Internal and External Triggering Mechanism of “Smart” Nanoparticle-Based DDSs in Targeted Tumor Therapy

Background: Anticancer chemotherapeutics have a lot of problems via conventional Drug Delivery Systems (DDSs), including non-specificity, burst release, severe side-effects, and damage to normal cells. Owing to its potential to circumventing these problems, nanotechnology has gained increasing attention in targeted tumor therapy. Chemotherapeutic drugs or genes encapsulated in nanoparticles could be used to target therapies to the tumor site in three ways: “passive”, “active”, and “smart” targeting. Objective: To summarize the mechanisms of various internal and external “smart” stimulating factors on the basis of findings from in vivo and in vitro studies. Method: A thorough search of PubMed was conducted in order to identify the majority of trials, studies and novel articles related to the subject. Results: Activated by internal triggering factors (pH, redox, enzyme, hypoxia, etc.) or external triggering factors (temperature, light of different wavelengths, ultrasound, magnetic fields, etc.), “smart” DDSs exhibit targeted delivery to the tumor site, and controlled release of chemotherapeutic drugs or genes. Conclusion: In this review article, we summarize and classify the internal and external triggering mechanism of “smart” nanoparticle-based DDSs in targeted tumor therapy, and the most recent research advances are illustrated for better understanding.

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Tumor-Targeting Peptides Search Strategy for the Delivery of Therapeutic and Diagnostic Molecules to Tumor Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22010314 ◽

2020 ◽

Vol 22 (1) ◽

pp. 314

Author(s):

Maria D. Dmitrieva ◽

Anna A. Voitova ◽

Maya A. Dymova ◽

Vladimir A. Richter ◽

Elena V. Kuligina

Keyword(s):

Phage Display ◽

Cell Sorting ◽

Targeted Delivery ◽

Tumor Targeting ◽

Search Strategy ◽

Tumor Therapy ◽

Therapeutic Agents ◽

Phage Libraries

Background: The combination of the unique properties of cancer cells makes it possible to find specific ligands that interact directly with the tumor, and to conduct targeted tumor therapy. Phage display is one of the most common methods for searching for specific ligands. Bacteriophages display peptides, and the peptides themselves can be used as targeting molecules for the delivery of diagnostic and therapeutic agents. Phage display can be performed both in vitro and in vivo. Moreover, it is possible to carry out the phage display on cells pre-enriched for a certain tumor marker, for example, CD44 and CD133. Methods: For this work we used several methods, such as phage display, sequencing, cell sorting, immunocytochemistry, phage titration. Results: We performed phage display using different screening systems (in vitro and in vivo), different phage libraries (Ph.D-7, Ph.D-12, Ph.D-C7C) on CD44+/CD133+ and without enrichment U-87 MG cells. The binding efficiency of bacteriophages displayed tumor-targeting peptides on U-87 MG cells was compared in vitro. We also conducted a comparative analysis in vivo of the specificity of the accumulation of selected bacteriophages in the tumor and in the control organs (liver, brain, kidney and lungs). Conclusions: The screening in vivo of linear phage peptide libraries for glioblastoma was the most effective strategy for obtaining tumor-targeting peptides providing targeted delivery of diagnostic and therapeutic agents to glioblastoma.

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A supramolecular platform for controlling and optimizing molecular architectures of siRNA targeted delivery vehicles

Science Advances ◽

10.1126/sciadv.abc2148 ◽

2020 ◽

Vol 6 (31) ◽

pp. eabc2148

Author(s):

Yuting Wen ◽

Hongzhen Bai ◽

Jingling Zhu ◽

Xia Song ◽

Guping Tang ◽

...

Keyword(s):

Gene Delivery ◽

Targeted Delivery ◽

Tumor Therapy ◽

Sirna Delivery ◽

Targeted Gene Delivery ◽

Delivery Vehicles ◽

Molecular Architectures ◽

Host Polymer

It requires multistep synthesis and conjugation processes to incorporate multifunctionalities into a polyplex gene vehicle to overcome numerous hurdles during gene delivery. Here, we describe a supramolecular platform to precisely control, screen, and optimize molecular architectures of siRNA targeted delivery vehicles, which is based on rationally designed host-guest complexation between a β-cyclodextrin–based cationic host polymer and a library of guest polymers with various PEG shape and size, and various density of ligands. The host polymer is responsible to load/unload siRNA, while the guest polymer is responsible to shield the vehicles from nonspecific cellular uptake, to prolong their circulation time, and to target tumor cells. A series of precisely controlled molecular architectures through a simple assembly process allow for a rapid optimization of siRNA delivery vehicles in vitro and in vivo for therapeutic siRNA-Bcl2 delivery and tumor therapy, indicating the platform is a powerful screening tool for targeted gene delivery vehicles.

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Strains, Mechanism, and Perspective:Salmonella-Based Cancer Therapy

International Journal of Microbiology ◽

10.1155/2016/5678702 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 20

Author(s):

Cheng-Zhi Wang ◽

Robert A. Kazmierczak ◽

Abraham Eisenstark

Keyword(s):

Synthetic Biology ◽

Tumor Targeting ◽

Tumor Therapy ◽

The Other ◽

Cancer Therapies ◽

Chemotherapeutic Drugs ◽

Serovar Typhimurium ◽

Candidate Strain

Recently, investigation of bacterial-based tumor therapy has regained focus due to progress in molecular, cellular, and microbial biology. Many bacteria such asSalmonella,Listeria,Escherichia, andClostridiumhave proved to have tumor targeting and in some cases even tumor-destroying phenotypes. Furthermore, bacterial clinical treatments for cancer have been improved by combination with other therapeutic methods such as chemotherapeutic drugs and radioactive agents. Synthetic biology techniques have also driven the development of new bacterial-based cancer therapies. However, basic questions about the mechanisms of bacterial-mediated tumor targeting and destruction are still being elucidated. In this review, we focus on three tumor-therapeuticSalmonellamodels, the most intensively studied bacterial genus in this field. One of theseSalmonellamodels is ourSalmonella entericaserovar Typhimurium LT2 derived strain CRC2631, engineered to minimize toxicity but maximize tumor-targeting and destruction effects. The other two are VNP20009 and A1-R. We compare the means by which these therapeutic candidate strain models were selected for study, their tumor targeting and tumor destruction phenotypesin vitroandin vivo, and what is currently known about the mechanisms by which they target and destroy tumors.

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Targeted delivery of RGD-modified liposomes encapsulating both combretastatin A-4 and doxorubicin for tumor therapy: In vitro and in vivo studies

European Journal of Pharmaceutics and Biopharmaceutics ◽

10.1016/j.ejpb.2010.01.002 ◽

2010 ◽

Vol 74 (3) ◽

pp. 467-473 ◽

Cited By ~ 87

Author(s):

Yi-fei Zhang ◽

Jian-cheng Wang ◽

Dong-yan Bian ◽

Xuan Zhang ◽

Qiang Zhang

Keyword(s):

Targeted Delivery ◽

Tumor Therapy ◽

In Vivo Studies

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Preparation and Optimization of Moxifloxacin Microspheres for Colon Targeted Delivery Using Quality by Design Approach: In Vitro and In Vivo Study

Current Drug Delivery ◽

10.2174/1567201813666160512145625 ◽

2016 ◽

Vol 13 (7) ◽

pp. 1021-1033 ◽

Cited By ~ 4

Author(s):

Bhumika Prajapati ◽

Prasant Kumar Jena ◽

Tejal Mehta ◽

Sriram Seshadri

Keyword(s):

Targeted Delivery ◽

Quality By Design ◽

Design Approach ◽

In Vivo Study ◽

Quality By Design Approach

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Diaphanous related formin 3 knockdown suppresses cell proliferation and metastasis of osteosarcoma cells

Discover Oncology ◽

10.1007/s12672-021-00415-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Zehua Zhang ◽

Fei Dai ◽

Fei Luo ◽

Wenjie Wu ◽

Shuai Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Therapy ◽

Disease Free Survival ◽

Tumor Stage ◽

Migration And Invasion ◽

Osteosarcoma Cell ◽

Proliferation And Metastasis ◽

New Biomarkers

AbstractOsteosarcoma is a malignant osteoblastic tumor that can gravely endanger the lives and health of children and adolescents. Therefore, there is an urgent need to explore new biomarkers for osteosarcoma and determine new targeted therapies to improve the efficacy of osteosarcoma treatment. Diaphanous related formin 3 (DIAPH3) promotes tumorigenesis in hepatocellular carcinoma and lung adenocarcinoma, suggesting that DIAPH3 may be a target for tumor therapy. To date, there have been no reports on the function of DIAPH3 in osteosarcoma. DIAPH3 protein expression in osteosarcoma tissues and healthy bone tissues adjacent to cancer cells was examined by immunohistochemical staining. DIAPH3 mRNA expression correlates with overall survival and reduced disease-free survival. DIAPH3 protein is upregulated in osteosarcoma tissues, and its expression is significantly associated with tumor size, tumor stage, node metastasis, and distant metastasis. Functional in vitro experiments revealed that DIAPH3 knockdown suppressed cell proliferation and suppressed cell migration and invasion of osteosarcoma cell lines MG-63 and HOS. Functional experiments demonstrated that DIAPH3 knockdown inhibited subcutaneous tumor growth and lung metastasis in vivo. In conclusion, DIAPH3 expression can predict the clinical outcome of osteosarcoma. In addition, DIAPH3 is involved in the proliferation and metastasis of osteosarcoma, and as such, DIAPH3 may be a potential therapeutic target for osteosarcoma.

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Topotecan-loaded thermosensitive nanocargo for tumor therapy: In vitro and in vivo analyses

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2021.120871 ◽

2021 ◽

pp. 120871

Author(s):

Zhiyong Zhang ◽

Pan Yan ◽

Yan Zhao ◽

Mudan Ren ◽

Yarui Li ◽

...

Keyword(s):

Tumor Therapy

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Mechanisms and Pharmaceutical Action of Lipid Nanoformulation of Natural Bioactive Compounds as Efficient Delivery Systems in the Therapy of Osteoarthritis

Pharmaceutics ◽

10.3390/pharmaceutics13081108 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1108

Author(s):

Oana Craciunescu ◽

Madalina Icriverzi ◽

Paula Ecaterina Florian ◽

Anca Roseanu ◽

Mihaela Trif

Keyword(s):

Drug Delivery ◽

Bioactive Compounds ◽

Targeted Delivery ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Joint Disease ◽

Duration Of Action ◽

Immune System Activation

Osteoarthritis (OA) is a degenerative joint disease. An objective of the nanomedicine and drug delivery systems field is to design suitable pharmaceutical nanocarriers with controllable properties for drug delivery and site-specific targeting, in order to achieve greater efficacy and minimal toxicity, compared to the conventional drugs. The aim of this review is to present recent data on natural bioactive compounds with anti-inflammatory properties and efficacy in the treatment of OA, their formulation in lipid nanostructured carriers, mainly liposomes, as controlled release systems and the possibility to be intra-articularly (IA) administered. The literature regarding glycosaminoglycans, proteins, polyphenols and their ability to modify the cell response and mechanisms of action in different models of inflammation are reviewed. The advantages and limits of using lipid nanoformulations as drug delivery systems in OA treatment and the suitable route of administration are also discussed. Liposomes containing glycosaminoglycans presented good biocompatibility, lack of immune system activation, targeted delivery of bioactive compounds to the site of action, protection and efficiency of the encapsulated material, and prolonged duration of action, being highly recommended as controlled delivery systems in OA therapy through IA administration. Lipid nanoformulations of polyphenols were tested both in vivo and in vitro models that mimic OA conditions after IA or other routes of administration, recommending their clinical application.

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Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study

Biomolecules ◽

10.3390/biom11070927 ◽

2021 ◽

Vol 11 (7) ◽

pp. 927

Author(s):

Sebas D. Pronk ◽

Erik Schooten ◽

Jurgen Heinen ◽

Esra Helfrich ◽

Sabrina Oliveira ◽

...

Keyword(s):

Drug Delivery ◽

Targeted Delivery ◽

Single Domain ◽

Drug Conjugates ◽

Intracellular Drug Delivery ◽

Internalization Rate ◽

Single Domain Antibodies ◽

Different Characteristics

Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRβ, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.

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