Targeted Nanotherapy in Cancer Disease

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (20 January 2022) | Viewed by 29652

Special Issue Editors


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Guest Editor
Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
Interests: nanomedicine; drug delivery; gene therapy; pharmaceutics; pharmaceutical education; topical delivery
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: antimicrobial agents; breast cancer; cannabinoids; drug delivery; drug targeting; in situ-forming implants; nanomedicine; ovarian cancer; polymers
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, 28040 Madrid, Spain
Interests: nanomedicine; cancer; controlled release systems; prosthetic infection; microparticles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite all the continuous efforts, cancer disease is a leading cause of death worldwide. In the last decades, the development of targeted therapeutics has revolutionized cancer therapy, with numerous formulations based on monoclonal antibodies, small molecule enzyme inhibitors, and recombinant proteins approved or under clinical trials for the treatment of several neoplasms. In certain types of carcinomas and advanced stages of the disease, chemotherapy constitutes a major treatment strategy, showing, in general, high toxicity. Their selective delivery to cancer cells may resolve this problem and increase the anticancer efficacy. In this way, several strategies have been used for this purpose, including the development of monoclonal-antibodies drug conjugates or the use of nanocarriers coated with ligands specifically recognized by cancer cells.

In the present Special Issue, studies reporting original data or updated literature reviews concerning targeted chemonanotherapy are welcome.

Prof. Dr. Donatella Paolino
Prof. Dr. Ana Isabel Fraguas-Sánchez
Dr. Cristina Martin-Sabroso
Guest Editors

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Keywords

  • active targeting
  • cancer
  • chemotherapy
  • liposomes
  • monoclonal antibodies
  • nanomedicine

Published Papers (9 papers)

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Research

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23 pages, 5419 KiB  
Article
Folate-Decorated Cross-Linked Cytochrome c Nanoparticles for Active Targeting of Non-Small Cell Lung Carcinoma (NSCLC)
by Irivette Dominguez-Martinez, Freisa Joaquin-Ovalle, Yancy Ferrer-Acosta and Kai H. Griebenow
Pharmaceutics 2022, 14(3), 490; https://doi.org/10.3390/pharmaceutics14030490 - 24 Feb 2022
Cited by 3 | Viewed by 2032
Abstract
The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, [...] Read more.
The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, yet, when delivered to the cytoplasm of cancer cells, can kill them by inducing apoptosis. Cyt c nanoparticles (NPs, 169 ± 9 nm) were obtained by solvent precipitation with acetonitrile, and stabilized by reversible homo-bifunctional crosslinking to accomplish a Cyt-c-based drug delivery system that combines stimulus-responsive release and active targeting. Cyt c was released under intracellular redox conditions, due to an S–S bond in the NPs linker, while NPs remained intact without any release under extracellular conditions. The NP surface was decorated with a hydrophilic folic acid–polyethylene glycol (FA–PEG) polymer for active targeting. The FA-decorated NPs specifically recognized and killed cancer cells (IC50 = 47.46 µg/mL) that overexpressed FR, but showed no toxicity against FR-negative cells. Confocal microscopy confirmed the preferential uptake and apoptosis induction of our NPs by FR-positive cancer cells. In vivo experiments using a Lewis lung carcinoma (LLC) mouse model showed visible NP accumulation within the tumor and inhibited the growth of LLC tumors. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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13 pages, 3444 KiB  
Article
Ultrasound-Triggered Liposomes Encapsulating Quantum Dots as Safe Fluorescent Markers for Colorectal Cancer
by Nahid S. Awad, Mohamed Haider, Vinod Paul, Nour M. AlSawaftah, Jayalakshmi Jagal, Renu Pasricha and Ghaleb A. Husseini
Pharmaceutics 2021, 13(12), 2073; https://doi.org/10.3390/pharmaceutics13122073 - 03 Dec 2021
Cited by 11 | Viewed by 3694
Abstract
Quantum dots (QDs) are a promising tool to detect and monitor tumors. However, their small size allows them to accumulate in large quantities inside the healthy cells (in addition to the tumor cells), which increases their toxicity. In this study, we synthesized stealth [...] Read more.
Quantum dots (QDs) are a promising tool to detect and monitor tumors. However, their small size allows them to accumulate in large quantities inside the healthy cells (in addition to the tumor cells), which increases their toxicity. In this study, we synthesized stealth liposomes encapsulating hydrophilic graphene quantum dots and triggered their release with ultrasound with the goal of developing a safer and well-controlled modality to deliver fluorescent markers to tumors. Our results confirmed the successful encapsulation of the QDs inside the core of the liposomes and showed no effect on the size or stability of the prepared liposomes. Our results also showed that low-frequency ultrasound is an effective method to release QDs encapsulated inside the liposomes in a spatially and temporally controlled manner to ensure the effective delivery of QDs to tumors while reducing their systemic toxicity. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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17 pages, 1998 KiB  
Article
Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells
by Eduardo García-Garrido, Marco Cordani and Álvaro Somoza
Pharmaceutics 2021, 13(12), 2067; https://doi.org/10.3390/pharmaceutics13122067 - 03 Dec 2021
Cited by 17 | Viewed by 2433
Abstract
Mutant p53 proteins result from missense mutations in the TP53 gene, the most mutated in human cancer, and have been described to contribute to cancer initiation and progression. Therapeutic strategies for targeting mutant p53 proteins in cancer cells are limited and have proved [...] Read more.
Mutant p53 proteins result from missense mutations in the TP53 gene, the most mutated in human cancer, and have been described to contribute to cancer initiation and progression. Therapeutic strategies for targeting mutant p53 proteins in cancer cells are limited and have proved unsuitable for clinical application due to problems related to drug delivery and toxicity to healthy tissues. Therefore, the discovery of efficient and safe therapeutic strategies that specifically target mutant p53 remains challenging. In this study, we generated gold nanoparticles (AuNPs) chemically modified with low molecular branched polyethylenimine (bPEI) for the efficient delivery of gapmers targeting p53 mutant protein. The AuNPs formulation consists of a combination of polymeric mixed layer of polyethylene glycol (PEG) and PEI, and layer-by-layer assembly of bPEI through a sensitive linker. These nanoparticles can bind oligonucleotides through electrostatic interactions and release them in the presence of a reducing agent as glutathione. The nanostructures generated here provide a non-toxic and powerful system for the delivery of gapmers in cancer cells, which significantly downregulated mutant p53 proteins and altered molecular markers related to cell growth and apoptosis, thus overcoming chemoresistance to gemcitabine. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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16 pages, 2850 KiB  
Article
Sorafenib Repurposing for Ophthalmic Delivery by Lipid Nanoparticles: A Preliminary Study
by Angela Bonaccorso, Veronica Pepe, Cristina Zappulla, Cinzia Cimino, Angelo Pricoco, Giovanni Puglisi, Francesco Giuliano, Rosario Pignatello and Claudia Carbone
Pharmaceutics 2021, 13(11), 1956; https://doi.org/10.3390/pharmaceutics13111956 - 18 Nov 2021
Cited by 11 | Viewed by 2327
Abstract
Uveal melanoma is the second most common melanoma and the most common intraocular malignant tumour of the eye. Among various treatments currently studied, Sorafenib was also proposed as a promising drug, often administered with other compounds in order to avoid resistance mechanisms. Despite [...] Read more.
Uveal melanoma is the second most common melanoma and the most common intraocular malignant tumour of the eye. Among various treatments currently studied, Sorafenib was also proposed as a promising drug, often administered with other compounds in order to avoid resistance mechanisms. Despite its promising cellular activities, the use of Sorafenib by oral administration is limited by its severe side effects and the difficulty to reach the target. The encapsulation into drug delivery systems represents an interesting strategy to overcome these limits. In this study, different lipid nanoparticulate formulations were prepared and compared in order to select the most suitable for the encapsulation of Sorafenib. In particular, two solid lipids (Softisan or Suppocire) at different concentrations were used to produce solid lipid nanoparticles, demonstrating that higher amounts were able to achieve smaller particle sizes, higher homogeneity, and longer physical stability. The selected formulations, which demonstrated to be biocompatible on Statens Seruminstitut Rabbit Cornea cells, were modified to improve their mucoadhesion, evaluating the effect of two monovalent cationic lipids with two lipophilic chains. Sorafenib encapsulation allowed obtaining a sustained and prolonged drug release, thus confirming the potential use of the developed strategy to topically administer Sorafenib in the treatment of uveal melanoma. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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19 pages, 6593 KiB  
Article
Iron Oxide Nanoparticles Carrying 5-Fluorouracil in Combination with Magnetic Hyperthermia Induce Thrombogenic Collagen Fibers, Cellular Stress, and Immune Responses in Heterotopic Human Colon Cancer in Mice
by Mohammad Dabaghi, Seyed Mohammad Mahdi Rasa, Emilio Cirri, Alessandro Ori, Francesco Neri, Rainer Quaas and Ingrid Hilger
Pharmaceutics 2021, 13(10), 1625; https://doi.org/10.3390/pharmaceutics13101625 - 06 Oct 2021
Cited by 12 | Viewed by 2172
Abstract
In this study we looked for the main protein pathway regulators which were responsible for the therapeutic impact on colon cancers when combining magnetic hyperthermia with the chemotherapeutic agent 5-fluorouracil (5FU). To this end, chitosan-coated magnetic nanoparticles (MNP) functionalized with 5FU were intratumorally [...] Read more.
In this study we looked for the main protein pathway regulators which were responsible for the therapeutic impact on colon cancers when combining magnetic hyperthermia with the chemotherapeutic agent 5-fluorouracil (5FU). To this end, chitosan-coated magnetic nanoparticles (MNP) functionalized with 5FU were intratumorally injected into subcutaneous human colon cancer xenografts (HT-29) in mice and exposed to an alternating magnetic field. A decreased tumor growth was found particularly for the combined thermo-chemotherapy vs. the corresponding monotherapies. By using computational analysis of the tumor proteome, we found upregulated functional pathway categories termed “cellular stress and injury”, “intracellular second messenger and nuclear receptor signaling”, “immune responses”, and “growth proliferation and development”. We predict TGF-beta, and other mediators, as important upstream regulators. In conclusion, our findings show that the combined thermo-chemotherapy induces thrombogenic collagen fibers which are able to impair tumor nutrient supply. Further on, we associate several responses to the recognition of damage associated molecular patterns (DAMPs) by phagocytic cells, which immigrate into the tumor area. The activation of some pathways associated with cell survival implies the necessity to conduct multiple therapy sessions in connection with a corresponding monitoring, which could possibly be performed on the base of the identified protein regulators. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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12 pages, 1941 KiB  
Article
Zinc-Phthalocyanine-Loaded Extracellular Vesicles Increase Efficacy and Selectivity of Photodynamic Therapy in Co-Culture and Preclinical Models of Colon Cancer
by Pablo Lara, Ruben V. Huis in ‘t Veld, Carla Jorquera-Cordero, Alan B. Chan, Ferry Ossendorp and Luis J. Cruz
Pharmaceutics 2021, 13(10), 1547; https://doi.org/10.3390/pharmaceutics13101547 - 23 Sep 2021
Cited by 14 | Viewed by 2909
Abstract
Photodynamic therapy (PDT) is a promising and clinically approved method for the treatment of cancer. However, the efficacy of PDT is often limited by the poor selectivity and distribution of the photosensitizers (PS) toward the malignant tumors, resulting in prolonged periods of skin [...] Read more.
Photodynamic therapy (PDT) is a promising and clinically approved method for the treatment of cancer. However, the efficacy of PDT is often limited by the poor selectivity and distribution of the photosensitizers (PS) toward the malignant tumors, resulting in prolonged periods of skin photosensitivity. In this work, we present a simple and straightforward strategy to increase the tumor distribution, selectivity, and efficacy of lipophilic PS zinc phthalocyanine (ZnPc) in colon cancer by their stabilization in purified, naturally secreted extracellular vesicles (EVs). The PS ZnPc was incorporated in EVs (EV-ZnPc) by a direct incubation strategy that did not affect size distribution or surface charge. By using co-culture models simulating a tumor microenvironment, we determined the preferential uptake of EV-ZnPc toward colon cancer cells when compared with macrophages and dendritic cells. We observed that PDT promoted total tumor cell death in normal and immune cells, but showed selectivity against cancer cells in co-culture models. In vivo assays showed that after a single intravenous or intratumoral injection, EV-ZnPc were able to target the tumor cells and strongly reduce tumor growth over 15 days. These data expose opportunities to enhance the potential and efficacy of PDT using simple non-synthetic strategies that might facilitate translation into clinical practice. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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Review

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29 pages, 2980 KiB  
Review
Encapsulation, Release, and Cytotoxicity of Doxorubicin Loaded in Liposomes, Micelles, and Metal-Organic Frameworks: A Review
by Mihad Ibrahim, Waad H. Abuwatfa, Nahid S. Awad, Rana Sabouni and Ghaleb A. Husseini
Pharmaceutics 2022, 14(2), 254; https://doi.org/10.3390/pharmaceutics14020254 - 21 Jan 2022
Cited by 44 | Viewed by 6439
Abstract
Doxorubicin (DOX) is one of the most widely used anthracycline anticancer drugs due to its high efficacy and evident antitumoral activity on several cancer types. However, its effective utilization is hindered by the adverse side effects associated with its administration, the detriment to [...] Read more.
Doxorubicin (DOX) is one of the most widely used anthracycline anticancer drugs due to its high efficacy and evident antitumoral activity on several cancer types. However, its effective utilization is hindered by the adverse side effects associated with its administration, the detriment to the patients’ quality of life, and general toxicity to healthy fast-dividing cells. Thus, delivering DOX to the tumor site encapsulated inside nanocarrier-based systems is an area of research that has garnered colossal interest in targeted medicine. Nanoparticles can be used as vehicles for the localized delivery and release of DOX, decreasing the effects on neighboring healthy cells and providing more control over the drug’s release and distribution. This review presents an overview of DOX-based nanocarrier delivery systems, covering loading methods, release rate, and the cytotoxicity of liposomal, micellar, and metal organic frameworks (MOFs) platforms. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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20 pages, 1531 KiB  
Review
From Microenvironment Remediation to Novel Anti-Cancer Strategy: The Emergence of Zero Valent Iron Nanoparticles
by Ya-Na Wu, Li-Xing Yang, Pei-Wen Wang, Filip Braet and Dar-Bin Shieh
Pharmaceutics 2022, 14(1), 99; https://doi.org/10.3390/pharmaceutics14010099 - 02 Jan 2022
Cited by 4 | Viewed by 2549
Abstract
Accumulated studies indicate that zero-valent iron (ZVI) nanoparticles demonstrate endogenous cancer-selective cytotoxicity, without any external electric field, lights, or energy, while sparing healthy non-cancerous cells in vitro and in vivo. The anti-cancer activity of ZVI-based nanoparticles was anti-proportional to the oxidative status of [...] Read more.
Accumulated studies indicate that zero-valent iron (ZVI) nanoparticles demonstrate endogenous cancer-selective cytotoxicity, without any external electric field, lights, or energy, while sparing healthy non-cancerous cells in vitro and in vivo. The anti-cancer activity of ZVI-based nanoparticles was anti-proportional to the oxidative status of the materials, which indicates that the elemental iron is crucial for the observed cancer selectivity. In this thematic article, distinctive endogenous anti-cancer mechanisms of ZVI-related nanomaterials at the cellular and molecular levels are reviewed, including the related gene modulating profile in vitro and in vivo. From a material science perspective, the underlying mechanisms are also analyzed. In summary, ZVI-based nanomaterials demonstrated prominent potential in precision medicine to modulate both programmed cell death of cancer cells, as well as the tumor microenvironment. We believe that this will inspire advanced anti-cancer therapy in the future. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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25 pages, 2420 KiB  
Review
Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives
by Cristina Martín-Sabroso, Irene Lozza, Ana Isabel Torres-Suárez and Ana Isabel Fraguas-Sánchez
Pharmaceutics 2021, 13(10), 1705; https://doi.org/10.3390/pharmaceutics13101705 - 15 Oct 2021
Cited by 10 | Viewed by 3489
Abstract
In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the [...] Read more.
In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors. Full article
(This article belongs to the Special Issue Targeted Nanotherapy in Cancer Disease)
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