Development and Characterization of Leuprolide Acetate Encapsulated PLGA Microspheres for Parenteral Controlled Release Depot Injection

Satapathy, Soumya Ranjan; Sahoo, Rudra Narayan; Satapathy, Biswaranjan; Immani, Ramachandrarao; Panigrahi, Lalatendu; Mallick, Subrata

doi:10.5530/ijper.55.1.14

Cited by 7 publications

(4 citation statements)

References 22 publications

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“… 7 , 8 For example, PLGA microspheres encapsulating LEU were developed for parenteral controlled release depot injection. 9 In situ forming implant (ISFI) system using PLGA and nanohydroxyapatite (HA) particle also led to the sustained release of LEU and testosterone withholding over a 90-day period with a significant decrease in the burst release phase. 10 Currently, LEU depot suspension (Lupron Depot ® , TAP Pharmaceuticals Inc., Deerfield, IL, USA) is commercially available in a prefilled dual-chamber syringe containing sterile lyophilized microspheres, which is administered monthly as an intramuscular (IM) injection with sustained release.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity

Ngo¹,

Bak²,

Nguyen³

et al. 2023

IJN

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Background Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. Purpose To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). Methods LEU–fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Results Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. Conclusion The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.

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Section: Introductionmentioning

confidence: 99%

Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity

Ngo¹,

Bak²,

Nguyen³

et al. 2023

IJN

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“…Figure 4 shows FT-IR spectra of LEU acetate, fatty acids, physical mixtures, and LEU-fatty acid conjugate having different saturation levels (LSC, LOC, and LLC). As a result of LEU acetate, the O-H bond peak appeared at 3274 cm −1 , and the C=O stretch peak appeared at 1624 cm.−1 30 In the order of stearic acid, oleic acid, and linoleic acid, CH 2 stretching appeared at 2845 and 2914 cm −1 (stearic acid), 2853 and 2922 cm −1 (oleic acid), 2853, 2923 and 3008 cm −1 (linoleic acid), and in the case of carboxyl group, 1695 cm −1 , 1707.93 cm −1 , and 1707.75 cm −1 , respectively. The shifting of the -OH group into 3285 cm −1 for LSC, 3282 cm −1 for LOC, and 3286 cm −1 for LLC evidenced for esterification of these conjugates.…”

Section: Resultsmentioning

confidence: 99%

Hydroxyl Group-Targeted Conjugate and Its Self-Assembled Nanoparticle of Peptide Drug: Effect of Degree of Saturation of Fatty Acids and Modification of Physicochemical Properties

Park¹,

Ngo²,

Jin³

et al. 2022

IJN

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Purpose To conjugate different degree of saturation of C18 fatty acids (stearic acid, oleic acid, and linoleic acid) with the hydroxyl groups of leuprolide acetate (LEU acetate) and to investigate the controlled release and enhanced permeability through self-assembled nanoparticles (L18FNs). Methods Yamaguchi esterification with benzoyl chloride and DMAP (4-Dimethylaminopyridine) allowed the conjugation of the fatty acid to the hydroxyl group of LEU. The three conjugates were then designated as stearic acid-conjugated LEU, LSC, oleic acid-conjugated LEU, LOC, and linoleic acid-conjugated LEU, LLC, respectively. The conjugates (L18FCs) were purified using preparative HPLC (Prep-HPLC) and identified through various instrumental analyses. Results The zeta potential, particle size, and morphology of each L18FNs were evaluated. In the case of LSNs, the zeta potential value was relatively low and the particle size was larger than LONs and LLNs owing to the higher hydrophobicity of saturated fatty chain, while the LLNs showed a higher zeta potential and smaller particle size. In human plasma, LLC showed the fastest degradation rate with the highest accumulative drug release. The permeability of L18FNs was analyzed through the Franz diffusion cell experiment, confirming that the degree of saturation of fatty acids affects the permeability of LFNs. While the permeability of LSNs was not significantly enhanced due to higher particle size after nanonization, LONs and LLNs increased 1.56 and 1.85 times in permeation, respectively, compared to LEU. Conclusion Utilization of different degree of saturation of fatty acids to conjugate a peptide drug could provide pharmaceutical versatility via self-assembly and modification of physicochemical properties.

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“…Due to their vast superiority to conventional formulations, delivery carriers provide numerous intriguing options for management and successful treatment. The most dependable and well-liked delivery technology for parenteral controlled-release depot injections is the microparticulate drug delivery system [61]. The routes of administration for the parenteral microsphere preparations are generally intramuscular and subcutaneous, wherein the tissues are generally used for energy storage (muscle) and release of other tissues (adipose tissue).…”

Section: Parenteral Microspheres Drug Delivery Systemmentioning

confidence: 99%

An Up-to-Date Review: Microspheres as a New Drug Delivery System

DESNITA,

NOVIANA,

ZAI

et al. 2023

Int J App Pharm

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The application of microsphere systems in drug preparations has seen a significant increase in recent years for various purposes. Microsphere systems can be utilized in a range of drug preparations, utilizing polymer types that are appropriate for the intended release target. Microspheres offer numerous benefits and can be used in various applications, including spacer applications, medication administration, and medical diagnostics. Microspheres have minimal negative effects, a more extended therapeutic effect, require fewer doses, and provide more consistent medication absorption. Additionally, they are adaptable, offer effective encapsulation, and are cost-effective. This overview was compiled to provide an up-to-date summary of the latest developments in new drug delivery systems utilizing microsphere dosage forms. Literature from Scopus, ScienceDirect, and PubMed from 2019 to 2022 was searched to provide the latest information. The use of microsphere systems is categorized into various new drug delivery routes, including gastroretentive, colon, nasal and pulmonary, parenteral, ocular, and topical applications.

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Development and Characterization of Leuprolide Acetate Encapsulated PLGA Microspheres for Parenteral Controlled Release Depot Injection

Cited by 7 publications

References 22 publications

Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity

Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity

Hydroxyl Group-Targeted Conjugate and Its Self-Assembled Nanoparticle of Peptide Drug: Effect of Degree of Saturation of Fatty Acids and Modification of Physicochemical Properties

An Up-to-Date Review: Microspheres as a New Drug Delivery System

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