Advances in Stimuli-Responsive Tumor Targeting Nanotechnology

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

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 26396

Special Issue Editors

Department of Biomedical-Chemical Engineering, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, Republic of Korea
Interests: pharmacology; toxicology and pharmaceutics; extracellular vesicles
Department of Biomedical-Chemical Engineering, The Catholic University of Korea, Gyeonggi-do 14662, Republic of Korea
Interests: biomaterials; organic/inorganic hybrid materials, nanoparticles; drug delivery system (DDS); photodynamic therapy (PDT); image-guided local therapy; cancer immunotherapy; tissue engineering; regenerative medicines
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Special Issue Information

Dear Colleagues,

To target tumor tissues, numerous scientists are developing various nanoparticle systems based on functional organic/inorganic materials, and actively utilizing various biological events for highly efficient antitumor treatment. The intelligent reactivity of these nanoparticles will be very effective in increasing the efficiency of chemotherapy. For example, controlling the rate of drug release, promoting the binding of nanoparticles to tumor tissues, and changing the morphology of nanoparticles in response to various internal/external stimuli leads to scientific advances, and provides a variety of pharmaceutical approaches. Therefore, this Special Issue will provide a new paradigm for tumor treatment methods, including recent trends in stimuli-responsive nanotechnology and the recent in vitro/in vivo antitumor studies.

Prof. Dr. Eun Seong Lee
Prof. Dr. Wooram Park
Guest Editors

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Keywords

  • stimuli-responsive polymers
  • tumor therapy
  • organic/inorganic nanoparticles
  • nanocarriers
  • antitumor drug delivery systems

Published Papers (8 papers)

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Research

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16 pages, 2731 KiB  
Article
PD-L1-Targeted Co-Delivery of Two Chemotherapeutics for Efficient Suppression of Skin Cancer Growth
by Fatemeh Movahedi, Jie Liu, Bing Sun, Pei Cao, Luyao Sun, Christopher Howard, Wenyi Gu and Zhi Ping Xu
Pharmaceutics 2022, 14(7), 1488; https://doi.org/10.3390/pharmaceutics14071488 - 18 Jul 2022
Viewed by 1389
Abstract
To overcome the severe side effects of cancer chemotherapy, it is vital to develop targeting chemotherapeutic delivery systems with the potent inhibition of tumour growth, angiogenesis, invasion and migration at low drug dosages. For this purpose, we co-loaded a conventional antiworm drug, albendazole [...] Read more.
To overcome the severe side effects of cancer chemotherapy, it is vital to develop targeting chemotherapeutic delivery systems with the potent inhibition of tumour growth, angiogenesis, invasion and migration at low drug dosages. For this purpose, we co-loaded a conventional antiworm drug, albendazole (ABZ), and a TOPK inhibitor, OTS964, into lipid-coated calcium phosphate (LCP) nanoparticles for skin cancer treatment. OTS- and ABZ-loaded LCP (OTS-ABZ-LCP) showed a synergistic cytotoxicity against skin cancer cells through their specific cancerous pathways, without obvious toxicity to healthy cell lines. Moreover, dual-targeting the programmed death ligand-1 (PD-L1) and folate receptor overexpressed on the surface of skin cancer cells completely suppressed the skin tumour growth at low doses of ABZ and OTS. In summary, ABZ and OTS co-loaded dual-targeting LCP NPs represent a promising platform with high potentials against complicated cancers where PD-L1/FA dual targeting appears as an effective approach for efficient and selective cancer therapy. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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18 pages, 7637 KiB  
Article
Tumor Microenvironment-Responsive Shell/Core Composite Nanoparticles for Enhanced Stability and Antitumor Efficiency Based on a pH-Triggered Charge-Reversal Mechanism
by Qiuhua Luo, Wen Shi, Puxiu Wang, Yu Zhang, Jia Meng and Ling Zhang
Pharmaceutics 2021, 13(6), 895; https://doi.org/10.3390/pharmaceutics13060895 - 16 Jun 2021
Cited by 6 | Viewed by 2103
Abstract
High systemic stability and effective tumor accumulation of chemotherapeutic agents are indispensable elements that determine their antitumor efficacy. PEGylation of nanoparticles (NPs) could prolong the retention time in vivo by improving their stability in circulation, but treatment suffers reduced tumor penetration and cellular [...] Read more.
High systemic stability and effective tumor accumulation of chemotherapeutic agents are indispensable elements that determine their antitumor efficacy. PEGylation of nanoparticles (NPs) could prolong the retention time in vivo by improving their stability in circulation, but treatment suffers reduced tumor penetration and cellular uptake of nanomedicines. The tumor microenvironment (TME)-responsive NPs maintain their stealth features during circulation and undergo a stimuli-responsive dePEGylation once exposed to the site of action, thereby achieving enhanced internalization in tumor cells. Herein, TME-responsive shell/core composite nanoparticles were prepared and optimized with enhanced stability and tumor intake efficiency. We synthesized 12-hydroxystearic acid-poly (ethylene glycol)-YGRKKRRQRRR (HA-PEG-TAT) as a post-insert apparatus in disulfiram (DSF)-encapsulated naked nanoparticles (N-NPs) in order to form a cationic core (TAT-NPs). Accordingly, the negatively charged poly (glutamate acid)-graft-poly (ethylene glycol) (PGlu-PEG) was further applied to the surface of TAT-NPs as a negative charged shell (PGlu-PEG/TAT-NPs) via the electrostatic interaction between glutamic acids and arginine at the outer ring of the TAT-NPs. PGlu-PEG/TAT-NPs displayed a huge loading capability for DSF with reduced degradation in plasma and exhibited rapid charge reversal when pH decreased from 7.4 to pH 6.5, demonstrating an excellent systemic stability as well as intelligent stimuli-responsive performance within the acidic TME. Furthermore, the in vivo antitumor study revealed that PGlu-PEG/TAT-NPs provided greater antitumor efficacy compared with free DSF and N-NPs with no obvious systemic toxicity. In conclusion, the TME-responsive shell/core composite NPs, consisting of PGlu-PEG and HS-PEG-TAT, could mediate an effective and biocompatible delivery of chemotherapeutic agents with clinical potential. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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14 pages, 4750 KiB  
Article
Enhanced Anticancer Efficacy of Dual Drug-Loaded Self-Assembled Nanostructured Lipid Carriers Mediated by pH-Responsive Folic Acid and Human-Derived Cell Penetrating Peptide dNP2
by Zhe Ma, Jiaxin Pi, Ying Zhang, Huan Qin, Bing Zhang, Nan Li, Zheng Li and Zhidong Liu
Pharmaceutics 2021, 13(5), 600; https://doi.org/10.3390/pharmaceutics13050600 - 22 Apr 2021
Cited by 10 | Viewed by 2478
Abstract
The poor ability of recognition and penetration of chemotherapeutic agents to tumor cells are still great challenges for targeted breast cancer treatment. Herein, we established a tumor-targeted nanostructured lipid carrier encapsulating gambogic acid (GA) and paclitaxel (PTX), which was co-modified with acid-cleavable folic [...] Read more.
The poor ability of recognition and penetration of chemotherapeutic agents to tumor cells are still great challenges for targeted breast cancer treatment. Herein, we established a tumor-targeted nanostructured lipid carrier encapsulating gambogic acid (GA) and paclitaxel (PTX), which was co-modified with acid-cleavable folic acid (cFA) and a human-derived cell penetrating peptide dNP2 (CKIKKVKKKGRKKIKKVKKKGRK). The multi-functional nano-platform exhibited an enhanced targeting and penetrability to tumor tissues, which was accomplished by the combined action of cFA and dNP2. After intravenous injection, firstly, cFA could actively target the breast cancer tissues by the selective recognition of folate receptor (FR); then, upon arrival at the tumor microenvironment, the acid-cleavable FA and dNP2 dual modified nanostructured lipid carrier (cFA/dNP2-GA/PTX-NLC) exhibited sensitive cleavage of folic acid (FA), which could reduce the hindrance effect of FA to maximize the dNP2 cell-penetrating properties. The effect of different modification on cellular uptake, in vivo bio-distribution, and anticancer activity of NLCs proved our hypothesis that compared with NLCs modified by non-cleavable FA or a single ligand, cFA/dNP2-GA/PTX-NLC displayed more efficient intracellular delivery, stronger targeting ability in vivo, improved cytotoxicity on 4T1 cells, and produced the better therapeutic efficacy of GA and PTX. The strategy affords a feasible way to overcome the poor recognition and permeability of medicines in cancer treatment. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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16 pages, 7222 KiB  
Article
Transferrin-Conjugated pH-Responsive γ-Cyclodextrin Nanoparticles for Antitumoral Topotecan Delivery
by Seonyoung Yoon, Yoonyoung Kim, Yu Seok Youn, Kyung Taek Oh, Dongin Kim and Eun Seong Lee
Pharmaceutics 2020, 12(11), 1109; https://doi.org/10.3390/pharmaceutics12111109 - 18 Nov 2020
Cited by 10 | Viewed by 2807
Abstract
In this study, we developed γ-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a γ-cyclodextrin (γCD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed γCDP-(DMA/PEG-Tf) NPs. These γCDP-(DMA/PEG-Tf) NPs are effective in [...] Read more.
In this study, we developed γ-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a γ-cyclodextrin (γCD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed γCDP-(DMA/PEG-Tf) NPs. These γCDP-(DMA/PEG-Tf) NPs are effective in entrapping topotecan (TPT, as a model antitumor drug) resulting from the ionic interaction between pH-responsive DMA and TPT or the host–guest interaction between γCDP and TPT. More importantly, the γCDP-(DMA/PEG-Tf) NPs can induce ionic repulsion at an endosomal pH (~6.0) resulting from the chemical detachment of DMA from γCDP, which is followed by extensive TPT release. We demonstrated that γCDP-(DMA/PEG-Tf) NPs led to a significant increase in cellular uptake and MDA-MB-231 tumor cell death. In vivo animal studies using an MDA-MB-231 tumor xenografted mice model supported the finding that γCDP-(DMA/PEG-Tf) NPs are effective carriers of TPT to Tf receptor-positive MDA-MB-231 tumor cells, promoting drug uptake into the tumors through the Tf ligand-mediated endocytic pathway and increasing their toxicity due to DMA-mediated cytosolic TPT delivery. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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Review

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31 pages, 1423 KiB  
Review
Drug Delivery by Ultrasound-Responsive Nanocarriers for Cancer Treatment
by Kristin Entzian and Achim Aigner
Pharmaceutics 2021, 13(8), 1135; https://doi.org/10.3390/pharmaceutics13081135 - 26 Jul 2021
Cited by 50 | Viewed by 5994
Abstract
Conventional cancer chemotherapies often exhibit insufficient therapeutic outcomes and dose-limiting toxicity. Therefore, there is a need for novel therapeutics and formulations with higher efficacy, improved safety, and more favorable toxicological profiles. This has promoted the development of nanomedicines, including systems for drug delivery, [...] Read more.
Conventional cancer chemotherapies often exhibit insufficient therapeutic outcomes and dose-limiting toxicity. Therefore, there is a need for novel therapeutics and formulations with higher efficacy, improved safety, and more favorable toxicological profiles. This has promoted the development of nanomedicines, including systems for drug delivery, but also for imaging and diagnostics. Nanoparticles loaded with drugs can be designed to overcome several biological barriers to improving efficiency and reducing toxicity. In addition, stimuli-responsive nanocarriers are able to release their payload on demand at the tumor tissue site, preventing premature drug loss. This review focuses on ultrasound-triggered drug delivery by nanocarriers as a versatile, cost-efficient, non-invasive technique for improving tissue specificity and tissue penetration, and for achieving high drug concentrations at their intended site of action. It highlights aspects relevant for ultrasound-mediated drug delivery, including ultrasound parameters and resulting biological effects. Then, concepts in ultrasound-mediated drug delivery are introduced and a comprehensive overview of several types of nanoparticles used for this purpose is given. This includes an in-depth compilation of the literature on the various in vivo ultrasound-responsive drug delivery systems. Finally, toxicological and safety considerations regarding ultrasound-mediated drug delivery with nanocarriers are discussed. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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32 pages, 15088 KiB  
Review
Recent Advances in pH- or/and Photo-Responsive Nanovehicles
by Yuseon Shin, Patihul Husni, Kioh Kang, Dayoon Lee, Sehwa Lee, Eunseong Lee, Yuseok Youn and Kyungtaek Oh
Pharmaceutics 2021, 13(5), 725; https://doi.org/10.3390/pharmaceutics13050725 - 14 May 2021
Cited by 19 | Viewed by 3590
Abstract
The combination of nanotechnology and chemotherapy has resulted in more effective drug design via the development of nanomaterial-based drug delivery systems (DDSs) for tumor targeting. Stimulus-responsive DDSs in response to internal or external signals can offer precisely controlled delivery of preloaded therapeutics. Among [...] Read more.
The combination of nanotechnology and chemotherapy has resulted in more effective drug design via the development of nanomaterial-based drug delivery systems (DDSs) for tumor targeting. Stimulus-responsive DDSs in response to internal or external signals can offer precisely controlled delivery of preloaded therapeutics. Among the various DDSs, the photo-triggered system improves the efficacy and safety of treatment through spatiotemporal manipulation of light. Additionally, pH-induced delivery is one of the most widely studied strategies for targeting the acidic micro-environment of solid tumors. Accordingly, in this review, we discuss representative strategies for designing DDSs using light as an exogenous signal or pH as an endogenous trigger. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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26 pages, 5869 KiB  
Review
Smart Stimuli-Responsive Liposomal Nanohybrid Systems: A Critical Review of Theranostic Behavior in Cancer
by Jana K. Alwattar, Amina T. Mneimneh, Kawthar K. Abla, Mohammed M. Mehanna and Ahmed N. Allam
Pharmaceutics 2021, 13(3), 355; https://doi.org/10.3390/pharmaceutics13030355 - 08 Mar 2021
Cited by 26 | Viewed by 2608
Abstract
The epoch of nanotechnology has authorized novel investigation strategies in the area of drug delivery. Liposomes are attractive biomimetic nanocarriers characterized by their biocompatibility, high loading capacity, and their ability to reduce encapsulated drug toxicity. Nevertheless, various limitations including physical instability, lack of [...] Read more.
The epoch of nanotechnology has authorized novel investigation strategies in the area of drug delivery. Liposomes are attractive biomimetic nanocarriers characterized by their biocompatibility, high loading capacity, and their ability to reduce encapsulated drug toxicity. Nevertheless, various limitations including physical instability, lack of site specificity, and low targeting abilities have impeded the use of solo liposomes. Metal nanocarriers are emerging moieties that can enhance the therapeutic activity of many drugs with improved release and targeted potential, yet numerous barriers, such as colloidal instability, cellular toxicity, and poor cellular uptake, restrain their applicability in vivo. The empire of nanohybrid systems has shelled to overcome these curbs and to combine the criteria of liposomes and metal nanocarriers for successful theranostic delivery. Metallic moieties can be embedded or functionalized on the liposomal systems. The current review sheds light on different liposomal-metal nanohybrid systems that were designed as cellular bearers for therapeutic agents, delivering them to their targeted terminus to combat one of the most widely recognized diseases, cancer. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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18 pages, 10490 KiB  
Review
Stem Cell-Derived Exosomes and Nanovesicles: Promotion of Cell Proliferation, Migration, and Anti-Senescence for Treatment of Wound Damage and Skin Ageing
by Hyeonjin Cha, Seyoung Hong, Ju Hyun Park and Hee Ho Park
Pharmaceutics 2020, 12(12), 1135; https://doi.org/10.3390/pharmaceutics12121135 - 24 Nov 2020
Cited by 22 | Viewed by 4637
Abstract
Extracellular vesicles (EVs), such as exosomes, are nano-sized vesicles derived from endocytic membranes and contain biomolecules such as proteins, lipids, RNAs, and DNAs for the transfer of signals to recipient cells, playing significant roles in cell-to-cell communication. Discovery of exosomes has attracted attention [...] Read more.
Extracellular vesicles (EVs), such as exosomes, are nano-sized vesicles derived from endocytic membranes and contain biomolecules such as proteins, lipids, RNAs, and DNAs for the transfer of signals to recipient cells, playing significant roles in cell-to-cell communication. Discovery of exosomes has attracted attention for possible use as next generation therapies in clinical applications; however, several studies suggest that cells secrete exosomes that perform as mediators in the tumor niche and play several roles in tumorigenesis, angiogenesis, and metastasis. Recently, stem cell-derived exosomes have been suggested as a desirable source for regenerative medicine due to their roles in the promotion of angiogenesis via migratory and proliferative mechanisms. This review is aimed at demonstrating the present knowledge of stem cell-derived exosomes and cell-engineered nanovesicles (CNVs) as proliferative, migratory, and anti-senescent therapeutic biomaterial for use in tissue regeneration; wound healing and anti-ageing are explained. We conclude this review by discussing the future perspectives of stem cell-derived exosomes and CNVs as a platform in therapeutic strategies for treatment of wound damage and skin aging. Full article
(This article belongs to the Special Issue Advances in Stimuli-Responsive Tumor Targeting Nanotechnology)
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