl-20alkylenyl, Cl-20heteroalkylenyl or ethenylenyl moiety may bear one or more substituents selected from halogen or -OR where R may represent H or Cl-6alkyl, and the phenyl moiety may bear one or more substituents independently selected from halogen, Cl-6alkyl, -N02, -CN, isocyano, -ORp, -N(Rp)2 wherein each occurrence of Rp independently represents H or Cl-6alkyl;
  • R 6 independently represents -OR, -SR or -N(Rf)2; preferably -N(Rf) 2 ; wherein each occurrence of R and Rf independently represents H or Cl-6alkyl.
  • #-R 3 -L2-R 4 -# may be as defined generally and in any variant above.
  • #-R 3 -L2-R 4 -# may represent independently a responsively cleavable moiety selected from:
  • #-R 3 -L 2 -R 4 -# may be introduced in the hybrid organosilica framework via a precursor
  • L 2 , R 3 , and R 4 are as defined generally and any variant above, which is chemically inserted within the framework of the hybrid organosilica matrix via sol-gel chemistry.
  • Z may independently represent a hydrolysable or nonhydrolyzable group, provided that on each occurrence of Si, at least one occurrence of Z represents a hydrolysable group.
  • occurrences of Z represent a hydrolysable group, it may be selected from a Cl- 6 alkoxy, CI -6 acyloxy, halogen or amino moiety.
  • Z may represent CI, -OMe, -OEt, -OzPr or -OtBu.
  • occurrences of Z represent a nonhydrolyzable group, they may independently be selected from an optionally substituted CI -20 alkyl, C2-20 alkenyl or C2-20 alkynyl moiety, an optionally substituted CI -20 heteroalkyl, C2-20 heteroalkynyl or C2-20 heteroalkynyl moiety, or an optionally substituted phenyl moiety, wherein the substituents on the phenyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl moieties may be independently selected from halogen, -N0 2 , -CN, isocyano, CI -6 alkoxy, an oxirane/epoxyde moiety, -N(R) 2 wherein each occurrence of R is independently selected from H or CI -6 alkyl.
  • the insertion of the responsively cleavable linker #-R 3 -L 2 -R 4 -# within the framework of the hybrid organosilica matrix may be performed during the synthesis of the hybrid organosilica material itself, no additional step is required, if not the preparation of the required (Z)3Si-R 3 -L 2 -R 4 -Si(Z)3 precursor, which may also be carried out in situ.
  • R may independently represent Me, Et, z ' Pr
  • R 5 independently represents a CI -20 alkyl moiety, for example a Cl- 6alkyl, for example CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -.
  • R 6 independently represents N, preferably -N(Rf)2 wherein each occurrence of Rf independently represents H or Cl-6alkyl, for example -NH 2 .
  • Rf independently represents H or Cl-6alkyl, for example -NH 2 .
  • the outer surface of the nanocapsule comprises a group of formula #-R 5 R 6 , it improves the attachment of the nanocapsule to the hydrogel framework.
  • a group of formula #-R 5 R 6 as defined herein comprises an amino group, it allows to covalently link the nanocapsule to the hydrogel framework.
  • the amount of organosilica (nano)particles or core/shell nanocapsules with the encapsulated active molecules can vary between 0.1 and 20% w/v (weight of the silica nanoparticles vs volume of the pre-hydrogel). For example, it may be 1%, 2%, 5%, 0.1 % depending on the elasticity and delivery that is desired.
  • the stirring in step b) may be carried out at any suitable temperature with any suitable process and/or device known to the person of ordinary skill in the art.
  • a pH adjusting agent may be used to modulate the pH to the desired value, for example in step b).
  • the pH of the solution may be adjusted using any suitable technique.
  • the pH-adjusting agent there can be mentioned, for example, acids such as sulfuric acid, hydrochloric acid and the like; and alkalis such as sodium hydroxide, ammonia and the like.
  • the pH of the reaction system may be preferably adjusted to >7, for example 7.5-10, more preferably 8-9, most preferably about 8.
  • the organic solvent in step c) may be any suitable organic solvent known to the person of ordinary skill in the art. It may be for example an organic solvent selected from the group comprising methanol, ethanol, n-propanol and/or any other protic solvent, or mixture of two or more thereof.
  • the hydrogel comprising or not the nanoencapsulated bioactive macromolecule or bioactive macromolecule cluster and/or another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity, obtained with the process of the invention may be transparent.
  • the hydrogel comprising or not the nanoencapsulated bioactive macromolecule or bioactive macromolecule cluster and/or another molecule of interest that may or may not have biological activity and/or pharmaceutical or cosmetic activity may be obtained at room temperature, for example between 20 to 35°C, in an aqueous solvent.
  • the hydrogel of the invention may be obtained according to a catalyst-free Michael -type addition.
  • the hydrogel may be formed in-situ and does not need any external agent and/or supplemental agent for the reticulation/crosslinking process.
  • the hydrogel may be formed in-situ under physiological condition.
  • Another object of the present invention relates to a hydrogel obtainable by a method of the invention.
  • Hydrogels described herein are useful for any medical application where it is desirable to fill a hole, for example a lesion, a wound, etc.
  • Hydrogels described herein as mentioned above are also useful for any application where controlled release of a molecule of interest, bioactive molecule or biomolecule cluster is desired.
  • Hydrogels described herein are also particularly adapted for uses of this type of materials where the self-destructive behavior that characterizes the core/shell silica nanocapsules and the hydrogels of the invention provides an advantage, and for applications where preservation of the biological activity of the biomacromolecule is needed.
  • the hydrogels described herein have the unexpected property of being formed in-situ without any external stimuli.
  • hydrogels described herein allow to provide a physical support, notably for in vivo medical applications, and also be biodegradable.
  • hydrogels described herein may completely lose their structural integrity (disintegration) upon application of a suitable stimuli and/or under the biological activity of proteins, for example enzymes.
  • a suitable stimuli and/or under the biological activity of proteins for example enzymes.
  • hydrogel comprising core/shell silica nanocapsules prove much more efficient in releasing and delivering macro molecules that they encapsulate (e.g., therapeutically and/or cosmetically active macro molecular principles).
  • macro molecules e.g., therapeutically and/or cosmetically active macro molecular principles.
  • release of the macromolecules trapped/encapsulated in the core/shell silica nanocapsules occurs much more efficiently.
  • compositions comprising hydrogel described generally and in any variants herein and any compound and/or additive suitable for any one or more of the material's intended use describe above.
  • compositions comprising hydrogel described generally and in any variants herein, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • compositions comprising hydrogel described generally and in any variants herein, and a cosmetically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional cosmetically useful agents.
  • a veterinary composition comprising hydrogel described generally and in any variants herein, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • a hydrogel described generally and in any variants herein, for use as medicament for use as medicament.
  • hydrogel described generally and in any variants herein, for use as medicament for sealing a wound, for enhancing tissue regeneration, fillers for example for submucosal fluid cushion for surgery, tissue reconstitution in a subject-in- need thereof.
  • hydrogel described generally and in any variants herein for use as medicament for treating diabetes or spinal cord injury.
  • hydrogel described generally and in any variants herein for use as medicament for treating hernia or ulcers.
  • hydrogel described generally and in any variants herein, in a cosmetic composition.
  • hydrogel described generally and in any variants herein, or a cosmetic composition described generally and in any variants herein, for delivering a cosmetically bioactive macromolecule and/or a cosmetically bioactive macro molecule to the skin.
  • the cosmetically bioactive macromolecule may be any cosmetically bioactive macromolecule and/or a cosmetically bioactive macromolecule known in the art. It may be, for example, selected from the group comprising collagen, keratin, elastin, calcitonin, hyaluronic acid, amino acids, retinol, antioxidants, vitamins or silk proteins.
  • hydrogels described generally and in any variants herein for use as a medicament in the treatment of cancer, preferably tumors.
  • hydrogels described herein may be injected under a tumor to be excised, preferably a solid tumor, thereby allowing the resection of the tumor with minimal lesion to the surrounding tissue.
  • the person of ordinary skill in the art taking into consideration the common technical knowledge in the medical field, would know and/or select suitable therapeutic agents that may be used in association with the hydrogel for optimizing therapeutic success of the procedure.
  • the person of ordinary skill in the art would select which therapeutic agent should be included into the hydrogel, for example in the pores and/or core of organosilica particles (plain nanoparticles or core/shell nanoparticles) that may be embedded/covalently conjugated to the hydrogel network, as detailed supra. It may be for example any anti- cancerous drug or any suitable palliative drug appropriate for this type of surgical treatment
  • hydrogel described generally and in any variants herein for delivering a cosmetically bioactive macromolecule to the skin.
  • the cosmetically bioactive macromolecule may be collagen, keratin, elastin, calcitonin or silk proteins.
  • a method for systemically delivering a bioactive macro molecule, in a biologically active form, to a subject in need thereof comprising, administering to the subject a therapeutically effective amount of a hydrogel described generally and in any variants herein.
  • the bioactive macromolecule may be selected from proteins, oligonucleotides, antibodies, peptides, PNA, DNA, RNA, gene fragments, a hormone, a growth factor, a protease, an extra-cellular matrix protein, an enzyme, an infectious viral protein, an antisense oligonucleotide, a dsRNA, a ribozyme, a DNAzyme, antibiotics, antinflammatory, steroids, chemiotherapeutics.
  • the bioactive macromolecule may be an enzyme and said biological activity is a catalytic activity.
  • the bioactive macromolecule may be a hormone and said biological activity is a ligand binding activity.
  • a unit dosage form for local delivery of a molecule to a tissue of a subject, the unit dosage form comprising, a therapeutically effective amount of a hydrogel described generally and in any variants herein or a pharmaceutical composition described generally and in any variants herein.
  • the molecule may be selected from proteins, oligonucleotides, antibodies, peptides, PNA, DNA, RNA, gene fragments, a hormone, a growth factor, a protease, an extra-cellular matrix protein, an enzyme, an infectious viral protein, an antisense oligonucleotide, a dsRNA, a ribozyme and a DNAzyme.
  • a method for treating a disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of hydrogel described generally and in any variants herein, thereby treating the disease in the subject.
  • a delivery system for sealing a wound, for enhancing tissue regeneration, fillers for example for submucosal fluid cushion for surgery, tissue reconstitution in a subject-in-need thereof comprising hydrogel described generally and in any variants herein.
  • a method of using hydrogel described generally and in any variants herein as controlled-re lease agents or carriers for macromolecular drug, protein, and vaccine delivery comprising hydrogel described generally and in any variants herein.
  • a method of using hydrogel described generally and in any variants herein for sealing acute and/or chronic wounds and/or perforation in a subject- in-need thereof comprising administering to the subject a therapeutically effective amount of a hydrogel according to the invention or a pharmaceutical composition according to the invention, thereby sealing the wound and/or perforation.
  • a method for treating a disease, preferably cancer, most preferably cancer tumor, in a subject-in-need thereof comprising administering to the subject a therapeutically effective amount of a hydrogel according to the invention or a pharmaceutical composition according to the invention, thereby treating the disease in the subject.
  • hydrogels described herein may be injected under a tumor to be excised, preferably a solid tumor, in an amount sufficient to substantially detach/disengage the tumor from surrounding tissue, thereby allowing the resection of the tumor with minimal lesion to the surrounding tissue.
  • a method for treating diabetes in a subject-in-need thereof, the method comprising administering to the subject a therapeutically effective amount of a hydrogel according to the invention or a pharmaceutical composition according to the invention, thereby treating the disease in the subject.
  • the injected hydrogel may be advantageously loaded with insulin, for example encapsulated in core-shell organosilica nanoparticles conjugated to the hydrogel, as detailed supra, for sustained release of insulin.
  • a method for treating spinal cord injury in a subject- in-need thereof, the method comprising administering to the subject a therapeutically effective amount of a hydrogel according to the invention or a pharmaceutical composition according to the invention.
  • the administration may be carried out by locally injecting the hydrogel near the site of spinal cord injury.
  • the injected hydrogel may be advantageously loaded with any drug useful for treating spinal cord injury, such as methylprednisolone, for example encapsulated in core-shell organosilica nanoparticles conjugated to the hydrogel, as detailed supra, for sustained release of the drug.
  • a method for treating hernia or ulcers in a subject- in-need thereof, the method comprising administering to the subject a therapeutically effective amount of a hydrogel according to the invention or a pharmaceutical composition according to the invention.
  • the administration may be carried out by locally injecting the hydrogel at the site of hernia or ulcer, preferably at the hernia opening to close it.
  • the injected hydrogel may be advantageously loaded with any drug useful for ancillary treating hernia or ulcers, such as anti-infection agents or anti-inflammatory drugs, for example encapsulated in core-shell organosilica nanoparticles conjugated to the hydrogel, as detailed supra, for sustained release of the drug.
  • the hydrogel according to the invention therefore can find applications in in vitro and in vivo diagnostics, therapy, in cosmetics, in drug delivery, and in any other application where a release can be envisaged or prove useful.
  • the Hydrogels described generally and in any variants herein may be advantageously formed in situ via Michael-type addition reaction under physiological conditions from mixing of the monomers in aqueous solution through the formation of amine bonds.
  • Hydrogels described generally and in any variants herein can advantageously deliver active molecules, for example during the hydrogel degradation phase, and for example potentially assisting the healing of surrounding tissue at the site of injection.
  • Hydrogels described generally and in any variants herein are preferably injectable and biodegradable.
  • hydrogels described generally and in any variants herein may undergo degradation responding to cell-secreted molecules through reductive cleavage of the linker, for example of disulfide moieties, incorporated both in the nanocapsules and in the hydrogel structures.
  • hydrogels described generally and in any variants herein may release molecules of interest, for example proteins, for example from the nanocapsules, through the degradation of the nanocapsule shell.
  • hydrogels described generally and in any variants herein show advantageously a rapid gelation when injected in vivo, and for example may afforded a long- lasting high mucosal elevation.
  • silicon particles preferably silicon nanoparticles, most preferably porous silicon nanoparticles
  • the outer surface of silicon particles will oxidize to silicon oxide when exposed to water or an aqueous environment.
  • hydrogels of the invention may comprise silicone particles, preferably silicon nanoparticles, most preferably porous silicon nanoparticles, mixed in with the hydrogel matrix or covalently bound thereto much like the organosilica particles described herein.
  • Silicon porous particles are fully degradable and have the same role of the organosilicates systems (cf. J. Mater. Chem. B, 2016,4, 7050-7059.; and Nature Materials 8, 331-336 (2009)).
  • Porous silicon has exhibited considerable potential for biological applications owing to its biocompatibility, biodegradability, and the possible surface functionalization.
  • silicon nanoparticles provide attractive chemical alternatives to other quantum dots, which have been shown to be toxic in biological environments.
  • silicon is a common trace element in humans and a biodegradation product of porous silicon, orthosilicic acid (Si(OH ) t ), is the form predominantly absorbed by humans and is naturally found in numerous tissues.
  • Si(OH ) t orthosilicic acid
  • Porous silicon particles have been filled with therapeutics and they can be engineered to degrade in vivo into benign components that clear renal ly. Therefore porous silicon particles, in particular porous silicon nanoparticles, can replace or add as component of hybrid hydrogels according to the invention.
  • any hydrogel described generally and in any variant herein may be used.
  • Figure 1 Scheme of the synthesis and functionalization of BNCs containing disulfide moiety in the framework and loaded with Cyt-C inside the silica capsule (a); SEM image of the monodispersed functionalized BNCs, in the insert SEM picture of a naked nanoparticle (b); scheme of degradation after GSH exposure and release of Cyt-C (c).
  • Figure 3 represents the swelling ratio of the hydrogels incubated with 10 ⁇ GSH solution or Phosphate Buffer Saline (PBS), showing the degradation of the network (ordinate : swelling ratio) over time (abscissa : hours).
  • Figure 3 b are image of scanning transmission electron microscope representing the fragmentation of the particles in presence of the reducing GSH after 72 hours (ii) and image of scanning transmission electron microscope representing the particles in presence of the reducing PBS after 72 hours (i).
  • Figure 3 c represents cumulative release of Cyt-C from an hydrogel according to the invention by measure of absorbance at 410 nm (ordinate) overt time in hours (abscissa)
  • FIG. 4 HDFa-mediated degradation as function of time of dPAA hydrogels, solid line, containing 2.5xl0 5 cells and control (acellular dPAA), dashed line (a); macroscopic pictures showing the cell-mediated degradation of the dPAA (b).
  • Overlay images i.e brightfield and DiD channel
  • scale bar is 100 ⁇ .
  • FIG. 6 Endoscopic views of the different steps of the ESD procedure performed using a hydrogel according to the invention (dPAA) stained with Methylene Blue. Setting of the lesion, approx. 3 cm in diameter (a); injection of the dPAA solution (b); formation of the SFC after gelation of the dPAA (c); circumferential cutting (d); complete resection with protective layer of dPAA that remained adhered to the muscolaris (e); wound left after ESD with layer of the dPAA (f).
  • dPAA hydrogel according to the invention
  • FIG. 7 Mechanism of network degradation upon exposure to GSH, schematic representation and pictures of the hydrogel network before and after degradation.
  • the yellow lines represent the disulfide units; the degradation of the hydrogel scaffold occurs at the disulfide cleavage site by thiol-disulfide exchange.
  • FIG. 8 Swelling ratio of the hydrogels comprising nanoparticles containing different cystamine amounts, incubated with 10 ⁇ GSH solution, showing the degradation of the network (ordinate : swelling ratio) over time (abscissa : hours). Hydrogel containing 10 wt% of cystamine is displayed in green, the one with 40 wt% is in red; dPAA was added as a reference.
  • FIG. 9 Viability of HDFa onto the degradable nanocomposite measured with alamarBlue assay (a).
  • the plot displays the percentage of reduced alamarBlue, which is proportional to the cell metabolic activity of the cells, as function of time. The result shows an increase in metabolic activity, thus indicates the proliferation of cells onto the scaffold.
  • Proliferation of the cells in 3D (b); 3-channel visualization of the HDFa (c), scale bar is 100 ⁇ .
  • Cells in (b) and (c) were stained with Vybrant DiD (grey) to facilitate the imaging.
  • Figure 10 Injection of the dPAA solution stained with Methylene Blue via a surgical 23- gauge needle (a); formation of a mucosal elevation (b); gelation occurred in less than 10 minutes, achieving a solid and elastic hydrogel, adhered to the tissue.
  • Figure 14 Schematic representation of the light-induced cleavability experiments and SEM images of the investigated organosilica particles comprising light-induced cleavable linkers within the organosilica matrix.
  • hydrogels comprising particles synthesis and in-vitro and in- vivo uses Materials and methods ABBREVIATIONS
  • Redox-cleavable nanocapsules Synthesis Triton X-100 (7.08 mL) and n-hexanol (7,20 mL) were dissolved in Cyclohexane (30 mL). Separately, 1,20 mL of a 5 mg/mL aqueous solution of Cytochrome C from equine heart were mixed with 0, 16 of tetraethyl orthosilicate and 0,24 mL of bis [3 (triethoxy sily l)propy 1] disulfide .
  • the procedure can be adapted for the encapsulation of different globular proteins.
  • NPs also designated NH2-CytC@BNPs
  • NPs NH2-CytC@BNPs
  • Redox-responsive degradable hydrogel functionalized with silica nanoparticles 200 mg of methylenbisacrylamide (MBA), 65 mg of cystamine hydrochloride and 70 ⁇ ⁇ of ⁇ , ⁇ -dimethylethylendiamine are mixed together with 1.0 mL of a 1 mg/mL solution of NH2-functionalized breakable nanocapsules.
  • the procedure can be modified and other NH2-functionalized silica nanoparticles can be used, such as breakable or non-breakable mesoporous silica nanoparticles.
  • NH2-CytC@BNPs refers to NH2-functionalized core/shell redox-cleavable nanocapsules described above.
  • NH2-MSPs refers to NH2-functionalized hybrid light-sensitive MSPs described in Example 1.3 below.
  • the obtained solution was transferred to glass vials (500 ⁇ per vial) and allowed to react in static conditions at r.t. Glass vials with inner diameter of 8 mm were used as molds. The hydrogels were obtained after 48 hours.
  • the disk-shaped hydrogels were freeze-dried and weighted. Dried hydrogels were used to study the swelling ratio at different pH and the degradation kinetics with different concentrations of GSH. This step allowed us as well to sterilized the materials for in vitro experiments.
  • reaction product could be obtained in a 53% of yield and had been characterized by ! H- NMR and 13 C-NMR, FTIR spectroscopy and ESI- mass spectrometry. Furthermore the absorption spectra had been recorded for further light breakability experiments of the linker itself.
  • the light-induced breakability of the DCNS compound had been performed by irradiating the compound with light produced by a Hg lamp.
  • the compound was dissolved in DMSO-d 6 in a NMR tube.
  • the photo degradation could be followed by recording 'H-NMR spectra over a certain period of time. Indeed the photogradation reaction could be observed and it is indicated by the signal derived from the aldehyde proton at 10.92 ppm (Fig. 11).
  • model spherical MSPs were synthesised.
  • the model particles were synthesized according to a modified Stober synthesis, shown in Scheme 2
  • the model particles obtained were spherical characterized by an average diameter of ca 200 nm (SEM, TEM and DLS analysis in Fig. 12). Furthermore these model particles possess a hexagonal mesostructure with an estimated average pore size of 2.5 nm (see SAXS and pore size distribution in Fig. 12)
  • the hybrid light-sensitive MSPs may be further functionalized, as described for core/shell nanocapsules above, for covalent incorporation as crosslinkers into hydrogel networks.
  • 40 mg of hybrid light-sensitive MSPs are suspended in 5 mL of ethanol.
  • the resulting NH2-functionalized hybrid light-sensitive MSPs (NPs, also designated NH2-MSPs herein) are then washed five times with distilled water and dried.
  • the diether compound can be prepared from 5-hydroxy-2-nitrobenzylalchol through allylation and subsequent hydrosilylation reaction, as depicted in Scheme 4. The synthetic steps are described in detail in Scheme 5.
  • Adhesive MBA (mg) 200,00 GABA (mg) 66,00
  • Adhesive MBA (mg) 200,00 GABA (mg) 66,00
  • Adhesive MBA (mg) 200,00 GABA (mg) 66,00
  • Adhesive MBA (mg) 200,00 GABA (mg) 66,00
  • Adhesive MBA (mg) 200,00 GABA (mg) 67,00 (mg) 10,00
  • a 1 mm thick hydrogel cylinder is lyophilized and its dry weight is recorded.
  • the hydrogel is then placed in a vial and 5 mL of a 10 ⁇ solution of reduced GSH are added.
  • the swelling of the hydrogel is recorded at the appropriate time- points.
  • the experiment is repeated in triplicated and then with a solution of GSH 10 mM and with a solution of PBS as a reference.
  • the lyophilized hydrogels samples were incubated at 37 °C in 2 mL of a PBS solution with a GSH concentration of 10 ⁇ .
  • dPAA hydrogels were incubated in PBS alone as a control.
  • SR were measured by a gravimetric method.
  • lyophilized hydrogel samples were immersed in PBS at 37 °C. Then, the samples were removed from PBS at set time points (after lh, 6h, 12h, 24h, 48 h, 72 h, 144 h), blotted free of surface water using filter paper and their swollen weights were measured on an analytical balance.
  • the SR were then calculated as a ratio of weights of swollen hydrogel (Ws) to dried hydrogel (W), using the following equation:
  • Degradation time was defined as the time where there were no longer sufficient crosslinks to maintain the 3D network and the material was completely disintegrated. Experimentally,complete degradation was determined when we could observe a limpid solution, without solid residues.
  • HDFa were grown in Medium 106 supplemented with Low Serum Growth Supplement (LSGS, Thermo Fisher).
  • LSGS Low Serum Growth Supplement
  • Cells were kept in 75 cm 2 culture flasks (Corning Inc., NY, USA) at 37 °C with a controlled atmosphere of 5% C0 2 and were grown until reaching 80 to 85% of confluence. Then, they were washed twice with PBS and treated with trypsin/EDTA solution to detach them from the flask surface. Cells were split every 2-3 days; the medium was changed every other day.
  • hydrogel scaffolds equilibrated by adding culture media at 37°C.
  • HDFa were detached from the culture flask by trypsination and approximately 2.5xl0 5 cells were seeded onto the hydrogel scaffolds. Then, the samples were placed in the incubator (37°C, 5% CO2) for about 30 minutes and fresh media was cautiously added on the top of the hydrogels to supply cells with nutrients. This was done to allow anchorage of the cells onto the scaffolds.
  • the viability of cells after complete degradation of the dPAA was measured by with a TC20 (trade mark) Automated Cell Counter (Bio-Rad).
  • HDFa were stained withVybrant DiD (Life Technologies, Thermo Fisher Scientific, Waltham, MA, USA), following the reported protocol, prior to seeding them onto the scaffolds.
  • the hydrogel were freeze-dried and weighed (W). Then 2.5xl0 5 HDFa were seeded onto the samples (see above). The cell-laden samples were collected at pre-determined time points and were freeze-dried to obtain their dry weight after degradation (W).
  • Acellular hydrogels were used as degradation control.
  • Fresh porcine stomachs were used for the ex vivo tests.
  • the hydrogel solution was injected into the submucosal layers of the pig stomach using a 23 -gauge needle.
  • the dose was 2 ml for each sample and the stomach was kept to a temperature of about 37 °C with a lamp to ensure simulation of in vivo conditions.
  • Gelation of the dPAA samples was assessed by cutting open the tissue after the desired time. The experiment was repeated three times.
  • the pig was fasted for 1 day before operation.
  • Endoscopy was performed by the surgeon.
  • a standard endoscope (Karl Storz, Tuttlingen, Germany) was used in the pig under general anesthesia. Both the dPAA solution and the NS used as control contained a small amount of Methylene Blue as a color agent in order to facilitate visualization of the SFC. After setting appropriate lesion sizes of approx. 3 cm in diameter in the porcine stomach, 810 ml of dPAA solution and NS were injected in the stomach submucosa through the endoscope accessory channel using a 23-gauge injection needle.
  • the mucosal elevation due to the injected dPAA at the target site was observed endoscopically before starting the ESD. It was compared under direct view with the elevation caused by NS during the procedure.
  • the animal was euthanized after completion of experiments; the whole procedure was followed and recorded using a Silver Scope tm Video Gastroscope (Karl Storz, Tuttlingem, Germany).
  • the main outcome measures were (1) the rapid gelation of dPAA when injected into the submucosa and (2) the long-lasting SFC formed; (3) the feasibility of the dissection procedure during ESD; (3) the adhesion of dPAA to the muscolaris layer and thus the increase of protection during the procedure and after it.
  • a degradable nanocomposite hydrogel also called dPAA below, was synthetized and characterized. It is composed of a polyamidoamines-based network with embedded breakable silica hollow nanocapsules, BNCs.
  • Both, the BNCs and the polymeric backbone of the scaffold contain disulfide linkers that could be cleaved in presence of glutathione (GSH).
  • GSH glutathione
  • the nanocomposite could be completely degraded even at a very low concentration of GSH (i.e. 10 ⁇ ), which was chosen to mimic the extra-cellular environment. Degradation and release kinetics of model protein cytochrome, loaded into the particles, were evaluated.
  • the cell-mediated degradation of dPAA in the presence of adult Human Dermal Fibroblasts (HDFa) proliferating onto the scaffolds was tested.
  • the assay demonstrated the achievement of cell-controlled degradation of the material; complete dissolution of the scaffold was observed after 96 hours when 2.5 x 10 5 cells were seeded onto the nanocomposite.
  • the injection of the hydrogel solution i.e. before complete gelation
  • the dPAA was able to provide a stable and long-lasting mucosal elevation when tried as SFC.
  • dPAA was tested as SFC for ESD procedures in vivo, on a porcine stomach.
  • the formation of the hydrogel and SFC in vivo was observed after 3 minutes and allowed the surgeon to perform the ESD procedure with a single injection.
  • the adherence of part of the dPAA to the muscularis layer not only protected it during the procedure but also potentially offers several advantages in the phase following the surgery.
  • the cell-mediated degradation of the nanocomposite indeed has shown to lead to the release of the active component loaded into the particles. This behavior could be exploited to release antibiotics or active factors to assist the healing of the wounded tissue and finally to achieve a complete clearance of the hydrogel form the body.
  • the nanocapsules used are those disclosed in E. A. Prasetyanto, A. Bertucci, D. Septiadi, R. Corradini, P. Castro-Hartmann, L. De Cola, Angew. Chem. Int. Ed. 2016, 55, 3323. [21].
  • This platform is composed of a silica shell able to encapsulate functional proteins in their active folding and it is engineered to degrade upon contact with a reducing agent, such as GSH present in the biological environment with a complete release of the loading.
  • hydrogel comprising these BNCs to construct hydrogels comprising nanoparticles or nanocapsule able to release active molecules during the degradation of the material.
  • Cytochrome C (Cyt-C) was chosen as model cargo, since its strong absorption in the visible region allowed us to investigate the release kinetics during the hydrogel degradation.
  • the surface functionalization was confirmed by the shift from negative to positive values of the ⁇ -potential, from -10.5 mV of the pristine nanocapsules to + 2.2 mV.
  • the functionalized BNCs (1 mg/ml) were used to synthetize the dPAA nanocomposite hydrogel through surface-grafting of the aminated BNCs to the polyamidoamine backbone of the scaffold.
  • the inventors designed the network of the dPAA to achieve a degradation that could be triggered by cells proliferating onto the material, without the need of any additional stimulus.
  • a crosslinker for example a disulfide
  • Disulfide bonds are susceptible of thiol exchange in the presence of reducing agents, such as glutathione (GSH), which is a cell metabolite.
  • the inventors demonstrated that the reducing microenvironment given by the presence of GSH in the extra-cellular environment could trigger the cleavage of the disulfide bonds, therefore providing the dissolution of the scaffold.
  • Disulfide-modified polyamidoamines-based hydrogels containing BNCs were synthesized following the previously reported method with some modifications. 117] In particular, amino groups on BNCs were reacted with the unsaturated moiety of methylenbisacrylamide (MBA) through a one-pot Michael poly-addition in water, at room temperature ( Figure 2a)
  • FIGS. 2a,b show a schematic representation of the synthesis and structure of the nanocomposite network.
  • the morphological analysis of the obtained hydrogel scaffolds was assessed via scanning electron microscopy (SEM) of the lyophilized scaffolds. SEM showed a highly porous structure, with pores diameter in the range of 40 to 100 ⁇ , as can be seen in Figure 2d.
  • hydrogels should maintain the required mucosal elevation for a determined time (i.e. 30 min to 1 hour), and then degrade into fragments, in order to have a complete clearance from the body.
  • the nanocomposite presented in this work was degradable upon exposure to GSH, via the incorporation of cystamine cross-links throughout the polymeric network and in the particle (BNCs) framework.
  • the potential degradation mechanism of the network is shown in Figure 7.
  • the degradation kinetics of the dPAA was examined by measuring swelling ratio variations as function of time in the presence of a low concentrated GSH solution (i.e. 10 ⁇ GSH solution in PBS), mimicking the extracellular environment. Hydrogels, incubated in PBS in the absence of GSH were used as control.
  • a low concentrated GSH solution i.e. 10 ⁇ GSH solution in PBS
  • the swelling ratio curve of dPAA showed two different phases: an initial phase where clear increase in swelling was observed, followed by a rapid downward phase (Figure 3a).
  • the imbibing of the solvent into the hydrogel caused the initial increasing phase. This was then quickly outweighed by the cleavage of the disulfide bonds, leading to the complete degradation of the hydrogel.
  • a clear point of reverse gelation defined as the point where there are less than 2 crosslinks per polymer chain and the branched polymer chains dissolve, [22] was identified after 24 hours.
  • the dPAA equilibrated in PBS showed instead a first phase of swelling followed by a plateau that was reached after 24 hours, demonstrating that the nanocomposite is stable in absence of reducing agent. The swelling was followed for 6 days.
  • the degradation profiles of the three samples are reported in Figure 8.
  • the degradation time was found to be proportional to the amount of disulfide crosslinker; in particular a decrease was observed with the scaffold containing 10 wt% of cystamine, which completely after 24 hours. Instead the sample crosslinked with an higher amount of cystamine (40 wt%) displayed a longer degradation profile, terminating after 6 days with the complete disintegration of the network.
  • the degradable hydrogel was decorated with breakable nanocapsules able to degrade with the same mechanism of the hydrogel, through the reduction of the disulfide bonds, and able to release their content.
  • Cytochrome-C Cyt-C was used as a model protein to study the release kinetics thanks to its strong absorption in the visible region, due to the presence of the erne group.
  • the BNCs were thus embedded into the dPAA and the Cyt-C released from the nanocomposite was investigated, by incubating the scaffold in the 10 ⁇ solution of GSH in PBS.
  • the cumulative release of Cyt-C from the dPAA is reported in Figure 3c and shows a slow release in the first 6 hours, followed by an increase of detected Cyt-C.
  • the release was observed by measuring the absorbance of the solution at 410 nm.
  • the release of Cyt-C from the scaffold is highly augmented by the degradation of the hydrogel structure, which can be seen from the shape of the curve between 24 and 72 hours, showing a steep growth in absorption.
  • the overall amount of protein release from the scaffold was estimated to be 67% of the initial loading.
  • HDFa Human Dermal Fibroblast
  • the dPAA hydrogels for this test were synthetized in a 8 mm diameter and ⁇ 1 mm height disc shape and. 2.5 x 10 5 HDFa were seeded onto the hydrogels and cultured in the corresponding growth medium; acellular hydrogels incubated in growth medium were used as control.
  • FIG. 9a AlamarBlue assay indicated that the majority of the encapsulated cells were viable and proliferating onto the scaffold (Figure 9a) up to 4 days. This is consistent to what has been observed for similar polyamidoamines-based scaffolds and it confirmed that hydrogel containing disulfide moieties supported cell encapsulation and viability.
  • Figure 9b displays an image of the 3D proliferation of the cells stained in red (Vibrant DiD stain) for better visualization, indicating that they permeate in the depth of the scaffold.
  • a 3-channel visualization of the surface of the dPAA is reported in Figure 9c and is indicative of the growth of the cells onto the scaffold.
  • the hydrogel underwent degradation responding to cell-secreted GSH, in the absence of any external stimulus.
  • many cell surface molecules contain thiol groups and thus could contribute to the cleavage of the disulfide bonds of the network.
  • the scaffold resulted largely reduced in size and weight after 72 hours and the complete degradation was achieved after 96 hours.
  • the hydrogel according to the invention is a material that could be delivered in vivo via injection, and then rapidly gel inside the body.
  • Polyamidoamine-based hydrogels have the great advantage of allowing network formation under physiological conditions.
  • the nanocomposite hydrogel was found completely adhered to the submucosal layer and it had to be removed with scissors and tweezers. Moreover, it was confirmed that there had not been diffusion of the solution into the surrounding tissues.
  • the investigation of injectability and gelation time was then performed in vivo.
  • the hydrogel (dPAA) showed a gelation time of approximately 3 minutes when injected in the submucosal layer in a living pig.
  • the formation of mechanical entanglements between the collagen fibers and the dPAA backbone advantageously may also contribute to the formation of an interpenetrated hydrogel network, favoring the faster formation of a stable and elastic hydrogel in situ. This behavior was observed via SEM of the explanted tissues, which showed interactions between the hydrogel scaffold and collagen fibers (Figure 5a).
  • the hydrogel according to the invention comprising nanocomposite displayed higher mucosal lifting, 8.3 mm vs 6.7 mm, for the dPAA and the NS respectively, with the same amount of solution injected. This showed that already part of the NS solution was absorbed by the surrounding tissues after 10 seconds.
  • this example demonstrates the higher performance of the hydrogel of the invention nanocomposite in the formation of a higher and longer lasting mucosal elevation.
  • dPAA in vivo efficacy of hydrogel according to the invention
  • the ESD procedure was performed in triplicate in different areas of the same porcine stomach; NS solution was used as control.
  • Figure 6a is reported the endoscopic view of the stomach at time 0 before the injection of the pre-hydrogel solution. It shows the set of an appropriate lesion of approx. 3 cm in diameter.
  • the mucosal lifting obtained with dPAA allowed the surgeon to perform the entire ESD procedure (40 min) without requiring a second injection, therefore significantly simplifying the procedure and avoiding large injection of liquids.
  • Biomolecules such as adrenaline, proton-pump inhibitors or antibiotics could potentially be efficiently delivered to assist the cauterization of the resected tissue or the prevention of inflammations.
  • the design of the nanocomposite hydrogel enhances the versatility of the system, enabling the selection of different possible releasing factors, personalized in relation to the patient's requirements.
  • hydrogel of the invention in particular a degradable nanocomposite hydrogel was successfully developed by embedding breakable nanocapsules into a disulfide-containing polyamidoamines-based hydrogel.
  • a degradable nanocomposite hydrogel was successfully developed by embedding breakable nanocapsules into a disulfide-containing polyamidoamines-based hydrogel.
  • the example demonstrate that disulfide bonds of the embedded BNCs and of the network can be completely cleaved in 3 days when the hydrogel is incubated in a GSH solution mimicking the extra-cellular concentration (10 ⁇ ).
  • hydrogel according to the invention sustained the proliferation of HDFa and underwent complete degradation in response to cell-secreted molecules from HDFa seeded onto the scaffold without any external stimulus.
  • the degradation of the nanocomposite allowed the release of a model protein encapsulated into the BNCs.
  • the obtained hydrogel according to the invention can be delivered to the desired tissue, for example by facile injection through a 23-gauge needle. Its applicability in- vivo models was proved: the aqueous hydrogel solution was injected in the submucosa of a porcine stomach in vivo. It formed an elastic hydrogel in 3 minutes most likely due to temperature increase and interaction with collagen fibers present in the submucosal layer of the mammals.
  • hydrogel according to the invention is a novel injection agent, for example subcutaneous, for example for use in ESD.
  • the example demonstrate that the hydrogel formed a reliable SFC in vivo, enabling a long-lasting mucosal elevation, which was superior to commonly used NS. This facilitated en bloc resection of the lesion, which was successfully accomplished with just a single injection.

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Abstract

L'invention concerne un hydrogel, en particulier dégradable ou non dégradable, comprenant des monomères de formule (I) et des particules organosiliciques ou des particules poreuses de silicium liées par covalence à ceux-ci, éventuellement avec des particules organosiliciques et/ou de silicium liées de manière non covalente, mélangées à celles-ci, en particulier des nanoparticules organosiliciques dégradables ou des nanocapsules de type noyau-coquille dégradables ; des compositions pharmaceutiques, vétérinaires ou cosmétiques correspondantes ; et des utilisations correspondantes en tant que médicament. La présente invention trouve des applications dans les domaines techniques médicaux thérapeutiques et diagnostiques ainsi que dans les domaines techniques cosmétiques et vétérinaires.
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WO2022053875A1 (fr) * 2020-09-09 2022-03-17 Teoxane SA Hydrogel comprenant un polysaccharide reticule et silyle et son procede d'obtention
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WO2022053875A1 (fr) * 2020-09-09 2022-03-17 Teoxane SA Hydrogel comprenant un polysaccharide reticule et silyle et son procede d'obtention
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