Advances in Controlled Release and Targeting of Drugs

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Topic Information

Dear Colleagues,

Drug delivery focuses on the approaches to improve pharmaceutical practices by enhancing drug molecule fractions that reach the target cells and receptors. The importance of this topic lies in the necessity of reducing the drug side effects and drug dosage. Drug delivery compounds consist of molecules (polymers, macromolecules, small molecules) capable of coordinating, transporting, and releasing drugs selectively to their targets. The coordination must be reversible to allow the subsequent release. The targeting can be active (through functional groups that interact with the targets) or passive (the delivery drug exploits the physical characteristics of the physical environment sorrounding the targets). Commercial systems include liposome compounds, cyclodextrins, and prodrug compounds. Recent research is trying to develop more sophisticated strategies by exploiting the progress in organic synthesis, supramolecular chemistry, and molecular machines. This topic collection covers all manuscripts about drug delivery systems.

Dr. Carmine Coluccini
Dr. Paolo Coghi
Dr. Xingxing Fan
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Macromol macromol	-	5.2	2021	21.5 Days	CHF 1000
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700
Nanomaterials nanomaterials	4.4	8.5	2010	14.1 Days	CHF 2400
Pharmaceutics pharmaceutics	4.9	7.9	2009	15.5 Days	CHF 2900
Polymers polymers	4.7	8.0	2009	14.5 Days	CHF 2700

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Published Papers (7 papers)

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23 pages, 12119 KiB  

Open AccessArticle

Chondroitin Sulfate-Based Imatinib Nanoparticles Targeting Activated Hepatic Stellate Cells Against Hepatic Fibrosis

by Xunzhi Liu, Changlong Fang, Hongling Yu, Lu Huang, Jiaxing Feng, Shiqin Luo, Li Song, Mengying Wu, Yulu Tan, Jianxia Dong, Tao Gong and Peihong Xiao

Pharmaceutics 2025, 17(3), 351; https://doi.org/10.3390/pharmaceutics17030351 - 9 Mar 2025

Viewed by 630

Abstract

Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic [...] Read more.

Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis. Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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22 pages, 5169 KiB  

Open AccessArticle

Oral Administration of Neratinib Maleate-Loaded Lipid–Polymer Hybrid Nanoparticles: Optimization, Physical Characterization, and In Vivo Evaluation

by Radhika Rajiv Mahajan, Punna Rao Ravi, Sakshi Jadhav, Prinsi Kishorbhai Pansuriya, Bhushan Gopalsing Naik, Shalaka Hanmant Anture and Łukasz Szeleszczuk

Pharmaceutics 2025, 17(2), 221; https://doi.org/10.3390/pharmaceutics17020221 - 8 Feb 2025

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Abstract

Background: Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. Current oral therapy of NM suffers from low and variable bioavailability due to the solubility and permeability-related issues of the drug. To overcome the low oral [...] Read more.

Background: Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. Current oral therapy of NM suffers from low and variable bioavailability due to the solubility and permeability-related issues of the drug. To overcome the low oral bioavailability, the drug is recommended to be administered at high doses, causing severe gastrointestinal side effects leading to discontinuation of the drug therapy. Methods: In this work, NM-loaded lipid–polymer hybrid nanoparticles (NM-LPNs) were designed and optimized to improve the oral bioavailability of the drug. A systematic approach involving a screening design followed by an optimization design based on the principles of design of experiments (DoE) was used to prepare NM-LPNs. Minimum particle size (PS) ranging between 200 and 300 nm and maximum drug loading (DL (%)) were set as the target physicochemical properties. The optimized NM-LPNs, with a mean PS of 278.57 ± 21.16 nm and a DL (%) of 25.77 ± 1.11%, were further characterized for physicochemical properties, thermal and diffractometric analysis, stability, in vitro drug release, and oral pharmacokinetic studies. Results: The nanoparticles exhibited a burst release followed by a prolonged release up to 12 h in the in vitro drug release studies in pH 6.8 media. Conclusions: The mean C_max and the AUC_last values were found to increase significantly for NM-LPNs by 1.72 times (p < 0.01) and 1.58 times (p < 0.01), respectively, when compared to plain NM in the oral pharmacokinetic studies. The optimized NM-LPN formulation can reduce the oral dose of NM and, thereby, its dose-dependent side effects. Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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30 pages, 6770 KiB  

Open AccessArticle

Cellulose Acetate Butyrate-Based In Situ Gel Comprising Doxycycline Hyclate and Metronidazole

by Ei Mon Khaing, Nutdanai Lertsuphotvanit, Warakon Thammasut, Catleya Rojviriya, Siraprapa Chansatidkosol, Supanut Phattarateera, Wiwat Pichayakorn and Thawatchai Phaechamud

Polymers 2024, 16(24), 3477; https://doi.org/10.3390/polym16243477 - 13 Dec 2024

Cited by 1 | Viewed by 1230

Abstract

Cellulose acetate butyrate is a biodegradable cellulose ester bioplastic produced from plentiful natural plant-based resources. Solvent-exchange-induced in situ gels are particularly promising for periodontitis therapy, as this dosage form allows for the direct delivery of high concentrations of antimicrobial agents to the localized [...] Read more.

Cellulose acetate butyrate is a biodegradable cellulose ester bioplastic produced from plentiful natural plant-based resources. Solvent-exchange-induced in situ gels are particularly promising for periodontitis therapy, as this dosage form allows for the direct delivery of high concentrations of antimicrobial agents to the localized periodontal pocket. This study developed an in situ gel for periodontitis treatment, incorporating a combination of metronidazole and doxycycline hyclate, with cellulose acetate butyrate serving as the matrix-forming agent. Consequently, assessments were conducted on the physicochemical properties, gel formation, drug permeation, drug release, morphological topography, and antimicrobial activities of the formulation. The formulation demonstrated an increased slope characteristic of Newtonian flow at higher bioplastic concentrations. The adequate polymer concentration facilitated swift phase inversion, resulting in robust, solid-like matrices. The mechanical characteristics of the transformed in situ gel typically exhibit an upward trend as the polymer concentration increased. The utilization of sodium fluorescein and Nile red as fluorescent probes effectively tracked the interfacial solvent–aqueous movement during the phase inversion of in situ gels, confirming that the cellulose acetate butyrate matrix delayed the solvent exchange process. The initial burst release of metronidazole and doxycycline hyclate was minimized, achieving a sustained release profile over 7 days in in situ gels containing 25% and 40% cellulose acetate butyrate, primarily governed by a diffusion-controlled release mechanism. Metronidazole showed higher permeation through the porcine buccal membrane, while doxycycline hyclate exhibited greater tissue accumulation, both influenced by polymer concentration. The more highly concentrated polymeric in situ gel formed a uniformly porous structure. Metronidazole and doxycycline hyclate-loaded in situ gels showed synergistic antibacterial effects against S. aureus and P. gingivalis. Over time, the more highly concentrated polymeric in situ gel showed superior retention of antibacterial efficacy due to its denser cellulose acetate butyrate matrix, which modulated drug release and enhanced synergistic effects, making it a promising injectable treatment for periodontitis, particularly against P. gingivalis. Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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21 pages, 5767 KiB  

Open AccessArticle

Influence of Heat Treatment of Nitinol Wire on the Properties of Nitinol/Hybrid Layer for Ibuprofen Release

by Robert Mroczka, Agnieszka Słodkowska and Jerzy Kubacki

Molecules 2024, 29(21), 5200; https://doi.org/10.3390/molecules29215200 - 3 Nov 2024

Viewed by 1211

Abstract

The efficiency of drug delivery from coatings of metallic implants is one of the key factors. The influence of chemical and thermal treatments of nitinol wire on the corrosion properties, deposition of hydroxyapatite(HA)/poly ε-caprolactone-polyethylene glycol (PEG-b-PCL), and the amount of ibuprofen [...] Read more.

The efficiency of drug delivery from coatings of metallic implants is one of the key factors. The influence of chemical and thermal treatments of nitinol wire on the corrosion properties, deposition of hydroxyapatite(HA)/poly ε-caprolactone-polyethylene glycol (PEG-b-PCL), and the amount of ibuprofen released from that bilayer were studied. The hydroxyapatite layer was electrodeposited by pulse current, while the PEG-b-PCL layer was by drop-coating. It was shown that nitinol wire, chemically treated and thermally heated at 470 °C under optimized conditions, is the most optimal substrate for the deposition of uniform and compact hybrid HA/(PEG-b-PCL) bilayer. Ibuprofen incorporated into this hybrid bilayer exhibits the maximum release into phosphate-buffered saline (PBS) solution. About 80% of ibuprofen is released within 5 h. Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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18 pages, 2148 KiB  

Open AccessArticle

Nebivolol Polymeric Nanoparticles-Loaded In Situ Gel for Effective Treatment of Glaucoma: Optimization, Physicochemical Characterization, and Pharmacokinetic and Pharmacodynamic Evaluation

by Pradeep Singh Rawat, Punna Rao Ravi, Mohammed Shareef Khan, Radhika Rajiv Mahajan and Łukasz Szeleszczuk

Nanomaterials 2024, 14(16), 1347; https://doi.org/10.3390/nano14161347 - 14 Aug 2024

Cited by 1 | Viewed by 1498

Abstract

Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular [...] Read more.

Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular formulation (aqueous suspension), we designed and optimized polycaprolactone polymeric nanoparticles (NEB-PNPs) by applying design of experiments (DoE). The particle size and drug loading of the optimized NEB-PNPs were 270.9 ± 6.3 nm and 28.8 ± 2.4%, respectively. The optimized NEB-PNPs were suspended in a dual-sensitive in situ gel prepared using a mixture of P407 + P188 (as a thermo-sensitive polymer) and κCRG (as an ion-sensitive polymer), reported previously by our group. The NEB-PNPs-loaded in situ gel (NEB-PNPs-ISG) formulation was characterized for its rheological behavior, physical and chemical stability, in vitro drug release, and in vivo efficacy. The NEB-PNPs-loaded in situ gel, in ocular pharmacokinetic studies, achieved higher aqueous humor exposure (AUC_0–t = 329.2 ng × h/mL) and for longer duration (mean residence time = 9.7 h) than compared to the aqueous suspension of plain NEB (AUC_0–t = 189 ng × h/mL and mean residence time = 6.1 h) reported from our previous work. The pharmacokinetic performance of NEB-PNPs-loaded in situ gel translated into a pharmacodynamic response with 5-fold increase in the overall percent reduction in intraocular pressure by the formulation compared to the aqueous suspension of plain NEB reported from our previous work. Further, the mean response time of NEB-PNPs-loaded in situ gel (12.4 ± 0.6 h) was three times higher than aqueous suspension of plain NEB (4.06 ± 0.3 h). Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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18 pages, 13325 KiB  

Open AccessArticle

Dual-Functionalized Mesoporous Silica Nanoparticles for Celecoxib Delivery: Amine Grafting and Imidazolyl PEI Gatekeepers for Enhanced Loading and Controlled Release with Reduced Toxicity

by Diky Mudhakir, Ebrahim Sadaqa, Zuliar Permana, Jihan Eldia Mumtazah, Normalita Faraz Zefrina, Jovinka Natalie Xeliem, Latifa Fawzia Hanum and Neng Fisheri Kurniati

Molecules 2024, 29(15), 3546; https://doi.org/10.3390/molecules29153546 - 27 Jul 2024

Cited by 3 | Viewed by 2237

Abstract

The development of targeted drug delivery systems has been a pivotal area in nanomedicine, addressing challenges like low drug loading capacity, uncontrolled release, and systemic toxicity. This study aims to develop and evaluate dual-functionalized mesoporous silica nanoparticles (MSN) for targeted delivery of celecoxib, [...] Read more.

The development of targeted drug delivery systems has been a pivotal area in nanomedicine, addressing challenges like low drug loading capacity, uncontrolled release, and systemic toxicity. This study aims to develop and evaluate dual-functionalized mesoporous silica nanoparticles (MSN) for targeted delivery of celecoxib, enhancing drug loading, achieving controlled release, and reducing systemic toxicity through amine grafting and imidazolyl polyethyleneimine (PEI) gatekeepers. MSN were synthesized using the sol–gel method and functionalized with (3-aminopropyl) triethoxysilane (APTES) to create amine-grafted MSN (MSN-NH₂). Celecoxib was loaded into MSN-NH₂, followed by conjugation of imidazole-functionalized PEI (IP) gatekeepers synthesized via carbodiimide coupling. Characterization was conducted using Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (¹H-NMR). Drug loading capacity, entrapment efficiency, and in vitro drug release at pH 5.5 and 7.4 were evaluated. Cytotoxicity was assessed using the MTT assay on RAW 264.7 macrophages. The synthesized IP was confirmed by FTIR and ¹H-NMR. Amine-grafted MSN demonstrated a celecoxib loading capacity of 12.91 ± 2.02%, 2.1 times higher than non-functionalized MSN. In vitro release studies showed pH-responsive behavior with significantly higher celecoxib release from MSN-NH₂-celecoxib-IP at pH 5.5 compared to pH 7.4, achieving a 33% increase in release rate within 2 h. Cytotoxicity tests indicated significantly higher cell viability for IP-treated cells compared to PEI-treated cells, confirming reduced toxicity. The dual-functionalization of MSN with amine grafting and imidazolyl PEI gatekeepers enhances celecoxib loading and provides controlled pH-responsive drug release while reducing systemic toxicity. These findings highlight the potential of this advanced drug delivery system for targeted anti-inflammatory and anticancer therapies. Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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15 pages, 3171 KiB  

Open AccessArticle

Encapsulation of Gemcitabine on Porphyrin Aluminum Metal-Organic Framework by Mechano-Chemistry, Delayed Drug Release and Cytotoxicity to Pancreatic Cancer PANC-1 Cells

by Sheriff Umar and Alexander Samokhvalov

Molecules 2024, 29(13), 3189; https://doi.org/10.3390/molecules29133189 - 4 Jul 2024

Cited by 2 | Viewed by 1721

Abstract

Gemcitabine is a widely used antimetabolite drug of pyrimidine structure, which can exist as a free-base molecular form (Gem). The encapsulated forms of medicinal drugs are of interest for delayed and local drug release. We utilized, for the first time, a novel approach [...] Read more.

Gemcitabine is a widely used antimetabolite drug of pyrimidine structure, which can exist as a free-base molecular form (Gem). The encapsulated forms of medicinal drugs are of interest for delayed and local drug release. We utilized, for the first time, a novel approach of mechano-chemistry by liquid-assisted grinding (LAG) to encapsulate Gem on a “matrix” of porphyrin aluminum metal-organic framework Al-MOF-TCPPH₂ (compound 2). The chemical bonding of Gem to compound 2 was studied by ATR-FTIR spectroscopy and powder XRD. The interaction involves the C=O group of Gem molecules, which indicates the formation of the encapsulation complex in the obtained composite. Further, the delayed release of Gem from the composite was studied to phosphate buffered saline (PBS) at 37 °C using an automated drug dissolution apparatus equipped with an autosampler. The concentration of the released drug was determined by HPLC-UV analysis. The composite shows delayed release of Gem due to the bonded form and constant concentration thereafter, while pure Gem shows quick dissolution in less than 45 min. Delayed release of Gem drug from the composite follows the kinetic pseudo-first-order rate law. Further, for the first time, the mechanism of delayed release of Gem was assessed by the variable stirring speed of drug release media, and kinetic rate constant k was found to decrease when stirring speed is decreased (diffusion control). Finally, the prolonged time scale of toxicity of Gem to pancreatic cancer PANC-1 cells was studied by continuous measurements of proliferation (growth) for 6 days, using the xCELLigence real-time cell analyzer (RTCA), for the composite vs. pure drug, and their differences indicate delayed drug release. Aluminum metal-organic frameworks are new and promising materials for the encapsulation of gemcitabine and related small-molecule antimetabolites for controlled delayed drug release and potential use in drug-eluting implants. Full article

(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)

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