Chemical immobilization of retinoic acid within poly(ε‐caprolactone) nanoparticles based on drug–polymer bioconjugates
Abstract
All‐trans‐retinoic acid (RA) was chemically conjugated to biodegradable poly(ε‐caprolactone) (PCL 10; number‐average Mw ≈ 1250) via an ester linkage. The conjugation was carried out using N,N‐dicyclohexylcarbodiimide and 4‐dimethyl aminopyridine as a coupling agent. The molar ratio of the drug to the polymer was 1.11 as determined by 1 H‐NMR analysis. DSC and WAXD results showed that the formation of crystalline structures of RA was effectively suppressed by conjugation with PCL. The RA–PCL conjugates were formulated into nanoparticles by a spontaneous phase‐inversion technique. Morphological characteristics of the resultant nanoparticles and drug‐loading efficiencies were compared with those of free RA‐loaded nanoparticles. The drug‐loading efficiency of RA–PCL conjugates was almost 100%, while that of free RA was only ∼12%. The majority of unconjugated RA was found to form undesirable free‐drug crystals out of nanoparticles, as observed by TEM analysis. This study demonstrates that the conjugation approach of RA to PCL can be an effective means to immobilize and encapsulate RA within nanoparticles for pharmaceutical applications. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 1631–1637, 2003
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In chemical interaction, RA is typically conjugated chemically to one of the components of the nanoparticle by biodegradable ester, amide, or disulfide linkages.
“Concerning chemical interaction, RA is typically conjugated chemically to one of the components of the nanoparticle by biodegradable ester50,52, amide26,53–55, or disulfide56 linkages.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [50]
Several RA-polymer conjugates have been developed to release RA by hydrolytic cleavage of ester bonds, by enzymatic cleavage of amide bonds by proteases present in the targeted tissue, or by reducing environments such as the cell cytoplasm.
“For example, several RA-polymer conjugates have been developed to release RA by hydrolytic cleavage of ester bonds50,52, by enzymatic cleavage of amide bonds by proteases present in the targeted tissue28,65–67 or by reducing environments56 such as the cell cytoplasm.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [50]
Cites
Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid
Breitman, T. R., Selonick, S. E., & Collins, S. J. (1980) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.77.5.2936 · Cited by 1,966 · see citing works
The retinoids—Biology, chemistry and medicine
(1996) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/s0960-0760(97)80793-5 · Cited by 1,188 · see citing works
Castaigné, S., Chomienne, C., Daniel, M., Ballerini, P. F., Berger, R., Fenaux, P., & Degos, L. (1990) · Blood · doi:10.1182/blood.v76.9.1704.1704 · Cited by 1,182 · see citing works
The Retinoids-Biology, Chemistry and Medicine
Wolf, G. (1994) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/60.5.796a · Cited by 1,005 · see citing works
Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA–PEG block copolymer
Yoo, H. S., & Park, T. G. (2001) · Journal of Controlled Release · doi:10.1016/s0168-3659(00)00340-0 · Cited by 539 · see citing works
Liu, J., Loewe, R. S., & McCullough, R. D. (1999) · Macromolecules · doi:10.1021/ma9905324 · Cited by 319 · see citing works
Allen, C., Yu, Y., Maysinger, D., & Eisenberg, A. (1998) · Bioconjugate Chemistry · doi:10.1021/bc9702157 · Cited by 273 · see citing works
Biodegradable Nanoparticles Containing Doxorubicin-PLGA Conjugate for Sustained Release
Yoo, H. S., Oh, J. E., Lee, K. H., & Park, T. G. (1999) · Pharmaceutical Research · doi:10.1023/a:1018908421434 · Cited by 225 · see citing works
Gliadin nanoparticles for the controlled release of all-trans-retinoic acid
Ezpeleta, I., Irache, J. M., Stainmesse, S., Chabenat, C., Guéguen, J., Popineau, Y., & Orecchioni, A. M. (1996) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(95)04338-1 · Cited by 201 · see citing works
Naylor, H. M., & Newcomer, M. E. (1999) · Biochemistry · doi:10.1021/bi982291i · Cited by 188 · see citing works
Chemistry and Biology of Synthetic Retinoids
Dawson, M. I. (2018) · CRC Press eBooks · doi:10.1201/9781351070638 · Cited by 178 · see citing works
Jeong, J. H., & Park, T. G. (2001) · Bioconjugate Chemistry · doi:10.1021/bc010052t · Cited by 172 · see citing works
Gan, Z., Jim, T. F., Li, M., Zhao, Y., Wang, S., & Wu, C. (1999) · Macromolecules · doi:10.1021/ma981121a · Cited by 153 · see citing works
Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer
Niles, R. M. (2000) · Nutrition · doi:10.1016/s0899-9007(00)00436-6 · Cited by 150 · see citing works
Retinoid receptors in health and disease: co-regulators and the chromatin connection
Minucci, S., & Pelicci, P. G. (1999) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.1999.0303 · Cited by 110 · see citing works
Bronich, T. K., Nehls, A., Eisenberg, A., Kabanov, V. A., & Kabanov, A. V. (1999) · Colloids and Surfaces B Biointerfaces · doi:10.1016/s0927-7765(99)00075-2 · Cited by 93 · see citing works
Poly(ethylene oxide)-b-poly( l -lysine) Complexes with Retinoic Acid
Thünemann, A. F., Beyermann, J., & Kukula, H. (2000) · Macromolecules · doi:10.1021/ma000629m · Cited by 74 · see citing works
Retinoids in psoriasis and disorders of keratinization
Fritsch, P. O. (1992) · Journal of the American Academy of Dermatology · doi:10.1016/s0190-9622(08)80253-8 · Cited by 73 · see citing works
Polyethylenimine Complexes with Retinoic Acid: Structure, Release Profiles, and Nanoparticles
Thünemann, A. F., & Beyermann, J. (2000) · Macromolecules · doi:10.1021/ma000416x · Cited by 63 · see citing works
Oh, J.-Y. (1999) · Journal of Controlled Release · doi:10.1016/s0168-3659(98)00123-0 · Cited by 61 · see citing works
Thomson, B., Suddaby, K. G., Rudin, A., & Lajoie, G. (1996) · European Polymer Journal · doi:10.1016/0014-3057(95)00117-4 · Cited by 46 · see citing works
Chemical stability of tretinoin in dermatological preparations
Brisaert, M., Everaerts, I., & Plaizier-vercammen, J. A. (1995) · Pharmaceutica Acta Helvetiae · doi:10.1016/0031-6865(95)00016-3 · Cited by 40 · see citing works
Crystal Structure of the Transthyretin–Retinoic‐Acid Complex
Zanotti, G., D'acunto, M. R., Malpeli, G., Folli, C., & Berni, R. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.563_b.x · Cited by 40 · see citing works
Novel Mutual Prodrug of Retinoic and Butyric Acids with Enhanced Anticancer Activity
Nudelman, A., & Rephaeli, A. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm990540a · Cited by 38 · see citing works
Protein loaded biodegradable microspheres based on PLGA-protein bioconjugates
Nam, Y. S. (1999) · Journal of Microencapsulation · doi:10.1080/026520499288816 · Cited by 34 · see citing works
Altered metabolism of all-trans-retinoic acid in liposome-encapsulated form
Parthasarathy, R. V., & Mehta, K. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00226-2 · Cited by 33 · see citing works
Immobilization of Retinoic Acid by Polyamino Acids: Lamellar-Structured Nanoparticles
Thünemann, A. F., Beyermann, J., von Ferber, C., & Löwen, H. (1999) · Langmuir · doi:10.1021/la9906525 · Cited by 21 · see citing works
Manfredini, S., Simoni, D., Ferroni, R., Bazzanini, R., Vertuani, S., Hatse, S., Balzarini, J. M., & Clercq, E. D. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm9602322 · Cited by 20 · see citing works
Immobilization of Retinoic Acid by Cationic Polyelectrolytes
Thünemann, A. F. (1997) · Langmuir · doi:10.1021/la970756k · Cited by 20 · see citing works
Montenegro, L. (1996) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(96)04546-2 · Cited by 17 · see citing works
Childhood cancer etiology: Recent reports
Ross, J. A., & Davies, S. M. (2001) · Medical and Pediatric Oncology · doi:10.1002/mpo.1164 · Cited by 14 · see citing works
Contamination of poliovirus vaccine with SV40 and the incidence of medulloblastoma
Strickler, H. D., Rosenberg, P. S., Devesa, S. S., Fraumeni, J. F., & Goedert, J. J. (1999) · Medical and Pediatric Oncology · doi:10.1002/(sici)1096-911x(199901)32:1 · Cited by 14 · see citing works
HAKIMELAHI, G. H., Ly, T. W., Yu, S.-F., Zakerinia, M., Khalafi‐Nezhad, A., Soltani, M. N., Nemat‐Gorgani, M., Rabbani‐Chadegani, A., & Moosavi‐Movahedi, A. A. (2001) · Bioorganic & Medicinal Chemistry · doi:10.1016/s0968-0896(01)00127-4 · Cited by 11 · see citing works
Watanabe, H., & Chigira, M. (1992) · International Journal of Oncology · doi:10.3892/ijo.1.4.481 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ourique, A. F., Pohlmann, A. R., Guterres, S. S., & Beck, R. C. R. (2008) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.12.035 · Cited by 145 · see citing works
Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine
Ferreira, R., Napoli, J., Enver, T., Bernardino, L., & Ferreira, L. (2020) · Nature Communications · doi:10.1038/s41467-020-18042-2 · Cited by 138 · see citing works
Mechanical and dynamic viscoelastic properties of hydroxyapatite reinforced poly(ε-caprolactone)
Chen, B., & Sun, K. (2005) · Polymer Testing · doi:10.1016/j.polymertesting.2005.07.013 · Cited by 63 · see citing works
Retinol initiated poly(lactide)s: stability upon polymerization and nanoparticle preparation
Yildirim, I., Yildirim, T., Kalden, D., Festag, G., Fritz, N., Weber, C., Schubert, S., Westerhausen, M., & Schubert, U. S. (2017) · Polymer Chemistry · doi:10.1039/c7py00881c · Cited by 16 · see citing works
Kim, T. H. L., Yu, J. H., Jun, H., Yang, M. Y., Yang, M., Cho, J., Kim, J. W., Kim, J. S., & Nam, Y. S. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.08.042 · Cited by 16 · see citing works
A Novel Cell Penetrating Peptide for the Differentiation of Human Neural Stem Cells
Ma, W., Jin, G., Gehret, P. M., Chada, N. C., & Suh, W. H. (2018) · Biomolecules · doi:10.3390/biom8030048 · Cited by 13 · see citing works
Study on Preparation and Some Properties of Panretin-Loaded Nanocapsules
Shokuhi, A. (2010) · Biotechnology(Faisalabad) · doi:10.3923/biotech.2010.234.237 · Cited by 7 · see citing works
Rahman, R. T., Koo, B. I., Jang, J., Lee, D. J., Choi, S., Lee, J. B., & Nam, Y. S. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124409 · Cited by 6 · see citing works
Impallomeni, G., Mineo, P. G., Vento, F., & Ballistreri, A. (2020) · Polymer International · doi:10.1002/pi.6141 · Cited by 6 · see citing works
Kim, T. H. L., Jun, H., & Nam, Y. S. (2017) · Journal of Colloid and Interface Science · doi:10.1016/j.jcis.2017.04.079 · Cited by 5 · see citing works
Yeom, J., & Nam, Y. S. (2012) · Colloid & Polymer Science · doi:10.1007/s00396-012-2606-1 · Cited by 4 · see citing works
Poly(2-oxazoline) Homopolymers and Diblock Copolymers Containing Retinoate ω-End Groups
Stafast, L. M., Weber, C., Kuchenbrod, M. T., Hoeppener, S., Behnke, M., Schubert, S., Mehmetaj, K., Press, A. T., Bauer, M. W., & Schubert, U. S. (2022) · ACS Applied Polymer Materials · doi:10.1021/acsapm.2c00037 · Cited by 3 · see citing works
Michael, A. A., Balakrishnan, P., Tamizhmani, P., Thirunavukarasu, K., Subramaniam, S., & Velusamy, T. (2025) · Cancer Gene Therapy · doi:10.1038/s41417-025-00996-4 · Cited by 2 · see citing works
- Authors
- Sung Nam, Y., Joong Kim, K., Seok Kang, H., Gwan Park, T., Han, S., & Chang, I.
- Affiliations
- Amorepacific (South Korea) (KR)
- ORCID
- Han, Sang‐Hoon
- Venue
- Journal of Applied Polymer Science
- Publisher
- Wiley
- Published
- 2003-05-23
- Volume
- 89
- Issue
- 6
- Pages
- 1631-1637
- ISSN
- 0021-8995 (ISSN-L)
- 1097-4628
- OpenAlex
- W1972681425
- Cited by
- 13
- References
- 34
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2020: 2 · 2018: 1 · 2017: 3 · 2012: 1
- FWCI
- 0.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Applied Polymer Science (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- retinoic acid, polycaprolactone, ester linkage, chemical immobilization, nanoparticles, drug encapsulation, drug loading efficiency, crystallization suppression, phase inversion, biodegradable polymers, N,N'-dicyclohexylcarbodiimide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
