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Review

Subcutaneous sustained-release drug delivery system for antibodies and proteins

  • Received: 23 December 2024 Revised: 22 February 2025 Accepted: 06 March 2025 Published: 13 March 2025
  • Subcutaneous (SC) sustained release is an important drug delivery system (DDS) for antibody/protein drugs because it reduces dosing frequency. This review discusses formulations and biophysical parameters that affect the pharmacokinetics (PK) of DDSs. For example, SC injectable microspheres and polymeric hydrogels, as well as intradermal microneedles, suppress denaturation in loading and burst release of drugs [growth hormone, interferon-α2b, bevacizumab, and single-chain antibody fragment (scFv)]. These DDSs significantly prolong half-life (t1/2) in plasma with low maximum concentration (Cmax) and low relative bioavailability after SC dosing to animals and/or humans. Formulation parameters, such as (1) drug loading amount, (2) drug diffusion in DDS, (3) interactions of drugs with polymers, and (4) microneedle design, likely contribute to their PK profiles. This review also discusses the effects of many biophysical parameters on PK, including (5) in vivo behavior of polymers (swelling, aggregation, dissolution, and accumulation), (6) drug interactions with extracellular matrix and hypodermis diffusion, (7) drug unfolding, (8) hypodermic concentration of drugs, inherent proteins, and cells, (9) drug absorption through lymphatic or blood vessels, (10) degradation of drugs/polymers by proteases/phagocytic cells, (11) FcRn-mediated recycling, (12) FcγR-mediated endocytosis, and (13) target-mediated drug clearance. For safe dosing, (14) skin's thickness/viscoelastic properties and variations and (15) skin's recovery are also important factors. Consideration of these effects will increase the developmental speed and success of many SC sustained-release DDSs of antibody/protein drugs.

    Citation: Takayuki Yoshida, Hiroyuki Kojima. Subcutaneous sustained-release drug delivery system for antibodies and proteins[J]. AIMS Biophysics, 2025, 12(1): 69-100. doi: 10.3934/biophy.2025006

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  • Subcutaneous (SC) sustained release is an important drug delivery system (DDS) for antibody/protein drugs because it reduces dosing frequency. This review discusses formulations and biophysical parameters that affect the pharmacokinetics (PK) of DDSs. For example, SC injectable microspheres and polymeric hydrogels, as well as intradermal microneedles, suppress denaturation in loading and burst release of drugs [growth hormone, interferon-α2b, bevacizumab, and single-chain antibody fragment (scFv)]. These DDSs significantly prolong half-life (t1/2) in plasma with low maximum concentration (Cmax) and low relative bioavailability after SC dosing to animals and/or humans. Formulation parameters, such as (1) drug loading amount, (2) drug diffusion in DDS, (3) interactions of drugs with polymers, and (4) microneedle design, likely contribute to their PK profiles. This review also discusses the effects of many biophysical parameters on PK, including (5) in vivo behavior of polymers (swelling, aggregation, dissolution, and accumulation), (6) drug interactions with extracellular matrix and hypodermis diffusion, (7) drug unfolding, (8) hypodermic concentration of drugs, inherent proteins, and cells, (9) drug absorption through lymphatic or blood vessels, (10) degradation of drugs/polymers by proteases/phagocytic cells, (11) FcRn-mediated recycling, (12) FcγR-mediated endocytosis, and (13) target-mediated drug clearance. For safe dosing, (14) skin's thickness/viscoelastic properties and variations and (15) skin's recovery are also important factors. Consideration of these effects will increase the developmental speed and success of many SC sustained-release DDSs of antibody/protein drugs.



    Throughout this paper, we denote a field by k, an algebra R means a finite dimensional algebra over k, modR denotes the category of all finitely generated right R-modules, while indR denotes a full subcategory of modR containing one representative of each isomorphism class of indecomposable R-modules. We will use freely Auslander-Reiten translation τ=DTr, irreducible maps and properties of the Auslander-Reiten sequences. For an R-module X, the injective hull of X will be denoted by E(X), the projective (resp. injective) dimension of X will be denoted by pdRX (resp. idRX), and the global dimension of R will be denoted by gl.dimR.

    As a proper generalization of tilted algebras, Happel has introduced quasi-tilted algebras in [1]. An algebra R is called quasi-tilted if it satisfies the two conditions: (ⅰ) If U is an indecomposable R-module, then pdRU1 or idRU1, and (ⅱ) gl.dimR2.

    Let R and S be algebras and N be a finite dimensional left-S, right-R bimodule over k, and set

    T=(R0NS)={(r0ns)rR,nN,sS}.

    Meanwhile, the addition and multiplication are defined as follows:

    (r10n1s1)+(r20n2s2)=(r1+r20n1+n2s1+s2),
    (r10n1s1)(r20n2s2)=(r1r20n1r2+s1n2s1s2).

    Then, T is a finite-dimensional k-algebra, and T is called a generalized lower triangular matrix algebra.

    It follows from a result of [1] that every quasi-tilted artin algebra is isomorphic to a generalized lower triangular matrix algebra (R0NS), where R and S are hereditary. So to find all quasi-tilted algebras, it is enough to investigate when such generalized lower triangular matrix algebras are quasi-tilted.

    The conditions for the one-point extension algebra of a quasi-tilted algebra to be again quasi-tilted were given by Huard [2] and Coelho [3,4]. Recently, [5] has obtained a new proof concerning quasi-tilted algebras. In [6], Assem characterized cluster-tilted and quasi-tilted algebras. For more results, one can see [7,8,9].

    The construction of the generalized lower triangular matrix ring or algebra is a major issue in ring and algebraic representation theory, and it has been often used to construct counterexamples in rings and modules. Following [10], Gorenstein conditions over formal triangular matrix rings are studied by Enochs, and Gorenstein-projective modules over triangular matrix Artin algebras are also studied by Xiong and Zhang in [8]. As for more examples of generalized lower triangular matrix algebras, we refer to [7,11,12] and so on.

    Based on the above discussion, it is meaningful to discuss quasi-tilted property of generalized lower triangular matrix algebra. In the present paper, we consider the problem of characterizing when a generalized lower triangular matrix algebra is quasi-tilted.

    It is widely known that modT is equivalent to a category Ω of triples (U,W,φ), where UmodR,WmodS and φ:WSNU is a map in modR. The right T-module which corresponds to (U,W,φ) is the additive group UW with right T-action given by:

    (u,w)(r0ns)=(ur+φ(wn),ws).

    We consider the right T-modules as triples (U,W,φ). Given (U1,W1,φ1) and (U2,W2,φ2), a morphism f:(U1,W1,φ1)(U2,W2,φ2) is a pair (f1,f2), where f1:U1U2 is homomorphism in modR and f2:W1W2 is homomorphism in modS; furthermore, we can get that

    W1SNφ1U1f21 f1W2SNφ2U2

    is a commutative diagram. If f=(f1,f2):(U1,W1,φ1)(U2,W2,φ2) is a homomorphism map, then we have f is surjective (resp. injective) if and only if f1:U1U2 and f2:W1W2 are surjective (resp., injective).

    It is well-known that the right T-module (U,W,φ) is a projective module if, and only if, (U/φ(WN))R and WS are projective modules and φ:WNU is one-one. So, we can get the following.

    The T-module (U,W,φ) is a projective module if, and only if, WS is a projective module, φ:WNU is monic, and U=Pφ(WN), where PR is projective.

    For a right T-module (U,W,φ), define

    ˜φ:WHomR(N,U)

    given by ˜φ(w)(n)=φ(wn) for nN,wW. Then, we can get ˜φ is an S-homomorphism.

    The right T-module (U,W,φ) is an injective module if, and only if, UR is an injective module and the map Φ:WHomR(N,U)E(ker˜φ) given by Φ(w)=(˜φ(w),τ(w)) is an isomorphism of right S-modules, where τ:WE(ker˜φ) is an extension of the inclusion ker˜φE(ker˜φ).

    We know that a right T-module (UR,0,0) is a projective module if, and only if, UR is projective, hence, pdT(UR,0,0)=pdRUR. A right T-module (UR,0,0) is an injective module if, and only if, UR is an injective module and HomR(N,U)=0. A right T-module (0,WS,0) is a projective module if, and only if, WS is projective and WN=0. A right T-module (0,WS,0) is injective if, and only if, WS is injective, hence, idT(0,WS,0)=idSWS.

    In this section, we consider the problem of characterizing when a generalized lower triangular matrix algebra is quasi-tilted.

    Suppose T=(R0NS) is a generalized lower triangular matrix algebra, while Goodearl [2] gave a condition for T to be hereditary.

    Theorem 1 [13]. T is a hereditary ring if, and only if,

    (1) R and S are both hereditary.

    (2) SN is a projective module.

    (3) (N/IN)R is projective for all ISS.

    We know HomR(WSN,U)σHomS(W,HomR(N,U)); for φ:WNU, let φ:WHomR(N,U) be the map corresponding to φ, that is, σ(φ)=φ. So, we can get the following result.

    Theorem 2. Suppose T=(R0NS),(U,W,φ) is a right T-module such that φ is a monomorphism. Then, the following conditions are equivalent.

    (1) idT(U,W,φ)1.

    (2) There exists an exact sequence 0WHomR(N,I0)HomR(N,I1)I20 with I0,I1,I2 injective R-modules and idRU1.

    Proof: Since HomR(WSN,U)σHomS(W,HomR(N,U)), we can view (U,W,φ) as the triple (U,W,φ).

    Suppose

    0UiI0(U)I1(U)

    is a minimal injective resolution of U; thus, we can get

    HomR(N,U)HomR(N,i)HomR(N,I0(U)).

    Set φ=HomR(N,i)φ, then φ is a monomorphism because φ is a monomorphism. We have that

    (U,W,φ)(i,φ)(I0(U),HomR(N,I0(U)),1)

    is an injective envelope of T-module (U,W,φ).

    Then, we can get the following diagram:

    0WφHomR(N,I0(U))HomR(N,I0(U))/φ(W)0φ||g0HomR(N,U)HomR(N,I0(U))HomR(N,I0(U)/i(U)).

    So, Coker(i,φ)=(I0(U)/i(U),HomR(N,I0(U))/φ(W),g). The injective envelope of Coker(i,φ) is

    (I1(U),HomR(N,I1(U)),1)(0,E(I),0),

    where I=kergCokerφ. Set F=HomR(N,), hence, idT(U,W,φ)1 if, and only if,

    0(U,W,φ)(i,φ)(I0(U),F(I0(U)),1)(I1(U),F(I1(U)),1)(0,E(I),0)0

    is exact if, and only if,

    0UI0(U)I1(U)0

    and

    0WF(I0(W))F(I1(U))E(I)0

    are exact.

    Given an algebra C, suppose LC denotes the subset of indC defined by

    LC={UindC|pdCW1for each predecessor Wof U}.

    Also, we denote the full subcategory of LC of direct summands of finite direct sums of copies of LC by addLC.

    We now give the following necessary conditions for generalized lower triangular matrix algebra R to be quasi-tilted.

    Theorem 3. Let T=(R0NS). If T is quasi-tilted, then

    (1) Both R and S are quasi-tilted.

    (2) NRaddLR.

    Proof: Since T is quasi-tilted, we have gl.dimT2, and it follows from [3] that gl.dimR2,gl.dimS2.

    (1) If S is not quasi-tilted, then there is an indecomposable R-module WS with pdSW=2=idSW. Since idT(0,WS,0)=idSW=2 and T is quasi-tilted, we know that pdT(0,WS,0)1. Assume that π:PWS is a projective cover of WS, let ZS be the kernel of π, then (0,π):(PN,P,1)(0,WS,0) is a projective cover of (0,WS,0) with kernel (PN,ZS,g). Since pdT(0,WS,0)1, we know that (PN,ZW,g) is a projective T-module, and then ZW is a projective S-module, thus, pdSW1. This contradicts that pdSW=2, so S is quasi-tilted.

    If R is not quasi-tilted, then there exists an indecomposable R-module UR with pdRU=2=idRU. Since pdT(UR,0,0)=pdRU=2 and T is quasi-tilted, we know idT(UR,0,0)1, and by Theorem 2, idRU1. This contradicts that idRU=2, so R is quasi-tilted.

    (2) By (1), R is quasi-tilted. If some indecomposable summand N1 of N is not in LR, then, by definition of LR, there exists some indecomposable predecessor UR of N1 such that pdRU=2. Then, pdT(U,0,0)=2, and by [4], there exists an indecomposable injective T-module L such that HomT(L,τ(U,0,0))0. Thus, we have a sequence

    Lτ(U,0,0)(U,0,0)(N1,0,0)(N1,S,1)

    of nonzero maps between indecomposable T-modules starting with an injective module and ending with a projective module. Because no refinement of the path can be sectional, we have a contradiction to T being quasi-tilted. So, MRaddLR.

    Corollary 4 [1]. Suppose k is a field, and T=R[N]=(R0Nk) is the one-point extension of R by N. If T is quasi-tilted, then

    (1) R is quasi-tilted.

    (2) NaddLR.

    Next, we will investigate what conditions need to be added to ensure that T=(R0NS) is quasi-tilted.

    To investigate when T=(R0NS) is quasi-tilted, we first investigate when gl.dimT2. By [1], we have:

    Lemma 5. Let R and S be finite dimensional algebras over a field k and N a S-R bimodule finite dimensional over k. Let T=(R0NS). Then, we can get

    gl.dimT=max{gl.dimR,gl.dimS,pdSkRopN+1}.

    From this, we get that gl.dimT2 if, and only if, gl.dimR2 and gl.dimS2 and pdSkRopN1. From Lemma 5, we have

    Theorem 6. Let T=(R0NS),(U,W,φ) be a right T-module. Then,

    pdT(U,W,φ)sup{pdRU,pdT(0,W,0)}.

    If WS is a projective module, then

    pdT(U,W,φ)sup{pdRU,pdRN+1}.

    Proof: Consider the following exact sequence:

    0(U,0,0)(1U,0)(U,W,φ)(0,1W)(0,W,0)0

    in mod T. Then, it follows from a well-known result that

    pdT(U,W,φ)sup{pdT(U,0,0),pdT(0,W,0)}.

    Since pdT(U,0,0)=pdRU, then

    pdT(U,W,φ)sup{pdRU,pdT(0,W,0)}.

    If WS is a projective module, then we can get the following exact sequence:

    0(WN,0,0)(1,0)(WN,W,1)(0,1)(0,W,0)0

    in mod T. Because (WN,W,1) is projective, we can get that

    pdT(0,W,0)=pdT(WN,0,0)+1=pdRWN+1pdRN+1.

    In the equation above, suppose WS is not projective, and

    π:QSWS0

    is a projective cover of WS with the first syzygy ZS, then we have the projective cover

    (0,π):(QN,QS,1)(0,WS,0)0

    with the first syzygy (QN,ZS,η1), where η:ZSQS is the inclusion map. Hence,

    pdT(0,W,0)=pdT(QN,ZS,η1)+1.

    Corollary 7 [2]. Suppose k is a field and T=R[N]=(R0Nk) is the one-point extension of R by N. If (U,ks,φ) is a right T-module, then

    pdT(U,ks,φ)sup{pdRU,pdRN+1}.

    Corollary 8. Let T=(R0NS). If S is semi-simple and NR is projective, then pdT(U,W,φ)sup{pdRU,1} for any T-module (U,W,φ).

    Corollary 9 [13]. Let T=(R0NS). If R is hereditary, NR is projective, and S is semi-simple, then T is hereditary.

    From Theorem 6, we also have

    Corollary 10. Let T=(R0NS). If gl.dimR2 and S is semi-simple and pdRN1, then gl.dimT2. Proof: By Theorem 6, for any T-module (U,W,φ), we can get

    pdT(U,W,φ)sup{pdRU,pdRN+1}2.

    Theorem 11. Let T=(R0NS) with gl.dimR2. For any T-module (U,W,φ), if kerφ is not projective, then pdT(U,W,φ)2.

    Proof: Let ε2:HW be a projective cover, and δ1:PU/ϕ(WN) is a projective cover. Set θ=φ(ε21N):HNU. Let η:UU/φ(WN) be a natural homomorphism, ε1:(HN)PU such that ε1|HN=θ,ε1|P=γ1, where γ1:PU such that δ1=ηγ1. We have a projective cover

    ((HN)P,H,j)ε=(ε1,ε2)(U,W,φ).

    According to the above discussion, we can get the following commutative diagram:

    kerε2Nσ1NHNε21NWN0ψ(1,0)φ0K(HN)Pε1U0.

    According to the snake lemma, it is easy to get the two exact sequences

    0kerfcokerψPcokerφ0

    and

    0kerφcokerψΩ1(cokerφ)0.

    We know that pdT(U,W,φ)1 if, and only if, (K,kerε2,φ) is projective. Since gl.dimR2, we have pdRcokerφ2. Hence, kerφ is projective. Therefore, if kerφ is not projective, then pdT(U,W,φ)2.

    From the above proof, if R is a hereditary ring, then we can get that pdT(U,W,φ)1 if, and only if, kerφ is projective.

    A sufficient condition for T to be quasi-tilted is given by the following theorem.

    Theorem 12. Let T=(R0NS). If R is quasi-tilted, S is semi-simple and NR is projective, then T is quasi-tilted.

    Proof: According to Corollary 10, gl.dimT2. Let (U,W,φ) be an indecomposable T-module, then W is a semi-simple S-module and U is an indecomposable R-module. Because R is quasi-tilted, then pdRU1 or idRU1.

    If pdRU1, then, by Theorem 6, pdT(U,W,φ)1.

    Assume that idRU1 and 0UiI0jI10 is the minimal injective resolution of U, then

    0HomR(N,U)iHomR(N,I0)jHomR(N,I1)0

    is exact since NR is projective.

    Since HomR(YSN,U)σHomS(W,HomR(N,U)), for φ:WNU, let φ:WHomR(N,U) be the map corresponding to φ, that is, σ(φ)=φ. We can then view (U,W,φ) as the triple (U,W,φ) where φ:WHomR(N,U) is a S-module homomorphism. Hence, (U,W,φ) is an indecomposable T-module. If φ is not a monomorphism, then φ=0 and (U,W,φ)=(0,W,0), hence, idT(U,W,φ)<1. Thus, we can assume that φ is a monomorphism. Set φ=iφ, then φ is a monomorphism. We know that

    (U,W,φ)(i,φ)(I0,HomR(N,I0),1)

    is an injective envelope of T-module (U,W,φ).

    Furthermore, we have the following commutative diagram:

    0WφHomR(N,I0)HomR(N,I0)/φ(W)0φ||g0HomR(N,U)HomR(N,I0)HomR(N,I1)0.

    By the Five Lemma in homological algebra, g is epic.

    We know that Coker(i,φ)=(I1,HomR(N,I0)/φ(W),g), and the injective envelope of Coker(i,φ) is (I1,HomR(N,I1),1)(0,kerg,0).

    We now show that HomR(N,I0)/φ(W)HomR(N,I1)kerg.

    Since j and g are epics, we have

    HomR(N,I1)HomR(N,I0)/kerj,
    HomR(N,I1)HomR(N,I0)/φ(W)/kerg.

    Therefore,

    HomR(N,I0)/φ(Y)HomR(N,I0)/kerj+kergHomR(N,I1)kerg.

    So id(U,W,φ)1 and T is quasi-tilted.

    From Theorems 3 and 12, we have:

    Corollary 13 [2]. Let R be an algebra with gl.dimR2,N a projective R-module, and let T=R[N] be the one-point extension of R by N. Then, T is quasi-tilted if, and only if, R is quasi-tilted.

    The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.

    We would like to thank the referees for the very helpful comments and suggestions which improved the original version of this paper. This work is supported by the Natural Science Foundation for Yang Scholars of Anhui Province (No.1508085QA04). The authors are grateful to professor Xianneng Du for careful guidance and assistance in this research.

    The authors declare there is no conflicts of interest.


    Acknowledgments



    This work was supported by Astellas Pharma Inc.

    Conflict of interest



    The authors are employees of Astellas Pharma Inc. The authors declare no conflict of interest.

    Author contributions



    The two authors substantially contributed to the conception and design of this manuscript, and the analysis and interpretation of data. The authors drafted this work, reviewed it critically for important intellectual content, and finally approved the version to be published. The authors agree to be accountable for all aspects of this work in ensuring that questions related to the accuracy or integrity of any part of this work are appropriately investigated and resolved.

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