Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Synthesis Procedures
2.2.1. Synthesis of PEG-b-PCL Copolymers
2.2.2. Synthesis of PEG-PCL-COOH
2.2.3. Synthesis of PEG-PCL-RET
2.3. Characterization Techniques
2.4. Critical Micellar Concentration Measurements
2.5. Preparation of AmB Loaded Micelles
2.6. Determination of Encapsulated AmB
2.7. Assessment of Aggregation State
2.8. Release Study
2.9. In Vitro Biocompatibility
2.9.1. Haemolysis
2.9.2. Cytotoxicity against Fibroblasts
2.10. In Vitro Assessment of Antifungal Activity
3. Results
3.1. Synthesis of Polymeric Precursors
3.2. Critical Micellar Concentration
3.3. Differential Scanning Calorimetry
3.4. AmB Encapsulation
3.5. Assessment of AmB Aggregation
3.6. Release Study
3.7. In Vitro Biocompatibility
3.8. In Vitro Effectiveness
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample | Composition a | Mn (kDa) a | Mw/Mn b | CMC | |
---|---|---|---|---|---|
mg/L | μM | ||||
AB | (mPEG)114-(PCL)11-OH | 6.27 | 1.20 | 4.5 ± 0.26 | 4.9 |
AB-RET | (mPEG)114-b-(PCL)11-RET | 6.56 | 1.24 | 7.4 ± 0.78 | 8.0 |
ABA | HO-(PCL)9-(PEG)136-(PCL)9-OH | 8.04 | 1.13 | 2.7 ± 0.86 | 2.9 |
ABA-RET | RET-(PCL)9-(PEG)136-(PCL)9-RET | 8.61 | 1.29 | 5.5 ± 0.72 | 5.9 |
Sample | Thermal Properties | ||
---|---|---|---|
Tc (°C) | Tm (°C) | ΔHm (J/g) | |
mPEG | 40.6 | 60.2 | 171.9 |
AB | 28.2 18.6 | 48.0 | 86.2 |
AB-RET | 23.3 −7.15 | 39.4 | 61.9 |
PEG-diol | 35.4 | 63.9 | 107.9 |
ABA | 30.8 | 54.4 | 110.7 |
ABA-RET | 2.7 | 38.41 49.1 | 41.8 |
Formulation | EE (%) | DL (%) |
---|---|---|
AmB@AB | 13.7 ± 0.71 | 2.74 ± 0.17 |
AmB@AB-RET | 51.05 ± 0.79 | 10.21 ± 0.21 |
AmB@ABA | 10.19 ± 0.12 | 2.38 ± 0.03 |
AmB@ABA-RET | 33.65 ± 1.23 | 6.73 ± 0.28 |
Formulation | Empty Micelles | AmB@PMs | ||||||
---|---|---|---|---|---|---|---|---|
25 °C | 37 °C | 25 °C | 37 °C | |||||
Dh (nm) | PDI | Dh (nm) | PDI | Dh (nm) | PDI | Dh (nm) | PDI | |
AmB@AB | 31.1 ± 1.7 | 0.172 ± 0.032 | 35.5 ± 2.8 | 0.189 ± 0.081 | 57.7 ± 4.3 | 0.324 ± 0.072 | 69.0 ± 6.0 | 0.234 ± 0.032 |
AmB@AB-RET | 57.5 ± 4.2 | 0.213 ± 0.023 | 80.5 ± 7.5 | 0.204 ± 0.035 | 91.0 ± 3.5 | 0.391 ± 0.058 | 115.3 ± 7.2 | 0.359 ± 0.043 |
AmB@ABA | 22.0 ± 2.3 | 0.198 ± 0.035 | 32.4 ± 3.3 | 0.212 ± 0.014 | 45.9 ± 4.7 | 0.429 ± 0.063 | 67.8 ± 3.5 | 0.354 ± 0.065 |
AmB@ABA-RET | 53.4 ± 7.3 | 0.321 ± 0.041 | 77.6 ± 9.1 | 0.271 ± 0.037 | 80.2 ± 5.9 | 0.407 ± 0.024 | 81.7 ± 5.2 | 0.428 ± 0.027 |
Sample | Aggregation Ratio * | AgI/Ag ** |
---|---|---|
AmB in PBS | 0.66 | 0.49 |
Fungizone® | 0.70 | 0.74 |
AmB@AB | 0.21 | 0.17 |
AmB@AB-RET | 0.32 | 0.75 |
AmB@ABA | 0.23 | 0.14 |
AmB@ABA-RET | 0.37 | 0.81 |
Model | Parameter | ABA | ABA-RET | ABA | ABA-RET |
---|---|---|---|---|---|
Zero order | R2 | 0.975 | 0.903 | 0.973 | 0.969 |
K (%·h−1) | 2.426 | 2.061 | 0.138 | 0.173 | |
First order | R2 | 0.917 | 0.878 | 0.950 | 0.950 |
k (h−1) | 0.207 | 0.095 | 0.006 | 0.005 | |
Higuchi | R2 | 0.992 | 0.955 | 0.996 | 0.994 |
k (%·h−0.5) | 0.085 | 0.074 | 0.021 | 0.026 | |
Korsmeyer–Peppas | R2 | 0.994 | 0.975 | 0.999 | 0.999 |
n | 0.608 | 0.283 | 0.613 | 0.496 | |
k (h−n) | 0.063 | 0.166 | 0.072 | 0.141 |
Yeast | Reference | CLSI | Formulations | |||||
---|---|---|---|---|---|---|---|---|
FLC * | CAS * | Fungizone® | AmB@AB | AmB@ABA | AmB@AB-RET | AmB@ABA-RET | ||
MIC (µg/mL) | ||||||||
C. albicans | SC5314 | 1 | 0.06 | 0.46 | <0.11 | <0.11 | <0.11 | <0.11 |
C. glabrata | ATCC 2001 | 0.25 | 0.06 | 0.46 | <0.11 | <0.11 | <0.11 | <0.11 |
C. krusei | ATCC 6258 | 32 | 0.25 | 1.875 | 0.23 | 0.23 | 0.43 | 0.23 |
C. parapsilosis | ATCC 22019 | 1 | 0.25 | 0.23 | <0.11 | <0.11 | <0.11 | <0.11 |
C. auris | 435-PUJ-HUSI | 8 | 0.25 | 0.93 | 0.23 | 0.23 | 0.46 | 0.23 |
C. auris * | 537-PUJ-HUSI | 128 ** | <0.05 | 3.75 | 1.865 | 0.93 | 3.75 | 3.75 |
C. parapsilosis | 75-PUJ-FVL | 0.125 | <0.05 | 0.11 | <0.11 | <0.11 | 0.11 | <0.11 |
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Rodriguez, Y.J.; Quejada, L.F.; Villamil, J.C.; Baena, Y.; Parra-Giraldo, C.M.; Perez, L.D. Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol. Pharmaceutics 2020, 12, 196. https://doi.org/10.3390/pharmaceutics12030196
Rodriguez YJ, Quejada LF, Villamil JC, Baena Y, Parra-Giraldo CM, Perez LD. Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol. Pharmaceutics. 2020; 12(3):196. https://doi.org/10.3390/pharmaceutics12030196
Chicago/Turabian StyleRodriguez, Yeimy J., Luis F. Quejada, Jean C. Villamil, Yolima Baena, Claudia M. Parra-Giraldo, and Leon D. Perez. 2020. "Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol" Pharmaceutics 12, no. 3: 196. https://doi.org/10.3390/pharmaceutics12030196