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Pharmaceutics
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Drug Delivery Systems for Combination Therapy
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Drug Delivery Systems for Combination Therapy

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 (15 October 2021) | Viewed by 31964

Special Issue Editors

Prof. Dr. Gabriela Romero Uribe

E-Mail Website1 Website2
Guest Editor
Department of Chemical Engineering, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249 ,USA
Interests: drug delivery; nanomedicine; stimuli-responsive biomaterials; gene-editing tools; neurostimulation; brain healt
Dr. Sergio Moya

E-Mail Website
Guest Editor
CIC biomaGUNE, Donostia-San Sebastian, Spain
Interests: nanoparticles; nanobiotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The concept of combining multiple therapies, i.e., “Combination Therapy”, has arisen as a viable solution to overcome the major challenges in pharmacological treatments, as are dose-associated toxicity, multidrug resistance, nonspecific delivery, stability, pharmacokinetics, and cost of new drug discoveries. This treatment paradigm is not new and combines existing therapies to achieve a synergistic therapeutic effect by targeting different cellular pathways associated with a disease at safe therapeutic doses. However, with the assistance of nanotechnology, old combination therapy has taken a more successful path in recent years. Using nanotechnology, drug delivery systems for combination therapy can be designed not only to control multidrug release but to selectively target the diseased tissues, as well as to respond to an external or internal stimulus for detection, diagnosis or treatment. This issue captures recent advances in drug delivery systems for combination therapy, encompassing fundamental understanding, development and applications.

Prof. Dr. Gabriela Romero Uribe
Dr. Sergio Moya
Guest Editors

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Keywords

  • Drug delivery
  • Drug cocktail
  • Combination therapy
  • Nanomedicine
  • Nanoparticles
  • Synergistic therapeutic effects
  • Stimuli responsive
  • Biomaterials

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Published Papers (7 papers)

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Research

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16 pages, 4760 KiB  
Article
Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma
by Yige Fu, Aishwarya Saraswat, Zenghui Wei, Manas Yogendra Agrawal, Vikas V. Dukhande, Sandra E. Reznik and Ketan Patel
Pharmaceutics 2021, 13(7), 1005; https://doi.org/10.3390/pharmaceutics13071005 - 1 Jul 2021
Cited by 34 | Viewed by 4754
Abstract
A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A [...] Read more.
A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A modified hydration method with citric acid was used to improve the loading of both the molecules in liposomes. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency for both the drugs and was found to be physically stable for a month at 4 °C. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and down-regulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroids with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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15 pages, 2153 KiB  
Communication
Ternary Complexes of pDNA, Neuron-Binding Peptide, and PEGylated Polyethyleneimine for Brain Delivery with Nano-Bubbles and Ultrasound
by Yoko Endo-Takahashi, Ryo Kurokawa, Kanako Sato, Nao Takizawa, Fumihiko Katagiri, Nobuhito Hamano, Ryo Suzuki, Kazuo Maruyama, Motoyoshi Nomizu, Norio Takagi and Yoichi Negishi
Pharmaceutics 2021, 13(7), 1003; https://doi.org/10.3390/pharmaceutics13071003 - 1 Jul 2021
Cited by 19 | Viewed by 3453
Abstract
In brain-targeted delivery, the transport of drugs or genes across the blood−brain barrier (BBB) is a major obstacle. Recent reports found that focused ultrasound (FUS) with microbubbles enables transient BBB opening and improvement of drug or gene delivery. We previously developed nano-sized bubbles [...] Read more.
In brain-targeted delivery, the transport of drugs or genes across the blood−brain barrier (BBB) is a major obstacle. Recent reports found that focused ultrasound (FUS) with microbubbles enables transient BBB opening and improvement of drug or gene delivery. We previously developed nano-sized bubbles (NBs), which were prepared based on polyethylene glycol (PEG)-modified liposomes containing echo-contrast gas, and showed that our NBs with FUS could also induce BBB opening. The aim of this study was to enhance the efficiency of delivery of pDNA into neuronal cells following transportation across the BBB using neuron-binding peptides. This study used the RVG-R9 peptide, which is a chimeric peptide synthesized by peptides derived from rabies virus glycoprotein and nonamer arginine residues. The RVG peptide is known to interact specifically with the nicotinic acetylcholine receptor in neuronal cells. To enhance the stability of the RVG-R9/pDNA complex in vivo, PEGylated polyethyleneimine (PEG-PEI) was also used. The ternary complexes composed of RVG-R9, PEG-PEI, and pDNA could interact with mouse neuroblastoma cells and deliver pDNA into the cells. Furthermore, for the in vivo experiments using NBs and FUS, gene expression was observed in the FUS-exposed brain hemispheres. These results suggest that this systemic gene delivery system could be useful for gene delivery across the BBB. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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14 pages, 5906 KiB  
Article
Chondroitin Sulfate-Modified Liposomes for Targeted Co-Delivery of Doxorubicin and Retinoic Acid to Suppress Breast Cancer Lung Metastasis
by Zhiwei Zhang, Lixin Ma and Jingwen Luo
Pharmaceutics 2021, 13(3), 406; https://doi.org/10.3390/pharmaceutics13030406 - 19 Mar 2021
Cited by 11 | Viewed by 3250
Abstract
Breast cancer treatment remains challenging due to high levels of cell metastasis. Chemotherapy drug combinations can inhibit both tumor growth in situ and metastasis to distant organs. Therefore, here, we developed chondroitin sulfate liposomes (CSLs) as a carrier for the co-delivery of retinoic [...] Read more.
Breast cancer treatment remains challenging due to high levels of cell metastasis. Chemotherapy drug combinations can inhibit both tumor growth in situ and metastasis to distant organs. Therefore, here, we developed chondroitin sulfate liposomes (CSLs) as a carrier for the co-delivery of retinoic acid (RA) and doxorubicin (DOX) and examined their efficiency in suppressing lung metastasis of breast cancer. CSLs were prepared using CS–deoxycholic acid conjugates and found to encapsulate both RA and DOX via hydrophobic and hydrophilic interactions. The resulting DOX+RA-CSLs were uniformly spherical and showed good serum stability and encapsulation efficiency of 98.7% ± 1.3% for RA and 90.8% ± 2.9% for DOX. Pharmacodynamic experiments in vitro and in vivo also revealed that DOX+RA-CSLs had better anticancer and anti-metastatic activity than CS-free liposomes, single drug-loaded liposomes, and free drug solutions at the same dose (2 mg/kg DOX or RA). Our results suggest that this liposomal delivery system can effectively suppress lung metastasis of breast cancer. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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Review

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21 pages, 1752 KiB  
Review
Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers
by Nagabhishek Sirpu Natesh, Brianna M. White, Maia M. C. Bennett, Metin Uz, Rakhee Rathnam Kalari Kandy, Surinder K. Batra, Surya K. Mallapragada and Satyanarayana Rachagani
Pharmaceutics 2021, 13(12), 1987; https://doi.org/10.3390/pharmaceutics13121987 - 23 Nov 2021
Cited by 4 | Viewed by 2866
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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48 pages, 1621 KiB  
Review
Photodynamic Therapy and Hyperthermia in Combination Treatment—Neglected Forces in the Fight against Cancer
by Aleksandra Bienia, Olga Wiecheć-Cudak, Aleksandra Anna Murzyn and Martyna Krzykawska-Serda
Pharmaceutics 2021, 13(8), 1147; https://doi.org/10.3390/pharmaceutics13081147 - 27 Jul 2021
Cited by 25 | Viewed by 4831
Abstract
Cancer is one of the leading causes of death in humans. Despite the progress in cancer treatment, and an increase in the effectiveness of diagnostic methods, cancer is still highly lethal and very difficult to treat in many cases. Combination therapy, in the [...] Read more.
Cancer is one of the leading causes of death in humans. Despite the progress in cancer treatment, and an increase in the effectiveness of diagnostic methods, cancer is still highly lethal and very difficult to treat in many cases. Combination therapy, in the context of cancer treatment, seems to be a promising option that may allow minimizing treatment side effects and may have a significant impact on the cure. It may also increase the effectiveness of anti-cancer therapies. Moreover, combination treatment can significantly increase delivery of drugs to cancerous tissues. Photodynamic therapy and hyperthermia seem to be ideal examples that prove the effectiveness of combination therapy. These two kinds of therapy can kill cancer cells through different mechanisms and activate various signaling pathways. Both PDT and hyperthermia play significant roles in the perfusion of a tumor and the network of blood vessels wrapped around it. The main goal of combination therapy is to combine separate mechanisms of action that will make cancer cells more sensitive to a given therapeutic agent. Such an approach in treatment may contribute toward increasing its effectiveness, optimizing the cancer treatment process in the future. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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31 pages, 2296 KiB  
Review
Smart Nanoparticles for Chemo-Based Combinational Therapy
by Binita Shrestha, Lijun Wang, Eric M. Brey, Gabriela Romero Uribe and Liang Tang
Pharmaceutics 2021, 13(6), 853; https://doi.org/10.3390/pharmaceutics13060853 - 8 Jun 2021
Cited by 27 | Viewed by 4707
Abstract
Cancer is a heterogeneous and complex disease. Traditional cancer therapy is associated with low therapeutic index, acquired resistance, and various adverse effects. With the increasing understanding of cancer biology and technology advancements, more strategies have been exploited to optimize the therapeutic outcomes. The [...] Read more.
Cancer is a heterogeneous and complex disease. Traditional cancer therapy is associated with low therapeutic index, acquired resistance, and various adverse effects. With the increasing understanding of cancer biology and technology advancements, more strategies have been exploited to optimize the therapeutic outcomes. The rapid development and application of nanomedicine have motivated this progress. Combinational regimen, for instance, has become an indispensable approach for effective cancer treatment, including the combination of chemotherapeutic agents, chemo-energy, chemo-gene, chemo-small molecules, and chemo-immunology. Additionally, smart nanoplatforms that respond to external stimuli (such as light, temperature, ultrasound, and magnetic field), and/or to internal stimuli (such as changes in pH, enzymes, hypoxia, and redox) have been extensively investigated to improve precision therapy. Smart nanoplatforms for combinational therapy have demonstrated the potential to be the next generation cancer treatment regimen. This review aims to highlight the recent advances in smart combinational therapy. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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38 pages, 4867 KiB  
Review
Multifunctional Scaffolds and Synergistic Strategies in Tissue Engineering and Regenerative Medicine
by Nicolas Muzzio, Sergio Moya and Gabriela Romero
Pharmaceutics 2021, 13(6), 792; https://doi.org/10.3390/pharmaceutics13060792 - 26 May 2021
Cited by 33 | Viewed by 6652
Abstract
The increasing demand for organ replacements in a growing world with an aging population as well as the loss of tissues and organs due to congenital defects, trauma and diseases has resulted in rapidly evolving new approaches for tissue engineering and regenerative medicine [...] Read more.
The increasing demand for organ replacements in a growing world with an aging population as well as the loss of tissues and organs due to congenital defects, trauma and diseases has resulted in rapidly evolving new approaches for tissue engineering and regenerative medicine (TERM). The extracellular matrix (ECM) is a crucial component in tissues and organs that surrounds and acts as a physical environment for cells. Thus, ECM has become a model guide for the design and fabrication of scaffolds and biomaterials in TERM. However, the fabrication of a tissue/organ replacement or its regeneration is a very complex process and often requires the combination of several strategies such as the development of scaffolds with multiple functionalities and the simultaneous delivery of growth factors, biochemical signals, cells, genes, immunomodulatory agents, and external stimuli. Although the development of multifunctional scaffolds and biomaterials is one of the most studied approaches for TERM, all these strategies can be combined among them to develop novel synergistic approaches for tissue regeneration. In this review we discuss recent advances in which multifunctional scaffolds alone or combined with other strategies have been employed for TERM purposes. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Combination Therapy)
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