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Advanced Drug Delivery Systems for Natural Products

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: 31 January 2027 | Viewed by 10867

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Editors

Dr. Velichka Andonova

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Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria
Interests: emulsion polymerization; drug stability; pharmaceutical nanotechnology; pharmaceutical research and development; pharmacokinetics
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Dr. Viliana Eduardova Gugleva

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Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, 9000 Varna, Bulgaria
Interests: vesicular systems; niosomes; stimuli-sensitive nanocarriers; inorganic nanoparticles
Special Issues, Collections and Topics in MDPI journals

Dr. Stanila Stoeva

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Guest Editor

Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University of Varna, 9002 Varna, Bulgaria
Interests: natural products; phytotherapy; HPLC; in vivo modeling; pharmacology; toxicology; pharmacokinetics

Special Issue Information

Dear Colleagues,

Even in the era of technological advancement, natural products play a pivotal role in drug development, offering a vast repertoire of bioactive molecules with diverse pharmacological properties. However, their clinical potential is often constrained by their poor solubility and permeability, low bioavailability, rapid metabolism, and instability.

In recent decades, interdisciplinary efforts spanning chemistry, physics, biology, mathematics, technology, and biomedical sciences have driven the successful development of advanced drug delivery systems (ADDSs). These innovations enable the precise targeting of complex biological sites while ensuring optimal concentrations of bioactive compounds at the right time and for the appropriate duration. Such advancements undoubtedly refine the pharmacokinetic and/or pharmacodynamic profiles of encapsulated natural products. Additionally, patient compliance is enhanced, while safety is improved by administering lower doses, reducing drug exposure, and limiting distribution to non-target tissues, among other benefits. Nevertheless, the development of ADDSs continues to encounter challenges that require further investigation and remain a central focus of intense scientific inquiry.

The Pharmaceutics Special Issue, entitled “Advanced Drug Delivery Systems for Natural Products”, aims to present the latest advancements in this field. We invite all interested researchers to submit their innovative approaches (original research articles or comprehensive reviews), which will contribute to expanding knowledge in this rapidly developing area.

Dr. Velichka Andonova
Dr. Viliana Eduardova Gugleva
Dr. Stanila Stoeva
Guest Editors

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Keywords

natural products
advanced drug delivery systems
liposomes
niosomes
phytosomes
lipid nanoparticles
smart polymers
biodegradable nanoparticles
polymeric nanoparticles
drug carriers

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Published Papers (9 papers)

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Research

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17 pages, 5446 KB

Open AccessArticle

Optimized TELIP, an Echogenic Liposomal Nano-Carrier Loaded with Alteplase for Preclinical Studies

by Maryam Ranjpour, Brion Frierson, Rebekah Lynn Emerine, Christian Jordan De Vera, Krishna Sarva, Melvin Earl Klegerman, David Dugald McPherson, Steven Idell, Galina Florova and Andrey Anatolievich Komissarov

Pharmaceutics 2026, 18(6), 646; https://doi.org/10.3390/pharmaceutics18060646 - 24 May 2026

Viewed by 696

Abstract

Background: Pharmacological treatment under conditions of slow fibrinolysis/thrombolysis requires the targeted delivery of plasminogen-activating activity. Echogenic liposomal formulations (regular TELIP) of single-chain tissue plasminogen activator (sctPA), while possessing high affinity to fibrin, contain free/loosely bound sctPA. We hypothesized that removal of free sctPA, which competes with liposomes and plasmin for fibrin, enhances unique features of the TELIP. Methods: Optimized and regular TELIP were assessed for the distribution of active sctPA (loosely bound, tightly bound, encapsulated), stability, binding to fibrin, initiating fibrinolysis in vitro and ex vivo using a battery of biochemical methods. Results: One milligram of the regular TELIP consists of 2.0–5.0 × 10⁹ echogenic liposomes (700–900 nm diameter). Non-specifically bound sctPA readily dissociates at the physiological ionic strength and pH. While up to 60% of sctPA in the regular TELIP is loosely bound with 6–15% encapsulated, and the rest is tightly bound to the liposomes; in the optimized TELIP, more than 80% of active sctPA is tightly bound with up to 40% of encapsulated. The latter is protected from high-molecular-weight ligands and could be released by an ultrasound pulse. Optimized TELIP shows low competition with plasmin for fibrin and effectively supports fibrinolysis in vitro and ex vivo. The optimized TELIP with maximal load of sctPA 3% (w/w) retains integrity at 37 °C for 5 h in vitro and up to 2 h ex vivo. Conclusions: The optimized TELIP is stable in vitro and ex vivo, does not interfere with fibrinolysis and retains a high level of encapsulated sctPA delivered precisely to the thrombus/fibrin clot. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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16 pages, 5504 KB

Open AccessArticle

Chitosan-Coated Mesoporous Silica Nanoparticles Co-Loaded with Curcumin and Amphotericin B: A Drug Delivery Approach for Photodynamic Inhibition of Dual-Species Biofilms

by Shima Afrasiabi, Mohammad Reza Karimi, Sepideh Khoee, Stefano Benedicenti and Antonio Signore

Pharmaceutics 2026, 18(6), 644; https://doi.org/10.3390/pharmaceutics18060644 - 23 May 2026

Viewed by 824

Abstract

Background/Objectives: Metabolic dormancy in biofilms leads to reduced drug efficacy in these communities. Different pharmacokinetics and adverse side effects complicate the simultaneous delivery of multiple drugs at appropriate concentrations to the infection site. This study aimed to develop chitosan-coated mesoporous silica nanoparticles loaded with curcumin and amphotericin B (CS@MSNs-Cur-AmB) and to evaluate their antibiofilm activity combined with antimicrobial photodynamic therapy (PDT) against Streptococcus mutans and Candida albicans dual-species biofilms. Methods: CS@MSNs-Cur-AmB were developed. The structure and morphology of the nanoparticles were evaluated using Fourier transform-infrared spectroscopy (FTIR), zeta potential, field emission scanning electron microscopy (FESEM), and thermogravimetric analysis (TGA). Cytotoxicity toward human gingival fibroblasts was assessed. Colony-forming units per milliliter (CFU/mL) were determined. The metabolic activity of biofilm-forming cells was measured using the tetrazolium (MTT) assay. Results: Physicochemical analyses confirmed the synthesis of CS@MSNs-Cur-AmB, revealing a particle size of 228 nm and thermal stability up to 600 °C. Cytotoxicity assays showed that CS@MSNs-Cur-AmB exhibited good biocompatibility (>90%). CS@MSNs-Cur-AmB improved antimicrobial activity, which was further enhanced by blue light-emitting diode (LED) irradiation. CS@MSNs-Cur-AmB under LED irradiation showed the strongest effect, reducing metabolic activity to 27.74 ± 4.08% (1 W/cm², 1 min), p < 0.001). Conclusions: Formulating two drugs in nanocarrier systems may improve therapeutic efficacy by increasing local concentration and reducing systemic exposure. This offers an effective strategy for combating oral biofilms. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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12 pages, 2452 KB

Open AccessArticle

Double-Blind Placebo-Controlled Randomized Study of Sporopollenin Exine (SpEC) Fragrance Encapsulation

by Mariam Murad, Pearl Wasif, Laura Dempsey, G. Roshan Deen, Alexandra E. Butler and Stephen L. Atkin

Pharmaceutics 2026, 18(5), 609; https://doi.org/10.3390/pharmaceutics18050609 - 17 May 2026

Viewed by 539

Abstract

Objective: Sporopollenin exine capsules (SpECs) have been used to encapsulate active pharmaceutical agents for oral drug delivery. This study investigated whether fragrance encapsulated within SpECs prolonged perceived fragrance intensity compared with fragrance oil alone. Methods: A double-blind, placebo-controlled, randomized pilot study was conducted (clinical trial number: NCT07383337); ten healthy female participants (mean age 35.4 ± 5.6 years) received fragrance with SpEC-encapsulated fragrance (SpECs) on one wrist and fragrance alone (control) on the contralateral wrist. The fragrance intensity was assessed using a visual analogue scale (0–10) by both the participants and an independent blinded reviewer at baseline and after 2, 4 and 8 h. Paired Wilcoxon signed-rank tests and linear mixed-effects models were used for analysis. In vitro cytotoxicity was assessed using an ATP viability assay in human bronchial epithelial (BEAS-2B) cells exposed to SpECs or raw Lycopodium clavatum spores. Results: There were no significant differences between the formulations at baseline. From 2 h onward, SpECs was associated with significantly a higher fragrance intensity compared with the control for both participant-rated (p = 0.03 at 2 and 4 h; p = 0.005 at 8 h) and reviewer-rated assessments (p = 0.02 at 2 h; p = 0.01 at 4 h; and p = 0.008 at 8 h). Mixed-model analyses suggested a greater decline in intensity for control at 8 h for reviewer-rated assessments. In vitro, raw spores significantly reduced cell viability (as an indicator of potential allergenicity), whereas SpECs did not differ from control. Conclusions: Fragrance encapsulation within SpECs significantly prolongs measured fragrance intensity with no evidence of cytotoxicity. These findings support the potential of SpECs as a safe and effective sustained-release platform for topical fragrance formulations. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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13 pages, 2897 KB

Open AccessArticle

Fabrication of Hybrid Alginate Hydrogel Beads Reinforced with Activated Carbon and Evaluation of Their Potential for Controlled Eugenol Release

by Kaan Karaoğlu, Mehtap Atak, Nuray Yılmaz Baran and Talat Baran

Pharmaceutics 2026, 18(5), 598; https://doi.org/10.3390/pharmaceutics18050598 - 14 May 2026

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Abstract

Background/Objectives: This study presents the development of an activated carbon/sodium alginate-based gastric-retentive delivery system aimed at enhancing the gastroprotective efficacy of eugenol (Eug) in simulated body fluids. Methods: Hybrid hydrogel beads were fabricated using tea waste-derived activated carbon (AC) as a core material and sodium alginate as a wall material. Results: The system achieved a loading capacity of 3.37 ± 0.11 mg Eug/g hydrogel beads, and in vitro assays revealed a controlled release profile, with cumulative release reaching 0.694 ± 0.006 mg/g hydrogel beads in simulated gastric fluid (SGF) and 0.198 ± 0.002 mg Eug/g hydrogel beads in simulated intestinal fluid (SIF). Conclusions: Kinetic modeling confirmed a predominantly diffusion-controlled process with non-Fickian transport mechanism, indicating combined diffusion and matrix relaxation. By maintaining local therapeutic concentrations in the gastric mucosa, this pH-responsive Alg/Eug@AC system offers a sustainable strategy to overcome Eug’s low bioavailability and provide effective gastroprotection against oxidative damage. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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27 pages, 9046 KB

Open AccessArticle

Formulation, Characterization, and In Vitro Biological Evaluation of a Triple-Phytochemical Nano Delivery System for Colon Cancer Therapy—A Preliminary Feasibility Study

by Dhanalekshmi Unnikrishnan Meenakshi, Gurpreet Kaur Narde, Shah Alam Khan and Alka Ahuja

Pharmaceutics 2026, 18(2), 277; https://doi.org/10.3390/pharmaceutics18020277 - 23 Feb 2026

Viewed by 1415

Abstract

Background/Objectives: Poor oral bioavailability and limited intestinal permeation restrict the clinical translation of phytochemicals for colorectal cancer (CRC) therapy. The present preliminary study explored the development of a nanoparticle-based combinatorial formulation of resveratrol (Resv), acetyl-11-keto-β-boswellic acid (AKBA), and quercetin (Quer), to improve intestinal permeation and anti-cancer efficacy. Methods: A triple phytochemical nano formulation (designated as 3X) was developed and evaluated for morphology, particle size, zeta potential, encapsulation efficiency, and in vitro pharmaceutical characteristics. Safety was evaluated using in vitro cytotoxicity assays, while anticancer efficacy and apoptotic potential were preliminarily evaluated in Caco-2 CRC cell lines. Gene expression analysis was performed to examine the modulation of inflammation and cancer-related markers. Results: The 3X formulation exhibited a particle size of 198.5 nm with a polydispersity index of 0.492 and a zeta potential of −32.7, indicating good nanoscale stability. The encapsulation efficiencies were 90% for AKBA, 80% for Resv, and 75% for Quer. In vitro permeation studies demonstrated a controlled release mechanism. The formulation showed minimal hemolysis (3%) and had acceptable in vitro safety. The IC50 of the formulation was found to be 365 µg in the cytotoxicity assay. Treatment with the 3X nanoformulation significantly modulated anti-inflammatory and cancer-related gene expression in Caco2 cells, evidenced by downregulation of TGFβ (Transforming Growth Factor-beta) and COX-2 (cyclooxygenase-2), and upregulation of TNFα (Tumor necrosis factor-alpha) and nitric oxide (NO) and reduced IL-1β (Interleukins-1 beta) expression compared with control cells. Conclusions: The findings demonstrate that the developed 3X nano formulation exhibits favorable permeation characteristics and exerts anticancer activity against CRC. Based on preliminary findings, the formulation represents a promising phytochemical-based combination strategy for CRC, warranting further in vivo studies to validate its efficacy and elucidate the underlying molecular mechanisms. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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17 pages, 1703 KB

Open AccessArticle

β-Cyclodextrin Inclusion Complexes of Cinnamomum camphora Essential Oil: A Comparative Study on Encapsulation Strategies, Physicochemical Stability, and Cytotoxic Profile

by José Adão Carvalho Nascimento Júnior, Anamaria Mendonça Santos, Ana Maria Santos Oliveira, Cláudio Carvalho Santana Júnior, Saravanan Shanmugam, Antonella Osses Toledo, Natalia Juica, Mikele Cândida Sousa de Sant’Anna, Adriano Antunes de Souza Araújo, Luis Constandil, Jeffri S. Retamal and Mairim Russo Serafini

Pharmaceutics 2026, 18(1), 117; https://doi.org/10.3390/pharmaceutics18010117 - 16 Jan 2026

Cited by 1 | Viewed by 1526

Abstract

Background/Objectives: Essential oils (EOs) from plants of the genus Cinnamomum have been widely used based on their antimicrobial, antioxidant, and anti-inflammatory properties. However, their elevated volatility and limited aqueous solubility restrict their use in pharmaceutical and food formulations. Cyclodextrins (CDs) have emerged as a promising strategy to overcome these limitations through the formation of inclusion complexes. Methods: In this study, inclusion complexes of essential oil from C. camphora L. (EOCNM) with β-cyclodextrin (β-CD) were developed using physical mixing (PM), ultrasonic treatment (US), and freeze-drying (FD). The inclusion complexes were physicochemically characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TG/DTG), X-ray diffraction (XRD), and scanning electron microscopy (SEM) to evaluate their physicochemical interactions and complexation efficiency. Results: Our results demonstrated successful complex formation, with the FD and US methods showing greater amorphization and stronger inclusion characteristics compared to the PM method. Thermal analysis confirmed improved physicochemical stability of the essential oil when complexed with β-CD. Furthermore, the cytotoxicity assay of the complexes was assessed using the MTT assay and J774 macrophage cells. The complexes exhibited low cytotoxicity, indicating their potential biocompatibility for biomedical and food applications. Conclusions: Overall, β-CD encapsulation effectively enhanced the physicochemical stability and safety profile of C. camphora essential oil, providing a promising strategy for its controlled delivery and protection against degradation. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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46 pages, 7647 KB

Open AccessArticle

Harnessing Nature for Breast Cancer Management: Effects of Fisetin-Loaded Nigellasomes Embedded in Microneedles Improve Tumor Suppression and Reduce Oxidative Stress

by Sammar Fathy Elhabal, Eman Mohammed Ali, Sandra Hababeh, Fatma E. Hassan, Suzan Awad AbdelGhany Morsy, Dalia Ahmed Elbahy, Sahar K. Ali, Khaled M. Allam, Ibrahim Mousa, Marwa A. Fouad and Ahmed Mohsen Elsaid Hamdan

Pharmaceutics 2025, 17(11), 1392; https://doi.org/10.3390/pharmaceutics17111392 - 27 Oct 2025

Cited by 8 | Viewed by 2467

Abstract

Background: Natural compounds such as fisetin have promising in breast cancer treatment, but their poor pharmacokinetics limit their therapeutic application. This study utilized a synergistic approach by combining fisetin-loaded Nigella sativa (N.S.) oil nanovesicles (FIS-NSs) and carbohydrate-based microneedles (FIS-NSs-MNs) to improve breast cancer management. Methods: Chemical composition of NS petroleum ether extract using gas chromatography–mass spectrometry (GC/MS). FIS-NSs were prepared and characterized for particle size, polydispersity, zeta potential, encapsulation efficiency, and stability. These vesicles were embedded into gelatin, hyaluronic acid, and carboxymethyl cellulose microneedles. In vitro drug release, ex vivo permeation, cytotoxicity against breast cancer cells, and in vivo antitumor efficacy in Ehrlich tumor models were evaluated. Results: Optimized FIS-NSs displayed nanoscale size (190 ± 0.74 nm), low P.D.I (0.25 ± 0.07), high surface charge (+37 ± 0.57 mV), and high encapsulation (88 ± 0.77%). In vitro investigations showed sustained FIS release (~85% over 72 h), while ex vivo permeation showed higher absorption than free fisetin. Both FIS-NSs and FIS-NSs-MNs showed dose-dependent cytotoxicity against breast cancer cells, with lower IC₅₀ than free fisetin (24.7 µM). In vivo, FIS-NSs-MNs and tumor burden inhibition (~77%), reduced oxidative stress (54%), restored antioxidant defenses, and decreased inflammatory markers. Immunohistochemical analysis for caspase-3 showed apoptosis activation within tumor tissues. Conclusions: These findings demonstrate that FIS administration via NS-MNs improves drug stability, penetration, and apoptotic activity, resulting in enhanced anticancer effects. This innovative nanovesicle–microneedle platform provides a non-invasive, effective, and patient-friendly approach for the effective treatment of breast cancer, with potential for broader applications in oncological nanomedicine. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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Review

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33 pages, 4817 KB

Open AccessReview

Renaissance of Traditional Mineral Drugs in Cancer: Advanced Delivery Strategies and Bioengineering Approaches

by Aolin Chen, Ping Luo, Jing Cao, Taohong Su, Xinxin Ding, Xinzhi Guo, Wenhao Zhou, Yang Chen and Fang Wang

Pharmaceutics 2026, 18(7), 768; https://doi.org/10.3390/pharmaceutics18070768 - 23 Jun 2026

Viewed by 369

Abstract

Traditional mineral drugs represent an underexploited reservoir of natural antitumor agents; however, their clinical translation has historically been hindered by poor bioavailability, non-specific biodistribution, and dose-limiting toxicity. This review comprehensively examines the pharmacological mechanisms and modern formulation strategies driving the renaissance of mineral-based oncology therapeutics. We highlight how mineral drugs exert potent anticancer effects through interconnected pathways, including regulated cell death (e.g., apoptosis, ferroptosis), cell-cycle arrest, and immunomodulation. Crucially, we evaluate recent advances in drug delivery systems, such as liposomes, polymeric nanoparticles, inorganic frameworks, and stimuli-responsive (e.g., pH, redox, enzyme) release systems that successfully overcome traditional pharmacological barriers. These bioengineering strategies not only improve solubility and tumor targeting but also significantly widen the therapeutic window, as evidenced by enhanced tumor suppression and reduced systemic toxicity in preclinical models. Despite this progress, challenges regarding in vivo chemical transformations and tumor heterogeneity remain. Ultimately, we propose a closed-loop “Composition–Mechanism–Delivery” design paradigm to guide future research, facilitating the translation of ethnopharmacological heritage into precision mineral-based therapeutics. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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33 pages, 5952 KB

Open AccessReview

Cannabidiol for Mucosal Diseases: Therapeutic Potential and Advanced Delivery Strategies

by Bo Han, Yue Zhang, Yangmin Wang, Yue Shen, Jinping Niu, Shipo Li, Yuxi Li, Jingyu Wang, Xingyuan Ma and Wenyun Zheng

Pharmaceutics 2026, 18(6), 638; https://doi.org/10.3390/pharmaceutics18060638 - 22 May 2026

Viewed by 1243

Abstract

Cannabidiol (CBD), a major non-psychoactive phytocannabinoid, has attracted considerable attention owing to its broad therapeutic potential. Its anti-inflammatory, antimicrobial, and antitumor properties make it a promising candidate for the treatment of mucosa-associated diseases. However, the clinical translation of CBD is significantly hindered by its unfavorable physicochemical properties, particularly high lipophilicity and poor aqueous solubility, which result in low bioavailability. To overcome these limitations, the rational selection of administration routes in combination with advanced drug delivery systems tailored to disease pathophysiology is essential. Such strategies are critical for improving the stability of CBD, enhancing mucosal permeation, and enabling controlled and targeted release at diseased sites. Nevertheless, a systematic review focusing on these aspects is still lacking. This review first summarizes the relationship between CBD and the mucosal endocannabinoid system, together with its pharmacological effects. It then discusses the therapeutic potential of CBD in mucosal disorders of the digestive and respiratory systems. In addition, current administration routes and advanced delivery systems for CBD are reviewed to provide insights for future research and clinical translation. Finally, the remaining challenges associated with the clinical application of CBD and future development directions are discussed. Full article

(This article belongs to the Special Issue Advanced Drug Delivery Systems for Natural Products)

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