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Pharmaceutics
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Combination Therapeutic Delivery Systems
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Combination Therapeutic Delivery Systems

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

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 23185

Special Issue Editor

Dr. Qingxin Mu

E-Mail Website
Guest Editor
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA
Interests: nanomedicine; combination therapy; drug delivery

Special Issue Information

Dear Colleagues,

The utilization of multiple agents to treat a single disease has been increasingly investigated in the past few decades. Combination regimens that aim to act on multiple therapeutic targets may help to overcome drug resistance and alleviate dose-limiting toxicity arising from single agents and enhance pharmacologic activity through synergistic or additive effects, thus expanding the therapeutic window. Various combination delivery platforms and approaches have been investigated, aiming to leverage those benefits to further improve therapeutic outcomes. Those may include the design and fabrication of novel drug carriers (e.g., nano- and microparticles), incorporation of pharmacologically complementary agents, long-acting and/or ratiometric drug co-delivery, combination delivery of multi-modal agents (e.g., drugs, therapeutic vaccines, genes, radio/photosensitizers), etc. With these advanced delivery approaches, improved outcomes have been achieved in both preclinical and clinical investigations.

Despite the remarkable progress made in these combination therapeutic delivery systems, several questions remain, such as the improvement of formulation approaches for further development and translational research, controlled and sustained release, tissue-targeted delivery, optimization of pharmacological effects with single- or multi-modal agents, reduction in systemic toxicity, etc. This Special Issue aims to further advance the field by publishing studies that emphasize on the combination therapeutic delivery approaches for critical health demands. All relevant studies, spanning from basic formulation and dosage form innovations to pharmacokinetic/pharmacodynamic studies and translational investigations, are invited.

Dr. Qingxin Mu
Guest Editor

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Published Papers (8 papers)

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Research

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18 pages, 5942 KiB  
Article
An Efficient Fabrication Approach for Multi-Cancer Responsive Chemoimmuno Co-Delivery Nanoparticles
by Jianxi Huang, Yu-Ting Chien, Qingxin Mu and Miqin Zhang
Pharmaceutics 2024, 16(10), 1246; https://doi.org/10.3390/pharmaceutics16101246 - 25 Sep 2024
Viewed by 711
Abstract
Background/Objectives: Cancer remains one of the leading causes of death, with breast, liver, and pancreatic cancers significantly contributing to this burden. Traditional treatments face issues including dose-limiting toxicity, drug resistance, and limited efficacy. Combining therapeutic agents can enhance effectiveness and reduce toxicity, but [...] Read more.
Background/Objectives: Cancer remains one of the leading causes of death, with breast, liver, and pancreatic cancers significantly contributing to this burden. Traditional treatments face issues including dose-limiting toxicity, drug resistance, and limited efficacy. Combining therapeutic agents can enhance effectiveness and reduce toxicity, but separate administration often leads to inefficiencies due to differing pharmacokinetics and biodistribution. Co-formulating hydrophobic chemotherapeutics such as paclitaxel (PTX) and hydrophilic immunologic agents such as polyinosinic-polycytidylic acid (Poly IC) is particularly challenging due to their distinct physicochemical properties. This study presents a novel and efficient approach for the co-delivery of PTX and Poly IC using chitosan-based nanoparticles. Method: Chitosan-PEG (CP) nanoparticles were developed to encapsulate both PTX and Poly IC, overcoming their differing physicochemical properties and enhancing therapeutic efficacy. Results: With an average size of ~100 nm, these nanoparticles facilitate efficient cellular uptake and stability. In vitro results showed that CP-PTX-Poly IC nanoparticles significantly reduced cancer cell viability in breast (4T1), liver (HepG2), and pancreatic (Pan02) cancer types, while also enhancing dendritic cell (DC) maturation. Conclusions: This dual-modal delivery system effectively combines chemotherapy and immunotherapy, offering a promising solution for more effective cancer treatment and improved outcomes. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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31 pages, 7021 KiB  
Article
Preparation, Optimization, and In-Vitro Evaluation of Brusatol- and Docetaxel-Loaded Nanoparticles for the Treatment of Prostate Cancer
by Tayo Alex Adekiya, Madison Moore, Michael Thomas, Gabriel Lake, Tamaro Hudson and Simeon K. Adesina
Pharmaceutics 2024, 16(1), 114; https://doi.org/10.3390/pharmaceutics16010114 - 16 Jan 2024
Cited by 2 | Viewed by 2005
Abstract
Challenges to docetaxel use in prostate cancer treatment include several resistance mechanisms as well as toxicity. To overcome these challenges and to improve the therapeutic efficacy in heterogeneous prostate cancer, the use of multiple agents that can destroy different subpopulations of the tumor [...] Read more.
Challenges to docetaxel use in prostate cancer treatment include several resistance mechanisms as well as toxicity. To overcome these challenges and to improve the therapeutic efficacy in heterogeneous prostate cancer, the use of multiple agents that can destroy different subpopulations of the tumor is required. Brusatol, a multitarget inhibitor, has been shown to exhibit potent anticancer activity and play an important role in drug response and chemoresistance. Thus, the combination of brusatol and docetaxel in a nanoparticle platform for the treatment of prostate cancer is expected to produce synergistic effects. In this study, we reported the development of polymeric nanoparticles for the delivery of brusatol and docetaxel in the treatment of prostate cancer. The one-factor-at-a-time method was used to screen for formulation and process variables that impacted particle size. Subsequently, factors that had modifiable effects on particle size were evaluated using a 24 full factorial statistical experimental design followed by the optimization of drug loading. The optimization of blank nanoparticles gave a formulation with a mean size of 169.1 nm ± 4.8 nm, in agreement with the predicted size of 168.333 nm. Transmission electron microscopy showed smooth spherical nanoparticles. The drug release profile showed that the encapsulated drugs were released over 24 h. Combination index data showed a synergistic interaction between the drugs. Cell cycle analysis and the evaluation of caspase activity showed differences in PC-3 and LNCaP prostate cancer cell responses to the agents. Additionally, immunoblots showed differences in survivin expression in LNCaP cells after treatment with the different agents and formulations for 24 h and 72 h. Therefore, the nanoparticles are potentially suitable for the treatment of advanced prostate cancer. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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24 pages, 5202 KiB  
Article
Combined Role of Interleukin-15 Stimulated Natural Killer Cell-Derived Extracellular Vesicles and Carboplatin in Osimertinib-Resistant H1975 Lung Cancer Cells with EGFR Mutations
by Aakash Nathani, Li Sun, Islauddin Khan, Mounika Aare, Arvind Bagde, Yan Li and Mandip Singh
Pharmaceutics 2024, 16(1), 83; https://doi.org/10.3390/pharmaceutics16010083 - 8 Jan 2024
Cited by 4 | Viewed by 2573
Abstract
In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle [...] Read more.
In this study, we evaluated IL-15 stimulated natural killer cell-derived EVs (NK-EVs) as therapeutic agents in vitro and in vivo in Osimertinib-resistant lung cancer (H1975R) with EGFR mutations (L858R) in combination with carboplatin (CBP). NK-EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, and atomic force microscopy imaging revealed vesicles with a spherical form and sizes meeting the criteria of exosomal EVs. Further, Western blot studies demonstrated the presence of regular EV markers along with specific NK markers (perforin and granzyme). EVs were also characterized by proteomic analysis, which demonstrated that EVs had proteins for natural killer cell-mediated cytotoxicity (Granzyme B) and T cell activation (perforin and plastin-2). Gene oncology analysis showed that these differentially expressed proteins are involved in programmed cell death and positive regulation of cell death. Further, isolated NK-EVs were cytotoxic to H1975R cells in vitro in 2D and 3D cell cultures. CBP’s IC50 was reduced by approximately in 2D and 3D cell cultures when combined with NK-EVs. The EVs were then combined with CBP and administered by i.p. route to H1975R tumor xenografts, and a significant reduction in tumor volume in vivo was observed. Our findings show for the first time that NK-EVs target the PD-L1/PD-1 immunological checkpoint to induce apoptosis and anti-inflammatory response by downregulation of SOD2, PARP, BCL2, SET, NF-κB, and TGF-ß. The ability to isolate functional NK-EVs on a large scale and use them with platinum-based drugs may lead to new clinical applications. The results of the present study suggest the possibility of the combination of NK-cell-derived EVs and CBP as a viable immunochemotherapeutic strategy for resistant cancers. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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13 pages, 2673 KiB  
Article
Fe3O4 Nanoparticles in Combination with 5-FU Exert Antitumor Effects Superior to Those of the Active Drug in a Colon Cancer Cell Model
by Sidika Genc, Ali Taghizadehghalehjoughi, Yesim Yeni, Abbas Jafarizad, Ahmet Hacimuftuoglu, Dragana Nikitovic, Anca Oana Docea, Yaroslav Mezhuev and Aristidis Tsatsakis
Pharmaceutics 2023, 15(1), 245; https://doi.org/10.3390/pharmaceutics15010245 - 11 Jan 2023
Cited by 10 | Viewed by 2229
Abstract
(1) Background: Colon cancer is one of the most common cancer types, and treatment options, unfortunately, do not continually improve the survival rate of patients. With the unprecedented development of nanotechnologies, nanomedicine has become a significant direction in cancer research. Indeed, chemotherapeutics with [...] Read more.
(1) Background: Colon cancer is one of the most common cancer types, and treatment options, unfortunately, do not continually improve the survival rate of patients. With the unprecedented development of nanotechnologies, nanomedicine has become a significant direction in cancer research. Indeed, chemotherapeutics with nanoparticles (NPs) in cancer treatment is an outstanding new treatment principle. (2) Methods: Fe3O4 NPs were synthesized and characterized. Caco-2 colon cancer cells were treated during two different periods (24 and 72 h) with Fe3O4 NPs (6 μg/mL), various concentrations of 5-FU (4–16 μg/mL), and Fe3O4 NPs in combination with 5-FU (4–16 μg/mL) (Fe3O4 NPs + 5-FU). (3) Results: The MTT assay showed that treating the cells with Fe3O4 NPs + 5-FU at 16 µg/mL for 24 or 72 h decreased cell viability and increased their LDH release (p < 0.05 and p < 0.01, respectively). Furthermore, at the same treatment concentrations, total antioxidant capacity (TAC) was decreased (p < 0.05 and p < 0.01, respectively), and total oxidant status (TOS) increased (p < 0.05 and p < 0.01, respectively). Moreover, after treatment with Fe3O4-NPs + 5-FU, the IL-10 gene was downregulated and PTEN gene expression was upregulated (p < 0.05 and p < 0.01, respectively) compared with those of the control. (4) Conclusions: Fe3O4 NPs exert a synergistic cytotoxic effect with 5-FU on Caco-2 cells at concentrations below the active drug threshold levels. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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Review

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25 pages, 3078 KiB  
Review
Recent Advances of Tumor Microenvironment-Responsive Nanomedicines-Energized Combined Phototherapy of Cancers
by Kehan Liu, Yao Yao, Shujuan Xue, Mengyao Zhang, Dazhao Li, Tao Xu, Feng Zhi, Yang Liu and Dawei Ding
Pharmaceutics 2023, 15(10), 2480; https://doi.org/10.3390/pharmaceutics15102480 - 17 Oct 2023
Cited by 4 | Viewed by 1616
Abstract
Photodynamic therapy (PDT) has emerged as a powerful tumor treatment tool due to its advantages including minimal invasiveness, high selectivity and thus dampened side effects. On the other side, the efficacy of PDT is severely frustrated by the limited oxygen level in tumors, [...] Read more.
Photodynamic therapy (PDT) has emerged as a powerful tumor treatment tool due to its advantages including minimal invasiveness, high selectivity and thus dampened side effects. On the other side, the efficacy of PDT is severely frustrated by the limited oxygen level in tumors, thus promoting its combination with other therapies, particularly photothermal therapy (PTT) for bolstered tumor treatment outcomes. Meanwhile, nanomedicines that could respond to various stimuli in the tumor microenvironment (TME) provide tremendous benefits for combined phototherapy with efficient hypoxia relief, tailorable drug release and activation, improved cellular uptake and intratumoral penetration of nanocarriers, etc. In this review, we will introduce the merits of combining PTT with PDT, summarize the recent important progress of combined phototherapies and their combinations with the dominant tumor treatment regimen, chemotherapy based on smart nanomedicines sensitive to various TME stimuli with a focus on their sophisticated designs, and discuss the challenges and future developments of nanomedicine-mediated combined phototherapies. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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22 pages, 2587 KiB  
Review
Nanomaterial-Based Drug Delivery Systems for Pain Treatment and Relief: From the Delivery of a Single Drug to Co-Delivery of Multiple Therapeutics
by Yuhang Xu, Xingpeng Dong, Heming Xu, Peifu Jiao, Lin-Xia Zhao and Gaoxing Su
Pharmaceutics 2023, 15(9), 2309; https://doi.org/10.3390/pharmaceutics15092309 - 13 Sep 2023
Cited by 7 | Viewed by 2311
Abstract
The use of nanomaterials in drug delivery systems for pain treatment is becoming increasingly common. This review aims to summarize how nanomaterial-based drug delivery systems can be used to effectively treat and relieve pain, whether via the delivery of a single drug or [...] Read more.
The use of nanomaterials in drug delivery systems for pain treatment is becoming increasingly common. This review aims to summarize how nanomaterial-based drug delivery systems can be used to effectively treat and relieve pain, whether via the delivery of a single drug or a combination of multiple therapeutics. By utilizing nanoformulations, the solubility of analgesics can be increased. Meanwhile, controlled drug release and targeted delivery can be realized. These not only improve the pharmacokinetics and biodistribution of analgesics but also lead to improved pain relief effects with fewer side effects. Additionally, combination therapy is frequently applied to anesthesia and analgesia. The co-encapsulation of multiple therapeutics into a single nanoformulation for drug co-delivery has garnered significant interest. Numerous approaches using nanoformulation-based combination therapy have been developed and evaluated for pain management. These methods offer prolonged analgesic effects and reduced administration frequency by harnessing the synergy and co-action of multiple targets. However, it is important to note that these nanomaterial-based pain treatment methods are still in the exploratory stage and require further research to be effectively translated into clinical practice. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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25 pages, 3855 KiB  
Review
Pluronic F-68 and F-127 Based Nanomedicines for Advancing Combination Cancer Therapy
by Nisar Ul Khaliq, Juyeon Lee, Sangwoo Kim, Daekyung Sung and Hyungjun Kim
Pharmaceutics 2023, 15(8), 2102; https://doi.org/10.3390/pharmaceutics15082102 - 9 Aug 2023
Cited by 27 | Viewed by 6928
Abstract
Pluronics are amphiphilic triblock copolymers composed of two hydrophilic poly (ethylene oxide) (PEO) chains linked via a central hydrophobic polypropylene oxide (PPO). Owing to their low molecular weight polymer and greater number of PEO segments, Pluronics induce micelle formation and gelation at critical [...] Read more.
Pluronics are amphiphilic triblock copolymers composed of two hydrophilic poly (ethylene oxide) (PEO) chains linked via a central hydrophobic polypropylene oxide (PPO). Owing to their low molecular weight polymer and greater number of PEO segments, Pluronics induce micelle formation and gelation at critical micelle concentrations and temperatures. Pluronics F-68 and F-127 are the only United States (U.S.) FDA-approved classes of Pluronics and have been extensively used as materials for living bodies. Owing to the fascinating characteristics of Pluronics, many studies have suggested their role in biomedical applications, such as drug delivery systems, tissue regeneration scaffolders, and biosurfactants. As a result, various studies have been performed using Pluronics as a tool in nanomedicine and targeted delivery systems. This review sought to describe the delivery of therapeutic cargos using Pluronic F-68 and F-127-based cancer nanomedicines and their composites for combination therapy. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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25 pages, 4939 KiB  
Review
Recent Progress of Rational Modified Nanocarriers for Cytosolic Protein Delivery
by Xiao He, Su Xiong, Yansun Sun, Min Zhong, Nianting Xiao, Ziwei Zhou, Ting Wang, Yaqin Tang and Jing Xie
Pharmaceutics 2023, 15(6), 1610; https://doi.org/10.3390/pharmaceutics15061610 - 29 May 2023
Cited by 2 | Viewed by 2818
Abstract
Therapeutic proteins garnered significant attention in the field of disease treatment. In comparison to small molecule drugs, protein therapies offer distinct advantages, including high potency, specificity, low toxicity, and reduced carcinogenicity, even at minimal concentrations. However, the full potential of protein therapy is [...] Read more.
Therapeutic proteins garnered significant attention in the field of disease treatment. In comparison to small molecule drugs, protein therapies offer distinct advantages, including high potency, specificity, low toxicity, and reduced carcinogenicity, even at minimal concentrations. However, the full potential of protein therapy is limited by inherent challenges such as large molecular size, delicate tertiary structure, and poor membrane penetration, resulting in inefficient intracellular delivery into target cells. To address these challenges and enhance the clinical applications of protein therapies, various protein-loaded nanocarriers with tailored modifications were developed, including liposomes, exosomes, polymeric nanoparticles, and nanomotors. Despite these advancements, many of these strategies encounter significant issues such as entrapment within endosomes, leading to low therapeutic efficiency. In this review, we extensively discussed diverse strategies for the rational design of nanocarriers, aiming to overcome these limitations. Additionally, we presented a forward-looking viewpoint on the innovative generation of delivery systems specifically tailored for protein-based therapies. Our intention was to offer theoretical and technical support for the development and enhancement of nanocarriers capable of facilitating cytosolic protein delivery. Full article
(This article belongs to the Special Issue Combination Therapeutic Delivery Systems)
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