Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems
Abstract
:1. Introduction
2. Results and Discussion
2.1. Polymer Carriers and Their Characteristics
2.2. Mobility of Different Nanoparticles in Vitreous Humor
2.3. Effect of Polypeptide Nanoparticles on ARPE-19 Cell Proliferation
2.4. Synthesis and Characterization of Polypeptide-DEX Conjugates
2.4.1. DEX Modification and General Strategy for Conjugation with Polypeptides
2.4.2. Conjugation of DEX with Glutamic Acid- and Lysine-Containing Polypeptides
2.4.3. Storage Stability
2.5. Release of DEX from Conjugates in Different Media
3. Materials and Methods
3.1. Materials
3.2. Methods
3.2.1. Synthesis and Characterization of Delivery Systems
3.2.2. Stability of Nanoparticles and Movement in Vitreous Humor
3.2.3. Proliferation Assay
3.2.4. Modification of DEX
3.2.5. Modification of poly(Glutamic Acid-co-Phenylalanine) with Ethylenediamine
3.2.6. Synthesis and Characterization of Conjugates
3.2.7. DEX Release Study
3.2.8. DEX Quantitative HPLC Analysis
3.2.9. Morphology and Stability Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Copolymer a | Sample Abbreviation | Composition b (mol%) | [Lys]/[Phe] or [Glu]/[Phe] | Mn (for Protected Copolymers) | Ðc | |
---|---|---|---|---|---|---|
Lys or Glu | Phe | |||||
P(Glu-co-DPhe) | P[EF]-1 | 74 | 26 | 2.8 | 6700 c | 1.19 |
P[EF]-2 | 81 | 19 | 4.3 | 11,220 d | − | |
P(Lys-co-LPhe) | P[KF]L | 77 | 23 | 3.4 | 12,250 c | 1.31 |
P(Lys-co-D,LPhe) | P[KF]DL-1 | 81 | 19 | 4.3 | 11,000 c | 1.33 |
P[KF]DL-2 | 88 | 12 | 7.3 | 12,150 c | 1.37 |
Sample | DH (nm) | PDI | Zeta-Potential a (mV) | CAC b (μg/mL) |
---|---|---|---|---|
P[EF]-1 | 90 | 0.08 | −37 ± 2 | n/d |
P[EF]-2 | 165 | 0.11 | −40 ± 2 | 4.2 ± 0.2 |
P[KF]L | 210 | 0.27 | 36 ± 1 | 9.4 ± 0.2 |
P[KF]DL-1 | 110 | 0.16 | 41 ± 1 | 6.7 ± 0.3 |
P[KF]DL-2 | 135 | 0.19 | 45 ± 2 | 7.4 ± 0.1 |
P[KF]DL-2/HEP | 110 | 0.22 | −20 ± 1 | − c |
Nanoparticles | Surface Charge | Dw (µm2/s) | Dv (µm2/s) | Dw/Dv |
---|---|---|---|---|
P[KF]DL-2 | positive | 4.9 | 0.015 ± 0.06 | 329 |
P[KF]DL-2/HEP | negative | 6.9 | 0.61 ± 0.10 | 11.3 |
P[EF]-2 | negative | 7.7 | 0.67 ± 0.15 | 11.5 |
Nanoparticle-Based Polypeptide-DEX Conjugates | Glu/Phe or Lys/Phe Molar Ratio | DEX Fraction in Polymer (wt%) | DH (nm) | Zeta-Potential (mV) |
---|---|---|---|---|
P[EF]-1-DEX | 2.8 | 3.0 | 200 ± 20 | −30 ± 3 |
P[EF]-2-DEX | 4.3 | 3.8 | 225 ± 35 | −35 ± 4 |
P[KF]L-DEX | 3.4 | 4.2 | 370 ± 30 | 11 ± 1 |
P[KF]DL-1-DEX | 4.3 | 5.2 | 320 ± 10 | 12 ± 1 |
P[KF]DL-2-DEX | 7.2 | 8.6 | 290 ± 20 | 15 ± 3 |
P[KF]DL-2-DEX/HEP | 7.2 | 8.6 | 250 ± 10 | −19 ± 1 |
Sample | Average Diameter Determined by TEM (nm) |
---|---|
P[EF]-2 | 119 ± 39 |
P[EF]-2-DEX | 181 ± 36 |
P[KF]DL-2 | 71 ± 20 |
P[KF]DL-2-DEX | 178 ± 90 |
P[KF]DL-2-DEX/HEP | 158 ± 37 |
Model | Encapsulated Systems | Conjugated Systems | ||||||
---|---|---|---|---|---|---|---|---|
0.01 M PBS, pH 7.4 | 0.01 M PBS, pH 7.4 | Vitreous/0.01 M PBS, pH 7.4 (50/50, v/v) | ||||||
P[KF]D,L-2(DEX) | P[KF]D,L-2(DEX)/HEP | P[KF]D,L-2/DEX | P[KF]D,L-2/DEX/HEP | P[EF]-2/DEX | P[KF]D,L-2/DEX | P[KF]D,L-2/DEX/HEP | P[EF]-2/DEX | |
Zero-order * | R2 = 0.9644 | R2 = 0.9565 | R2 = 0.9653 | R2 = 0.9985 | R2 = 0.9517 | R2 = 0.9811 | R2 = 0.9937 | R2 = 0.9616 |
Kzo = 14.32 | Kzo = 13.79 | Kzo = 0.764 | Kzo = 0.598 | Kzo = 0.820 | Kzo = 1.564 | Kzo = 1.568 | Kzo = 0.782 | |
First-order * | R2 = 0.9950 | R2 = 0.9924 | R2 = 0.9945 | R2 = 0.9962 | R2 = 0.9907 | R2 = 0.9943 | R2 = 0.9956 | R2 = 0.9888 |
kfo = 0.246 | kfo = 0.231 | kfo = 1.2 × 10−2 | kfo = 7.9 × 10−3 | kfo = 1.4 × 10−2 | kfo = 2.3 × 10−2 | kfo = 2.3 × 10−2 | kfo = 1.3 × 10−2 | |
Higuchi * | R2 = 0.9896 | R2 = 0.9805 | R2 = 0.9941 | R2 = 0.9675 | R2 = 0.9896 | R2 = 0.9892 | R2 = 0.9801 | R2 = 0.9932 |
KH = 29.629 | KH = 28.418 | KH = 6.085 | KH = 4.486 | KH = 6.558 | KH = 8.714 | KH = 8.562 | KH = 6.600 | |
Korsmeyer-Peppas * | R2 = 0.9926 | R2 = 0.9845 | R2 = 0.9948 | R2 = 0.9990 | R2 = 0.9885 | R2 = 0.9945 | R2 = 0.9964 | R2 = 0.9932 |
KKP = 25.842 | KKP = 23.627 | KKP = 3.480 | KKP = 0.752 | KKP = 3.936 | KKP = 5.422 | KKP = 3.393 | KKP = 4.375 | |
n = 0.605 | n = 0.641 | n = 0.643 | n = 0.947 | n = 0.631 | n = 0.645 | n = 0.780 | n = 0.602 | |
Hixon-Crowell * | R2 = 0.9900 | R2 = 0.9858 | R2 = 0.9884 | R2 = 0.9981 | R2 = 0.9826 | R2 = 0.9920 | R2 = 0.9965 | R2 = 0.9827 |
KHC = 7.0 × 10−2 | KHC = 6.6 × 10−2 | KHC = 3.5 × 10−3 | KHC = 2.4 × 10−3 | KHC = 3.9 × 10−3 | KHC = 6.8 × 10−3 | KHC = 6.7 × 10−3 | KHC = 3.7 × 10−3 | |
Hopfenberg * | R2 = 0.9950 | R2 = 0.9924 | R2 = 0.9945 | R2 = 0.9990 | R2 = 0.9907 | R2 = 0.9943 | R2 = 0.9960 | R2 = 0.9888 |
KHb = 1.8 × 10−4 | KHb = 6.2 × 10−5 | KHb = 3.4 × 10−6 | KHb = 4.8 × 10−3 | KHb = 5.9 × 10−6 | KHb = 5.2 × 10−5 | KHb = 2.3 × 10−3 | KHb = 4.3 × 10−6 | |
Baker-Lonsdale * | R2 = 0.9822 | R2 = 0.9736 | R2 = 0.9913 | R2 = 0.9590 | R2 = 0.9882 | R2 = 0.9840 | R2 = 0.9713 | R2 = 0.9909 |
KBL = 2.0 × 10−2 | KBL = 1.8 × 10−2 | KBL = 7.6 × 10−4 | KBL = 3.8 × 10−4 | KBL = 9.1 × 10−4 | KBL = 1.6 × 10−3 | KBL = 1.5 × 10−3 | KBL = 9.5 × 10−4 | |
Weibull ** | R2 = 0.9963 | R2 = 0.9940 | R2 = 0.9987 | R2 = 0.9992 | R2 = 0.9990 | R2 = 0.9963 | R2 = 0.9987 | R2 = 0.9912 |
α = 2.51 | α = 2.26 | α = 53.228 | α = 587.182 | α = 23.440 | α = 325.204 | α = 191.949 | α = 58.592 | |
β = 0.64 | β = 0.51 | β = 0.887 | β = 1.345 | β = 0.716 | β = 1.504 | β = 1.379 | β = 0.943 | |
Gompertz ** | R2 = 0.9960 | R2 = 0.9984 | R2 = 0.9911 | R2 = 0.9901 | R2 = 0.9967 | R2 = 0.9875 | R2 = 0.9923 | R2 = 0.9763 |
α = 1.442 | α = 1.529 | α = 39.371 | α = 168.455 | α = 16.931 | α = 213.930 | α = 223.724 | α = 30.684 | |
β = 1.903 | β = 1.822 | β = 2.390 | β = 3.007 | β = 1.954 | β = 3.942 | β = 3.935 | β = 2.320 | |
Peppas-Sahlin ** | R2 = 0.9866 | R2 = 0.9782 | R2 = 0.9992 | R2 = 0.9934 | R2 = 0.9980 | R2 = 0.9971 | R2 = 0.9984 | R2 = 0.9970 |
K1 = 34.304 | K1 = 32.556 | K1 = 3.146 | K1 = 18.141 | K1 = 3.665 | K1 = 3.697 | K1 = 3.329 | K1 = 4.107 | |
K2 = 2.965 | K2 = 2.778 | K2 = 0.025 | K2 = 14.802 | K2 = 0.037 | K2 = 0.032 | K2 = 0.026 | K2 = 0.018 | |
m = 0.492 | m = 0.484 | m = 0.707 | m = 0.210 | m = 0.696 | m = 0.821 | m = 0.835 | m = 0.631 |
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Zashikhina, N.; Gladnev, S.; Sharoyko, V.; Korzhikov-Vlakh, V.; Korzhikova-Vlakh, E.; Tennikova, T. Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems. Int. J. Mol. Sci. 2023, 24, 3702. https://doi.org/10.3390/ijms24043702
Zashikhina N, Gladnev S, Sharoyko V, Korzhikov-Vlakh V, Korzhikova-Vlakh E, Tennikova T. Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems. International Journal of Molecular Sciences. 2023; 24(4):3702. https://doi.org/10.3390/ijms24043702
Chicago/Turabian StyleZashikhina, Natalia, Sergei Gladnev, Vladimir Sharoyko, Viktor Korzhikov-Vlakh, Evgenia Korzhikova-Vlakh, and Tatiana Tennikova. 2023. "Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems" International Journal of Molecular Sciences 24, no. 4: 3702. https://doi.org/10.3390/ijms24043702