Review

Drug delivery application of extracellular vesicles; insight into production, drug loading, targeting, and pharmacokinetics

  • Extracellular vesicles (EVs) are secreted from any types of cells and shuttle between donor cells and recipient cells. Since EVs deliver their cargos such as proteins, nucleic acids, and other molecules for intercellular communication, they are considered as novel mode of drug delivery vesicles. EVs possess advantages such as inherent targeting ability and non-toxicity over conventional nanocarriers. Much efforts have so far been made for the application of EVs as a drug delivery carrier, however, basic techniques, such as mass-scale production, drug loading, and engineering of EVs are still limited. In this review, we summarize following four points. First, recent progress on the production method for EVs is described. Second, current techniques of drug loading methods are summarized. Third, targeting approach to specifically deliver cargo molecules for diseased sites by engineered EVs is discussed. Lastly, strategies to control pharmacokinetics and improve biodistribution are discussed.

    Citation: Masaharu Somiya, Yusuke Yoshioka, Takahiro Ochiya. Drug delivery application of extracellular vesicles; insight into production, drug loading, targeting, and pharmacokinetics[J]. AIMS Bioengineering, 2017, 4(1): 73-92. doi: 10.3934/bioeng.2017.1.73

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  • Extracellular vesicles (EVs) are secreted from any types of cells and shuttle between donor cells and recipient cells. Since EVs deliver their cargos such as proteins, nucleic acids, and other molecules for intercellular communication, they are considered as novel mode of drug delivery vesicles. EVs possess advantages such as inherent targeting ability and non-toxicity over conventional nanocarriers. Much efforts have so far been made for the application of EVs as a drug delivery carrier, however, basic techniques, such as mass-scale production, drug loading, and engineering of EVs are still limited. In this review, we summarize following four points. First, recent progress on the production method for EVs is described. Second, current techniques of drug loading methods are summarized. Third, targeting approach to specifically deliver cargo molecules for diseased sites by engineered EVs is discussed. Lastly, strategies to control pharmacokinetics and improve biodistribution are discussed.


    The security of sensitive information has become a significant concern in the age of 5G networks. digital images, including agreements, paintings, medical reports, agreements, and other scanned documents, are a primary source of information requiring the highest sensitivity level. Protecting the privacy of digital images when shared between authorized parties in systems such as the cloud is of utmost importance [1]. There have been advancements in developing multiple effective encryption algorithms to protect multimedia data's security and privacy. These algorithms rely on two distinct principles: symmetric and asymmetric key algorithms. Confusion and diffusion modules are the major techniques used for symmetric algorithms [2,3]. The confusion module is usually applied after the diffusion operation has successfully severed the relationship between the ciphered data and the keys employed in image, audio and video encryption [2,4,5,6,7]. The data used in both modules are obtained from a range of numbers generated by a pseudo-random number generator (PRNG). Modern image cryptography relies heavily on well-designed PRNGs that utilize mathematical mechanisms [3,8,9]. As a result, numerous effective algorithms have been created to produce substitution boxes (S-boxes) and pseudo-random number (PRN) sequences [10,11,12,13]. In [14,15], the authors introduced a comprehensive scheme for securing images, employing a combination of chaos-based block permutation and weighted bit plane chain diffusion. Furthermore, the authors proposed a face image privacy protection scheme that relies on chaos and DNA cryptography. This dual approach addresses image security through advanced encryption techniques and the emerging need for robust privacy protection in the context of face images. In [16,17], the authors give an idea of an Image encryption algorithm based on plane-level image filtering, discrete logarithmic transform, and RNA-encoded color image encryption scheme based on a chain feedback structure. There are two types of S-boxes available: static and dynamic. Static S-boxes operate and generate outputs in fixed modes, whereas dynamic S-boxes possess multiple operating modes. Dynamic S-box algorithms are preferred because they increase computational costs for cryptanalysts. Recent studies have proposed several techniques to enhance the security of cryptographic systems. For example, Ibrahim et al. [3] introduced a method that utilizes permuted elliptic curves (ECs) to generate key-dependent dynamic S-boxes, aiming to minimize computational expenses. Alhandawi et al. [18] suggested an S-box configuration based on a modified Firefly algorithm, claiming to exhibit satisfactory cryptographic characteristics. In addition, a new algorithm utilizing a group structure was introduced in [19], which provides high nonlinearity for secure S-box generation. Furthermore, Toughi et al. [20] presented an image encryption scheme utilizing PRNG and advanced encryption standard (AES) modules, while [21] designed an image encryption method using a chaotic model with sufficient pseudo-creation capability. Recently, chaotic systems and error-correcting codes have gained popularity for generating PRNS and constructing S-boxes for image encryption algorithms.

    These approaches have received recognition for their characteristics, such as non-periodicity, responsiveness to input parameters, ergodicity, key sensitivity, and chaotic properties, as mentioned in references [3,18,22,23,24,25]. In [26], the authors devised a secure algorithm capable of operating in digital and optical environments. Wang et al. [27] introduced a cryptosystem that leverages diverse techniques like chaotic maps, Fisher-Yates shuffling, and DNA sequence encoding to deliver precise encryption and rapid convergence. Although chaotic maps can generate random sequences quickly, EC structures are more suitable for generating random sequences due to their computational precision [28]. Reyad et al. [29] developed an idea based on ECs to obtain PRNs that operate effectively in image encryption. Moreover, El-Latif et al. [30] used cyclic ECs and hybrid-chaotic systems to develop an effective image encryption scheme. To generate PRNs, the authors in [3,20] employed an ECs group law operating tool in conjunction with a large prime field, while [2,23] utilized a recursive approach and group law operating tool to identify all points on ECs and generate both S-box and PRNs using algebraic arithmetic operations. However, these techniques can be computationally expensive when working with large prime fields. Using a small fixed prime field may not be effective for generating enough data with strong cryptographic features. Despite attempts to address these challenges, [2] could only produce two strong dynamic S-boxes using a minimum fixed odd prime field. Recently, Farwa et al. [31] proposed constructing the nonlinear component of block cipher by employing EC over binary extension field (BEF) and utilizing the group structure of EC. In [25,26,32,33], the author extended this idea using EC over the Galois field with n equals 8, 9 and odd n greater than 9 and utilized the operations of the corresponding Galois field. All the EC-based schemes discussed above use finite fields to achieve the desired level of security. The security of these cryptographic systems, which rely on EC over finite fields, is primarily determined by the computational resources required to solve the discrete logarithm problem. Computers typically perform mathematical operations with binary digits (bits), which can only have two possible values (0 or 1). In the context of cryptography, cryptographic algorithms must be designed to operate on binary data. By performing computations in a BEF, the computational complexity of cryptographic algorithms can be reduced, increasing their efficiency and security.

    In this context, we explain two distinct mechanisms that utilize the indexing technique: the S-box method and a collection of PRN streams, each with its unique approach. It is worth mentioning that the S-box construction technique (SCT) generates multiple dynamic S-boxes in 16×16 standard format employing features of BEF. The core sentiment behind SCT is that EC points and operations of the corresponding Galois field jointly equip it. This way, we reduce the time complexity and increase the proposed algorithm's security strength as the computer works in a binary field. Moreover, BEF enables a high degree of parallelism, essential in modern computer architectures. Parallelism allows multiple arithmetic operations to be performed simultaneously, leading to faster computation times. Moreover, the PRN technique is partly utilized by both EC points and basic algebraic operations in a BEF. Due to this, the PRN scheme produces numerous random patterns while ensuring that these patterns are non-repeating and verified. As a result, it is an effective method for achieving diffusion in large-scale multimedia data. Moreover, the findings obtained from implementing both modules confirm the suitability of utilizing SCT and PRN techniques and indexing techniques in various cryptographic protocols.

    The rest of the study is structured as follows: Section 2 presents the fundamental principles and discoveries of EC and BEF. Section 3 elucidates the suggested S-box and PRN mechanisms. Section 4 centers on the proposed encryption scheme. Consequently, Section 5 presents the results of simulations conducted on the SCT and proposed encryption scheme. Finally, Section 6 concludes the discussion.

    This section covers important concepts such as ECs, Galois fields, Euler's phi function, and primitive polynomials, which are essential and foundational.

    For any given prime field Fp, an EC of the form

    Y2=x3+ax+b,

    where a and b are non-zero elements of the corresponding prime field are called weierstrass form of an EC. Also, when we take a=0, then the obtained EC of the form

    Y2=x3+b,

    where b0 is called Mordell elliptic curve (MEC). The specialty of this curve is that it has p+1 points lying on that EC if we take prime field of the form

    p20mod3,

    where each integer in the field Fp appear once as y-coordinates [34].

    Let R be a commutative ring with identity, with binary operation addition and multiplication. Then IR is called an ideal of R if

    𝒶,𝒷I𝒶𝒷I

    and 𝒶II for every 𝒶R. An ideal in a ring R denoted as AR, is considered maximal ideal when no other proper ideal of R exists that contains A. A commutative ring with an identity whose nonzero elements forms a group under multiplication is called field F. The polynomial ring, denoted by Zp[x] is a set of polynomials whose coefficients are from the field Zp. A polynomial f(x) in Zp[x] is an irreducible polynomial, if it cannot be reduced into the product of lower-degree polynomials in Zp[x], and the ideal generated by f(x) will be the maximal ideal of the ring Zp[x] represented as

    <f(x)>={h(x):h(x)=f(x).g(x),forsomeg(x)Zp[x]}.

    The quotient Zp[x]<f(x)> is known as Galois field GF(pm) having pm elements, where m is the degree of PIP f(x) and p is any prime number. A polynomial

    f(x)GF(pm)[x]

    is said to have a PIP of degree m if all its roots are also primitive elements in the corresponding Galois field. Also, addition and subtraction are performed using the corresponding field Zp. The product of two polynomials in Zp[x] is equivalent to the remainder obtained from the Euclidean division by p. The extended Euclidean algorithm can compute the multiplicative inverse of any nonzero element. The total number of PIPs of degree n in the binary field is φ(2n1)n, where φ denotes Euler's phi function.

    In this segment, we suggest a cryptographic algorithm that relies primarily on two distinct methods of generating random data with a specific length. The precise instructions for each approach are described in subsequent sub-sections.

    Generating robust and adaptable S-boxes is a critical factor in developing effective cryptographic systems, as they are instrumental in performing nonlinear transformations that evaluate the strength of well-designed crypto-algorithms [35]. Consequently, generating dynamic S-boxes with optimal cryptographic properties is highly desirable in contemporary cryptography. To address the limitations of current S-box constructions and obtain multiple S-boxes, we suggest a rapid technique that employs ECs over the Galois field and their algebraic operations. The subsequent explanation illustrates how the proposed SCT operates.

    1) Choose PIP of degree 8 over the binary field

    P(𝓉)=𝓉8+𝓉5+𝓉3+𝓉2+1.

    Since the number of PIP of degree 8 over the binary field is 16, one can independently choose any other PIP of degree 8.

    2) Select an EC E(b,2,8) of the form

    E(b,2,8):𝓎2=𝓍3+b.

    3) Generate EC points (𝓍,𝓎) by utilizing above equation over the PIP.

    4) Apply a bijective map on the points of EC (𝓍,𝓎), such that

    π:E(b,2,8)𝓍,𝓎E(b,2,8)𝓍.

    Defined by

    π(𝓍,𝓎)=𝓍,

    where (𝓍,𝓎)E(b,2,8)𝓍,𝓎.

    5) Apply an inverse map under the corresponding BEF

    ξ:E(b,2,8)𝓍F256.

    Defined as

    ξ(𝓍)={h.𝓍1,if𝓍0,h.𝓍,if𝓍=0,

    where h be any fixed element of 𝓍-coordinates and 𝓍E(b,2,8)𝓍. Also, inverse is taken under the BEF of order 256 and PIP is taken as mentioned above.

    6) For the construction of S-box, further apply a map

    ξτ:F256F256,

    defined as

    ξτ(𝓍)=r+𝓍,

    where rF256 be any non-zero element fixed element and 𝓏rF256. Here + presents addition over the Galois field GF(28).

    Since the number of PIP of degree 8 over the binary field is 16, given in Table 1. So, the scheme is capable to generating 16×255×255 different number of 8×8 S-boxes corresponding to the BEF of degree 8 having optimal NL 112 of each which are given in Table 6. The S-boxes constructed through proposed SCT are depicted in Tables 25.

    Table 1.  PIP and their decimal representation (DR).
    PIP DR PIP DR
    t8+𝓉4+𝓉3+𝓉2+1 285 𝓉8+𝓉6+𝓉5+𝓉4+1 369
    𝓉8+𝓉5+𝓉3+𝓉1+1 299 𝓉8+𝓉7+𝓉2+𝓉1+1 391
    𝓉8+𝓉5+𝓉3+𝓉2+1 301 𝓉8+𝓉7+𝓉3+𝓉2+1 397
    𝓉8+𝓉6+𝓉3+𝓉2+1 333 𝓉8+𝓉7+𝓉5+𝓉3+1 425
    𝓉8+𝓉6+𝓉4+𝓉3+𝓉2+𝓉1+1 351 𝓉8+𝓉7+𝓉6+𝓉1+1 451
    𝓉8+𝓉6+𝓉5+𝓉1+1 355 𝓉8+𝓉7+𝓉6+𝓉3+𝓉2+𝓉1+1 463
    𝓉8+𝓉6+𝓉5+𝓉2+1 357 𝓉8+𝓉7+𝓉6+𝓉5+𝓉2+𝓉1+1 487
    𝓉8+𝓉6+𝓉5+𝓉3+1 361 𝓉8+𝓉7+𝓉6+𝓉5+𝓉4+𝓉2+1 501

     | Show Table
    DownLoad: CSV
    Table 2.  S-box 1 constructed by proposed SCT by choosing parameters n=8,b=101,h=23,r=11.
    11 20 247 163 117 206 95 67 52 51 154 184 33 159 47 72
    28 136 166 21 214 121 221 220 83 171 143 128 222 156 240 160
    243 44 185 198 174 48 4 90 150 157 50 41 96 12 147 17
    6 135 71 215 251 1 205 167 26 70 228 187 64 86 182 37
    119 209 235 114 82 107 158 245 170 219 229 253 255 183 208 207
    173 108 133 210 179 226 146 181 189 111 73 92 91 202 39 13
    254 38 77 22 45 237 101 34 115 153 14 142 104 106 93 191
    217 10 25 199 65 190 30 164 161 218 176 19 23 122 231 151
    53 188 102 155 123 138 196 141 212 233 59 78 178 134 116 9
    69 118 125 169 192 79 5 63 7 110 165 195 144 62 94 197
    88 249 203 16 76 0 148 100 87 177 140 145 180 31 84 244
    81 49 32 89 200 230 201 132 186 194 250 172 66 239 55 234
    130 204 238 224 40 129 246 15 24 252 120 223 60 56 236 43
    8 61 29 213 152 216 35 18 211 137 42 232 57 74 80 103
    98 58 248 3 2 68 109 75 46 36 162 126 242 54 175 127
    105 27 149 139 85 225 113 227 112 97 124 193 99 131 168 241

     | Show Table
    DownLoad: CSV
    Table 3.  S-box 2 constructed by proposed SCT by choosing parameters n=8,b=101,h=23,r=17.
    17 14 237 185 111 212 69 89 46 41 128 162 59 133 53 82
    6 146 188 15 204 99 199 198 73 177 149 154 196 134 234 186
    233 54 163 220 180 42 30 64 140 135 40 51 122 22 137 11
    28 157 93 205 225 27 215 189 0 92 254 161 90 76 172 63
    109 203 241 104 72 113 132 239 176 193 255 231 229 173 202 213
    183 118 159 200 169 248 136 175 167 117 83 70 65 208 61 23
    228 60 87 12 55 247 127 56 105 131 20 148 114 112 71 165
    195 16 3 221 91 164 4 190 187 192 170 9 13 96 253 141
    47 166 124 129 97 144 222 151 206 243 33 84 168 156 110 19
    95 108 103 179 218 85 31 37 29 116 191 217 138 36 68 223
    66 227 209 10 86 26 142 126 77 171 150 139 174 5 78 238
    75 43 58 67 210 252 211 158 160 216 224 182 88 245 45 240
    152 214 244 250 50 155 236 21 2 230 98 197 38 34 246 49
    18 39 7 207 130 194 57 8 201 147 48 242 35 80 74 125
    120 32 226 25 24 94 119 81 52 62 184 100 232 44 181 101
    171 241 152 71 242 154 44 15 149 214 37 137 67 58 120 96

     | Show Table
    DownLoad: CSV
    Table 4.  S-box 3 constructed by proposed SCT by choosing parameters n=8,b=101,h=23,r=19.
    19 12 239 187 109 214 71 91 44 43 130 160 57 135 55 80
    4 144 190 13 206 97 197 196 75 179 151 152 198 132 232 184
    235 52 161 222 182 40 28 66 142 133 42 49 120 20 139 9
    30 159 95 207 227 25 213 191 2 94 252 163 88 78 174 61
    111 201 243 106 74 115 134 237 178 195 253 229 231 175 200 215
    181 116 157 202 171 250 138 173 165 119 81 68 67 210 63 21
    230 62 85 14 53 245 125 58 107 129 22 150 112 114 69 167
    193 18 1 223 89 166 6 188 185 194 168 11 15 98 255 143
    45 164 126 131 99 146 220 149 204 241 35 86 170 158 108 17
    93 110 101 177 216 87 29 39 31 118 189 219 136 38 70 221
    64 225 211 8 84 24 140 124 79 169 148 137 172 7 76 236
    73 41 56 65 208 254 209 156 162 218 226 180 90 247 47 242
    154 212 246 248 48 153 238 23 0 228 96 199 36 32 244 51
    16 37 5 205 128 192 59 10 203 145 50 240 33 82 72 127
    122 34 224 27 26 92 117 83 54 60 186 102 234 46 183 103
    113 3 141 147 77 249 105 251 104 121 100 217 123 155 176 233

     | Show Table
    DownLoad: CSV
    Table 5.  S-box 4 constructed by proposed SCT by choosing parameters n=8,b=101,h=23,r=23.
    21 10 233 189 107 208 65 93 42 45 132 166 63 129 49 86
    2 150 184 11 200 103 195 194 77 181 145 158 192 130 238 190
    237 50 167 216 176 46 26 68 136 131 44 55 126 18 141 15
    24 153 89 201 229 31 211 185 4 88 250 165 94 72 168 59
    105 207 245 108 76 117 128 235 180 197 251 227 225 169 206 209
    179 114 155 204 173 252 140 171 163 113 87 66 69 212 57 19
    224 56 83 8 51 243 123 60 109 135 16 144 118 116 67 161
    199 20 7 217 95 160 0 186 191 196 174 13 9 100 249 137
    43 162 120 133 101 148 218 147 202 247 37 80 172 152 106 23
    91 104 99 183 222 81 27 33 25 112 187 221 142 32 64 219
    70 231 213 14 82 30 138 122 73 175 146 143 170 1 74 234
    79 47 62 71 214 248 215 154 164 220 228 178 92 241 41 244
    156 210 240 254 54 159 232 17 6 226 102 193 34 38 242 53
    22 35 3 203 134 198 61 12 205 151 52 246 39 84 78 121
    124 36 230 29 28 90 115 85 48 58 188 96 236 40 177 97
    119 5 139 149 75 255 111 253 110 127 98 223 125 157 182 239

     | Show Table
    DownLoad: CSV
    Table 6.  Experimental results of proposed S-boxes and their comparison.
    S-box NL BIC SAC LP DP
    Proposed-1 112 0.50614 0.503906 0.0625 0.015625
    Proposed-2 112 0.50614 0.503906 0.0625 0.015625
    Proposed-3 112 0.50614 0.503906 0.0625 0.015625
    Proposed-4 112 0.50614 0.503906 0.0625 0.015625
    [36] 107.50 0.500419 0.487300 0.1328 0.0390
    [2] 107 0.50635 0.499023 0.1250000 0.0390620
    [33] 111.25 - 0.487800 0.0703125 0.0234375
    [37] 107.25 0.5069 0.502441 0.125 0.039025
    [38] 105.5 0.50872 0.535100 0.140625 -
    [39] 106.75 - 0.497600 - 0.03906

     | Show Table
    DownLoad: CSV

    PRNs that have been verified are crucial in numerous cryptographic uses, such as data encryption and gambling. To ensure a strong masking effect in data encryption, PRNs are generated using various mathematical structures, including ECs. In this part, instead of using large prime field dependent schemes, we engaged BEF of order n to generate PRNs. The following lines define the proposed algorithm:

    1) Choose primitive irreducible polynomials (PIP) P(𝓉) of degree n over the binary field. Since the number of PIP of degree n over the binary field is φ(2n1)n, one can independently choose any other PIP of degree n.

    2) Select an EC E(b,2,n) of the form

    E(b,2,n):𝓎2=𝓍3+b,

    here b be any element of the corresponding Galois field excluding zero.

    3) Generate EC points E(b,2,n)𝓍,𝓎 by employing equation over given P(𝓉).

    4) Apply a map on the points of EC points such that

    T:E(b,2,n)𝓍,𝓎Ex

    defined by

    T(𝓍,𝓎)=𝓍,

    where (𝓍,𝓎)E(b,2,n)𝓍,𝓎.

    5) For the generation of PRN, further apply an inverse map under the corresponding BEF

    T1:ExFn

    defined as

    T1(𝓍)={𝓌.𝓍1,if𝓍0,𝓌.𝓍,if𝓍=0,

    where 𝓌GF(2n){0} be any fixed element. Also, inverse is taken under the GF(2n) and corresponding PIP is utilized.

    Since, the irreducible polynomials of degree n that are binary primitives are φ(2n1)n, where ϕ represents Euler's phi function. So, one can generate φ(2n1)n×(2n1) different number of PRN sequences corresponding to the BEF of degree n using the proposed mechanism.

    In domains like military, commercial, and medical, images are a form of visual content that requires cautious handling during transmission. Various mathematical frameworks are employed to establish standardized techniques for encrypting images to ensure reliability and safety. Typically, these encryption methods use chaotic and EC systems to create PRNs and S-boxes. This section introduces a novel approach to image encryption that assesses the appropriateness of prospective S-boxes and PRNs for facilitating secure image storage and communication over an insecure channel. Specifically, the proposed method involves encrypting an image I with dimensions of M×N×3, where M represents rows and N represents columns. Also, we use the symbols R, G and B to represent the color components red, green, and blue in an M×N image. When encrypting the image, all three channels are treated as a grayscale image, and each component is encrypted separately. The level of distortion introduced to the image defines the significance of the encryption scheme.

    The encryption process involves several steps.

    1) Let I denote the color image of pixels M×N×3, where M denotes rows and N denotes columns of the image. Here, 3 denotes the intensities of RGB layers. We work separately on these channels.

    2) Since, any two adjacent pixels in the digital image data have strong relationships with one another. To scramble image elements, we take n=9 and the corresponding PIP of the form

    f(𝓍)=𝓍9+𝓍4+1

    to generate points (x,y) of EC by employing proposed technique (described in Section 3.2). Then use the inclusion map on each both the coordinates of EC points, which is defined as follows:

    I256:GF(29)GF(28),
    I256(𝓍)={0,if𝓍=0,𝓍,if𝓍256,0,if𝓍>256,
    I256(𝓎)={0,if𝓎=0,𝓎,if𝓎256,0,if𝓎>256.

    So, after applying this inclusion map, the obtained positive values of 𝓍, 𝓎 coordinates of EC are employed to original image I such that

    Ip(i,j)=I(𝓍(i),𝓎(j)),

    where (i,j) denotes the integer position in the shuffling matrix Ip. Each color component of the image undergoes the permutation process to shuffle the pixels' positions. Consequently, one can get new layers denoted by Rp,Gp and Bp. By applying this process, we get the scrambled image.

    3) To enhance the security against chosen plain-text attacks, the substitution step is a crucial component of any cryptographic algorithm. To achieve this, the proposed method incorporates the use of S-boxes generated through the suggested S-box methodology described in Section 3.1. One of the suggested S-boxes is selected for implementation. These S-boxes possess strong cryptographic properties and contribute to the overall strength of the scheme. Following that, the acquired S-boxes are utilized to substitute the scrambled components Rp,Gp and Bp of the image using a technique identical to AES substitution. Consequently, the substituted components Rs,Gs and Bs can be obtained.

    4) The generation of PRNs holds great significance in multiple multimedia data protection applications. Numerous schemes for generating random numbers have been investigated in the research. Among them, EC is commonly employed for random number generation. In this section, a sequence of random numbers ψ is generated by selecting an appropriate value for n such that 2nM×W, ensuring the diffusion of encrypted data through the proposed technique (explained in Section 3.2). Consequently, take M×W number of elements ψr from that sequence and reduce the size of elements of that sequence in the range of image bits. In this part, we take n=16 and the corresponding PIP of the form

    f(𝓍)=𝓍16+𝓍5+𝓍3+𝓍2+1

    to generate PRNs sequence ψ by employing proposed technique (described in Section 3.2). Further, apply mode operation to the elements of sequence ψ and covert them in the range of 256 order Galois field

    F256:GF(216)GF(28)

    defined as

    F256(s)=smod256,

    where sψ. The reduced sequence ψr are then utilized for the diffusion phase using the below equations

    RE=Rs(i)+ψr(i),
    GE=Gs(i)+ψr(i),
    BE=Bs(i)+ψr(i),

    where RE, GE, and BE are the encrypted pixel values for the red, green, and blue channels, respectively, and ψr(i) is the ith-byte in PRNs stream ψr.Rs(i),Gs(i) and Bs(i) is the ith-byte in RGB channels Rs,Gs, and Bs respectively. Eventually, blend these components of the image, which is required ciphered image.

    In this study, we tested the color image of women, house, jellybeans, and couple of dimensions 256×256. The decryption process of the proposed algorithm is same as the encryption process but with the inverse order of operations. The flowchart of proposed algorithm is also depicted in Figure 1. Further, the outcomes and analyses are presented in the subsequent section.

    Figure 1.  Flowchart of proposed algorithm.

    In this subsection, we discussed the process of image decryption in detail. First, we take the cipher image obtained from the encryption process defined in the previous subsection. Then, we divide the image into RGB channels and XORed with the generated sequence, which each channel is applied in the encryption scheme. Further, substitute inverse S-boxes with each channel as we did in the encryption scheme. Moreover, an inverse permutation on each coordinate of 2) in Section 4.1 is applied to the obtained image to get the plain image.

    If an encryption algorithm passes several security tests and meets specific standards, it is deemed suitable for practical use. In this research, we evaluated the effectiveness of a proposed cryptosystem by encrypting different color images, such as women, house, jellybeans, and couple, shown in Figure 2. Following the encryption process, the encrypted images underwent several performance tests. These tests, which will be elaborated on in the upcoming subsection, strived to evaluate their stability against assorted attacks.

    Figure 2.  Original and ciphered images: (a) the original images of women, house, jellybeans, and couple; (b) ciphered images.

    The cryptographic strength of the S-boxes developed for the encryption procedure is evaluated using established metrics such as nonlinearity (NL), strict avalanche criteria (SAC), linear branch number (LBN), differential branch number (DBN), bit independence criteria (BIC), linear approximation probability (LP), differential approximation probability (DP), balance, and linear structure (LS). These assessments are commonly employed to gauge the effectiveness of S-boxes. The ensuing results present the performance index of the generated S-boxes.

    The NL of a Boolean function f refers to the minimum Hamming distance between the set of all affine Boolean functions and f. We denoted the nonlinearity off f by Nf and mathematically it can be defined as

    Nf=min{d(f,h):hA},

    where A is the set of all affine Boolean functions and Nf denotes the hamming distance between f and h. The maximum NL score of n×n S-box can have 2n12n21.

    Thus, in the case for n=8, the maximum possible NL score is 120. Also, the proposed S-boxes have an optimal NL score of 112 depicted in Table 6.

    The notions of completeness and avalanche were created by Webster and Tavares in 1985, who also detailed the analysis of the SAC. This criterion was investigated to see how the output bits performed when the input bits underwent alterations. Also, one can claim that the SAC criterion is satisfied if all SAC matrix entries are located within a small neighborhood of 0.5. Table 6 displays the SAC outcome of the suggested S-boxes and their comparison to various existing schemes. As a result, the proposed S-boxes met the requirements of the sac test.

    In 1985, Webster and Tavares also provided the significant Boolean function property known as the BIC. The individual bits generated by the eight-constitution function are compared using the BIC. This criterion assesses the correlation between the nth and mth output bits if the ith input bit undergoes a little change. An S-box is deemed to meet the BIC requirements if the entries of its BIC matrix are near 0.5. The different proposed and existing S-boxes are put to the BIC test. The BIC result of the proposed S-boxes and some existing S-boxes is shown in Table 6.

    The LP analysis is used to determine the scheme's maximum imbalance value. We assign Bi and Bo to the input and output masks, respectively. The sequence of equal output bits chosen by mask Bo is comparable to the equality of the input bits selected by mask Bi, according to Matsui's definition of LP, defined mathematically as follows:

    LP=maxBi,Bo0|{iY|i.Bi=S(i).B0}2n12|,

    where Y stands for the set input bits of order 2n. The performance results of the LP analysis are shown in Table 6, indicating that the suggested S-boxes successfully resist linear cryptanalysis.

    The value of DP is calculated using the differential uniformity of the S-box, which is defined as:

    DP(δuδv)={uX|f(u)f(u+δu)=δv}2n.

    This indicates that each input differential δu corresponds to a unique output differential δv, ensuring a uniform probability mapping for each i. The DP analysis of the S-boxes produced using the proposed construction approach indicates that the resulting values are close to the ideal value, as presented in Table 6.

    The Boolean function is said to be balanced when there is an equal chance of both 0 and 1 appearing as the output of the Boolean function after all input variable possibilities have been considered. Table 7 depicts that every S-box of the proposed scheme has that property.

    Table 7.  Experimental results of proposed S-boxes.
    S-box LBN DBN Balance LS
    Proposed-1 2 2 Yes 0
    Proposed-1 2 2 Yes 0
    Proposed-1 2 2 Yes 0
    Proposed-1 2 2 Yes 0

     | Show Table
    DownLoad: CSV

    The DBN of an n×n matrix M is a mapping φ:({0,1}m)n({0,1}m)n defined as

    βd(M)=min{wt(a)+wt(M.aT)|,a({0,1}m)n,a0}.

    The S-box has an input and output size of m-bits each, and the number of S-boxes in a diffusion layer is represented by n arranged in a matrix M. Furthermore, wt denotes the hamming weight of a codeword which gives us the nonzero vectors in that codeword [16]. On the other hand, in LBN, instead of using matrix M, the transpose of that matrix is engaged as defined below

    ψlbn(Sb)=ming,g'Fn2:cc(g,g')0({wt(g)+wt(g')}),

    where cc(g,g') presents the coefficient of auto correlation. Additionally, DBN is associated with the difference distribution table, whereas LBN is related to the correlation matrix. The proposed S-boxes LBN and DBN values are presented in Table 7.

    The cryptographic significance of the S-boxes LS is examined to ensure its robustness against attacks. It has been observed that block ciphers with linear techniques can be vulnerable to attacks that are faster than an exhaustive key search. Therefore, the confusion phase of the block cipher must avoid any LSs. The LS of an S-box is determined by the following mathematical expression

    (x)+(x+𝒶)=C,

    where

    (x)F2nxF2n

    and for some 𝒶F2n and CF2. The LS of an S-box is defined by its Boolean function C. If C is equal to zero, the LS is known as an invariant LS. If C is equal to one, the LS is known as a complementary LS. Table 7 demonstrates that the proposed S-boxes possess no LS, making them suitable for cryptographic purposes.

    In this part, several well-known security tests are used to evaluate the proposed encryption system's level of security. We used images of women, house, jellybeans, and couple for encryption.

    An image histogram visualizes the distribution of grayscale frequencies within an image, offering insights into its tonal distribution. When applying the suggested technique for image encryption, the frequency of occurrence for each grayscale value in the encrypted image tends to become more uniform, resulting in a flatter histogram. This indicates that the encryption method is highly resistant to traditional statistical attacks. The corresponding images and their histograms are illustrated in Figure 3, the findings indicate that the histograms of the encrypted images exhibit a nearly uniform distribution and differ significantly from those of the original images. This observation suggests that the proposed scheme demonstrates high resilience against statistical attacks.

    Figure 3.  Histograms of original images and ciphered images: (a) the original images: Women, house, jellybeans, and couple; (b) the histograms of the original images; (c) the ciphered images; (d) the histograms of the ciphered images.

    The amount of unpredictability and uncertainty of the gray-scale values in the encrypted image is calculated using information entropy. The appropriate entropy score is 8 bits because the encrypted image data's numeric range is 0 to 255. As a result, the encrypted image is increasingly resistant to popular statistical attacks, the closer it comes to 8 bits. The higher entropy value of the proposed scheme can be attributed to its ability to generate more random encrypted data. This randomness makes it difficult for an attacker to determine the original image from the encrypted data. As a result, the proposed scheme can efficiently resist statistical analysis, making it a suitable choice for various security applications. Overall, the results presented in Table 8 indicate that the proposed scheme has higher entropy.

    Table 8.  Comparison of the entropy results of the ciphered images.
    Scheme Images Entropy
    - Women 7.9991
    Proposed scheme House 7.9990
    - Jellybeans 7.9990
    - Couple 7.9991
    [40]
    -
    Lena
    Cameraman
    7.9970
    7.9848
    [41] Lena 7.9970
    [42]
    -
    Lena
    Baboon
    7.9962
    7.9971
    [43]
    -
    Lena
    Baboon
    7.9970
    7.9969

     | Show Table
    DownLoad: CSV

    The contrast ratio, which helps the viewer recognize the object in the image, is one of the key aspects of image quality. Contrast analysis determines how much contrast there is between adjacent pixels over the entire image. The encryption method is deemed to pass the contrast test if the contrast ratio in the ciphered image is increased. The following is a list of the contrast coefficient's mathematical representations:

    CA=i,jQ(i,j)1+|i+j|,

    where Q(i,j) denotes the number of gray level co-occurrence matrices of the image. Also, the constant image has a contrast value of zero. The contrast score of the encrypted image is approximately 10.49 presented in Table 9, indicating a significant variation in pixel intensity and its adjacent pixels throughout the entire image.

    Table 9.  Statistical analysis: (a) original images, (b) encrypted images and (c) existing schemes encrypted images.
    Images Contrast Energy Homogeneity
    a. Women
    b. Encrypted
    0.0804
    10.4684
    0.4304
    0.0156
    0.9688
    0.3896
    a. Home
    b. Encrypted
    0.2042
    10.4733
    0.1945
    0.0156
    0.9053
    0.3893
    a. Jellybeans
    b. Encrypted
    0.1279
    10.4861
    0.3412
    0.0156
    0.9441
    0.3906
    a. Couple
    b. Encrypted
    0.2084
    10.5344
    0.2637
    0.0156
    0.9172
    0.3884
    c. [3] 10.4148 0.0156 0.3887
    c. [36] 10.5716 0.0156 0.3865
    c. [32] 9.9954 0.0157 0.3908
    c. [33] 9.99240 0.0156 0.3887

     | Show Table
    DownLoad: CSV

    The gray level co-occurrence matrices of the encrypted image are required for analyzing the images energy. The square root of the angular second moment is used in energy analysis to determine the uniformity of pixel intensities. The energy is calculated using the mathematical equation provided below:

    EA=i,jQ(i,j)2,

    whereas Q(i,j) represents GLCM. The low homogeneity score of the encrypted images indicates a higher difference in the GLCM.

    We focus on assessing the GLCM, which is also known as a grey-tone spatial dependency matrix, to determine the proximity of dispersed elements in images to the GLCM diagonal. This is because images inherently contain dispersed contents when captured. The equation utilized for analyzing homogeneity is expressed mathematically as

    HA=ijQ(i,j)1|i+j|.

    The homogeneity score for the encrypted images is very low, which suggests that the difference in the GLCM is higher.

    There is a strong correlation between adjacent pixels in color images due to their close values. The correlation coefficient measures the linearity between neighboring pixel values in the vicinity. The primary objective of the encryption method is to distort the pixels to minimize the correlation among adjacent pixels in the image. For an image encryption algorithm to be considered robust and suitable for security purposes, the correlation coefficient of the encrypted image should approach zero. The experimental results of the correlation test, conducted on various plain and encrypted images for each color channel, are presented in Table 10. The correlation coefficient values obtained from the test indicate that the proposed encryption scheme is highly effective and resilient against statistical attacks. Additionally, the correlation plots depicted in Figure 4 provide evidence of the effectiveness of the proposed approach.

    Table 10.  Correlation analysis of original and encrypted images.
    Image Horizontal Vertical Diagonal
    Women 0.9710 0.9355 0.9162
    Encrypted-women 0.0432 0.0057 0.0245
    Home 0.9816 0.9601 0.9477
    Encrypted-home -0.0210 0.0028 -0.0042
    jellybeans 0.9825 0.9836 0.9694
    Encrypted-jellybeans 0.0277 0.0004 0.0041
    Couple 0.9217 0.9592 0.9223
    Encrypted-couple 0.0212 0.0073 -0.0054

     | Show Table
    DownLoad: CSV
    Figure 4.  Correlation plots of (a) women original image; (b,c,d) adjacent pixels of rgb channels of the original color image women; similarly (a1) women encrypted image; (b1,c1,d1) adjacent pixels of rgb channels of the women encrypted image; (a2) home original image; (b2,c2,d2) rgb channel plots; (a3) home encrypted image; (b3,c3,d3) rgb channel plots; (a4) jellybeans original image; (b4,c4,d4) rgb channel plots; (a5) jellybeans encrypted image; (b5,c5,d5) rgb channel plots; (a6) couple original image; (b6,c6,d6) rgb channel plots; (a7) couple encrypted image; (b7,c7,d7) rgb channel plot.

    Attackers commonly employ the differential attack method, where they seek to detect patterns in the encrypted data generated by two nearly identical plain inputs. If such a pattern exists, the attacker may exploit it to uncover the precise key or exploit a vulnerability in the encryption algorithm's security A secure encryption technique creates encrypted data that appears almost random, even when there is a minor change in the input data, as a barrier against differential assaults. The unified average changing intensity (UACI) and the number of pixels change rates (NPCR) are the relevant metrics to assess the encryption scheme's susceptibility to differential attacks. These findings illustrate the strong correlation between the suggested encryption method and the original image data, which could enhance its resilience to differential attacks. Table 11 assesses various color images with their respective NPCR and UACI scores measured. The proposed encryption approach scored higher than the optimal value of 99.58% for NPCR, while the UACI scores were within the optimal range of [33.3% to 33.5%]. These results imply that the proposed encryption method relies heavily on the original image data and has the potential to be more effective against differential attacks.

    Table 11.  Comparison of NPCR and UACI analysis with existing schemes.
    Scheme NPCR UACI
    - 99.6318 33.4281
    Proposed 99.5972 33.4706
    - 99.6175 33.4421
    - 99.6023 33.4634
    [44] 99.6067 33.5000
    [45] 99.6233 33.6733
    [46] 99.5681 33.4067
    [47] 99.6000 33.3867

     | Show Table
    DownLoad: CSV

    The MSE stands out as a widely used metric for quantifying the discrepancy between the original and encrypted images, thereby evaluating the efficacy between the pixels of the plain image and the corresponding pixel in the encrypted image for all pixels in the image. The resulting squared errors are summed and divided by the total number of pixels. Notably, greater MSE values indicate increased robustness of an encryption algorithm against statistical attacks.

    Utilizing the MSE as a foundation, the PSNR emerges as an additional performance measure for assessing encryption algorithms. As given by the following equation, PSNR is determined by taking the logarithm of the ratio between the square of the maximum pixel value (typically 255) and the MSE. As PSNR and MSE display an inverse relationship, diminished PSNR values signify enhanced robustness of an encryption algorithm

    PSNR=10log(I2maxMSE).

    Presented in Table 12 are the outcomes for both MSE and PSNR achieved through our newly proposed encryption algorithm across various images. Furthermore, we provide a comparison with the latest literature in Table 12, focusing on MSE and PSNR, respectively. Notably, the findings indicate that our proposed algorithm exhibits superior MSE and PSNR values when compared to [48,49].

    Table 12.  Comparison of MSE and PSNR values of the proposed scheme with existing schemes of plain-encrypted (PE) and plain-decrypted (PD) images.
    Images MSEPE MSEPD PSNRPE PSNRPD
    Women 3930.7 0 12.1861
    Home 8344.7 0 8.9167
    Jellybeans 7375.2 0 9.4531
    Couple 8909.9 0 8.6321
    [48] 40.264 0 9.1244
    [49] 7952.7 0 9.1812

     | Show Table
    DownLoad: CSV

    In the proposed scheme, an algorithm for image encryption is designed to combine an elliptic curve and arithmetic operations of a BEF and an invertible function under the Galois field. This algorithm has been designed to resist various attacks, including chosen-plaintext and chosen-ciphertext attacks. Since a robust encryption algorithm integrates confusion and diffusion properties to fortify its security measures. In the proposed algorithm, we employed permutation to disperse the pixels of images. Further, we generate the nonlinear component by utilizing EC over BEF and inverse function, introducing complexity and preventing simple algebraic relationships between the plain and obtained image. Further, the invertible function under the Galois field provides diffusion to ensure that any changes made to the ciphertext will significantly impact the decrypted image. Additionally, the key stream is generated by utilizing the points of EC and operations of the Galois field; the generated key stream is then XORed with the image entries. The randomness of the key stream ensures that the XOR operation is not easily predictable, enhancing the security of the encryption. The pseudo-randomness of PRNs helps prevent attackers from exploiting regularities or biases in the encryption process. Using these three cryptographic primitives in combination provides a high level of security and makes it difficult for an attacker to break the encryption.

    Additionally, using the complex structure of EC and operations of BEF ensures that the algorithm resists attacks. Collectively, these inherent properties impose significant challenges for potential attackers attempting to deduce information about the encryption key or plaintext from the ciphertext. Overall, this proposed algorithm is a robust and effective method for image encryption that provides resistance to various attacks. With the increasing importance of secure image transmission in today's digital world, this algorithm is an essential contribution to the field of cryptography.

    The complexity analysis involves assessing the resources, such as time and memory, required for execution. Various methods exist to determine algorithmic complexity, the most common being big "O" notation. In this section, we evaluated the proposed scheme using big O. Given that the scheme functions as a substitution permutation network, it initially generates S-boxes, employing them for substitution in the encryption process. Subsequently, the generated numbers are utilized in the permutation module, which linearly shuffles image data. Consequently, the permutation module's time complexity for data permutation is O(3×M×N). Similarly, substituting fixed pixels within the permutation module also requires constant time. In summary, the overall time complexity of the proposed algorithm is O(3×M×N).

    EC structure is commonly employed in image encryption applications. In this article, we designed a technique to protect RGB images while transmitting them through insecure channels. The proposed scheme employs a three-phase mechanism to encrypt data. In the first phase, each pixel value is dispersed using a piecewise function on EC points, while in the second phase, the proposed S-box is utilized to create confusion in the image. Subsequently, a PRNS is generated and applied to the confused image to achieve the desired diffusion. The key elements of this proposed image encryption technique include the following: Both SCT and PRNS are designed by utilizing the properties of BEF on EC points. Instead of using large primes, a novel technique is employed for both SCT and PRNS. BEF can resist side-channel attacks, a security attack that exploits information leaked during a cryptographic operation. Because BEF has a uniform distribution of values, which makes it difficult for attackers to obtain sensitive information, BEF can designate large numbers compactly, which is helpful in applications requiring efficient data storage and transmission.

    Regarding security analysis, the proposed scheme is up to the mark. Using various testing tools, we assessed the effectiveness of the proposed SCT and determined that it exhibits greater efficiency relative to its respective features. Moreover, standardized tests are performed on the encrypted image data to evaluate the encryption performance. The results of the simulations indicate that the proposed modules generate encrypted data that is highly resistant to typical attacks. Furthermore, a comparative analysis between our scheme and recent research demonstrates that our approach requires fewer operations than existing schemes. From a futuristic point of view, we can also extend this algorithm to the general algorithm.

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

    The authors extend their gratitude to the deanship of Scientific research at King Khalid University for funding this work through the research group's program under grant number R.G.P.2/5/44.

    The authors declare that they have no conflicts of interest.

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