Research

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11 pages, 1630 KiB

Open AccessCommunication

A New Cathepsin D Targeting Drug Delivery System Based on Immunoliposomes Functionalized with Lipidated Pepstatin A

by Andreja Kozak, Georgy Mikhaylov, Pavlo Khodakivskyi, Elena Goun, Boris Turk and Olga Vasiljeva

Pharmaceutics 2023, 15(10), 2464; https://doi.org/10.3390/pharmaceutics15102464 - 14 Oct 2023

Viewed by 896

Abstract

Cathepsin D is an aspartic protease and one of the most abundant proteases. It is overexpressed in many cancers and plays an important role in tumor development, progression, and metastasis. While it is a physiologically intracellular protein, cathepsin D is secreted into the [...] Read more.

Cathepsin D is an aspartic protease and one of the most abundant proteases. It is overexpressed in many cancers and plays an important role in tumor development, progression, and metastasis. While it is a physiologically intracellular protein, cathepsin D is secreted into the extracellular matrix under pathological conditions, making it an appealing target for drug delivery systems. Here, we present the development and evaluation of a new delivery system for tumor targeting based on immunoliposomes functionalized with pepstatin A—a natural peptide inhibitor of cathepsin D. A lipid tail was added to pepstatin A, enabling its incorporation into the liposomal lipid bilayer. The successful targeting of cathepsin D was confirmed using recombinant cathepsin D and in tumor cell lines, showing the feasibility of this targeting approach and its potential for in vivo use in theragnostic applications. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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16 pages, 6298 KiB

Open AccessArticle

Cyclic RGD-Functionalized pH/ROS Dual-Responsive Nanoparticle for Targeted Breast Cancer Therapy

by Pu Yao, Xiaowen Wang, Qianmei Wang, Qing Dai, Yu Peng, Qian Yuan, Nan Mou, Shan Lv, Bangbi Weng, Yu Wang and Fengjun Sun

Pharmaceutics 2023, 15(7), 1827; https://doi.org/10.3390/pharmaceutics15071827 - 26 Jun 2023

Cited by 2 | Viewed by 1424

Abstract

Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. [...] Read more.

Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. Herein, we report a docetaxel (DTX)-loaded pH/ROS-responsive NP that could achieve active targeting of cancer cells and selective and complete drug release for effective drug delivery. The pH/ROS-responsive NPs were fabricated using nanocarriers that consist of an ROS-responsive moiety (4-hydroxymethylphenylboronic acid pinacol ester, HPAP), cinnamaldehyde (CA, an aldehyde organic compound with anticancer activities) and cyclodextrin (α-CD). The NPs were loaded with DTX, modified with a tumor-penetration peptide (circular RGD, cRGD) and named DTX/RGD NPs. The cRGD could promote DTX/RGD NPs penetration into deep tumor tissue and specifically target cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, the pH-responsive acetal was cleaved to release CA in the lysosomal acidic environment. Meanwhile, the high ROS in tumor cells induced the disassembly of NPs with complete release of DTX. In vitro cellular assays verified that DTX/RGD NPs could be effectively internalized by 4T1 cells, obviously inducing apoptosis, blocking the cell cycle of 4T1 cells and consequently, killing tumor cells. In vivo animal experiments demonstrated that the NPs could target to the tumor sites and significantly inhibit the tumor growth in 4T1 breast cancer mice. Both in vitro and in vivo investigations demonstrated that DTX/RGD NPs could significantly improve the antitumor effect compared to free DTX. Thus, the DTX/RGD NPs provide a promising strategy for enhancing drug delivery and cancer therapy. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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18 pages, 13337 KiB

Open AccessArticle

Efficient Delivery of Gemcitabine by Estrogen Receptor-Targeted PEGylated Liposome and Its Anti-Lung Cancer Activity In Vivo and In Vitro

by Huan Tang, Zheng Zhang, Ming Zhu, Yizhuo Xie, Zhe Lv, Rui Liu, Yujia Shen and Jin Pei

Pharmaceutics 2023, 15(3), 988; https://doi.org/10.3390/pharmaceutics15030988 - 19 Mar 2023

Cited by 5 | Viewed by 1537

Abstract

Lung cancer is one of the main causes of cancer-related deaths. At present, the main treatment method for lung cancer is chemotherapy. Gemcitabine (GEM) is widely applied in lung cancer treatment, but its lack of targeting ability and serious side effects limit its [...] Read more.

Lung cancer is one of the main causes of cancer-related deaths. At present, the main treatment method for lung cancer is chemotherapy. Gemcitabine (GEM) is widely applied in lung cancer treatment, but its lack of targeting ability and serious side effects limit its application. In recent years, nanocarriers have become the focus of research to solve the above problems. Here, we prepared estrone (ES)-modified GEM-loaded PEGylated liposomes (ES-SSL-GEM) for enhanced delivery by identifying the overexpressed estrogen receptor (ER) on lung cancer A549 cells. We studied the characterization, stability, release behavior, cytotoxicity, targeting ability, endocytosis mechanism, and antitumor ability to prove the therapeutic effect of ES-SSL-GEM. The results showed that ES-SSL-GEM presented a uniform particle size of 131.20 ± 0.62 nm, a good stability, and a slowly released behavior. Moreover, ES-SSL-GEM enhanced tumor-targeting ability, and the endocytosis mechanism studies confirmed that the ER-mediated endocytosis had the most crucial effect. Furthermore, ES-SSL-GEM had the best inhibitory effect on A549 cell proliferation and significantly suppressed the tumor growth in vivo. These results suggest that ES-SSL-GEM is a promising agent for treating lung cancer. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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15 pages, 4821 KiB

Open AccessArticle

Liposomal Delivery of MIW815 (ADU-S100) for Potentiated STING Activation

by Nan Ji, Minjia Wang and Chalet Tan

Pharmaceutics 2023, 15(2), 638; https://doi.org/10.3390/pharmaceutics15020638 - 14 Feb 2023

Cited by 6 | Viewed by 2431

Abstract

Stimulator of interferon genes (STING) agonists can improve the anticancer efficacy of immune checkpoint blockade by amplifying tumor immunogenicity. However, the clinical translation of cyclic dinucleotides (CDNs) as STING agonists is hindered by their poor drug-like properties. In this study, we investigated the [...] Read more.

Stimulator of interferon genes (STING) agonists can improve the anticancer efficacy of immune checkpoint blockade by amplifying tumor immunogenicity. However, the clinical translation of cyclic dinucleotides (CDNs) as STING agonists is hindered by their poor drug-like properties. In this study, we investigated the design criteria for DOTAP/cholesterol liposomes for the systemic delivery of ADU-S100 and delineated the impact of key formulation factors on the loading efficiency, serum stability, and STING agonistic activity of ADU-S100. Our findings demonstrate that the cationic liposomal formulation of ADU-S100 can be optimized to greatly potentiate STING activation in antigen-presenting cells. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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21 pages, 4714 KiB

Open AccessArticle

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma

by Oxana Semyachkina-Glushkovskaya, Denis Bragin, Olga Bragina, Sergey Socolovski, Alexander Shirokov, Ivan Fedosov, Vasily Ageev, Inna Blokhina, Alexander Dubrovsky, Valeria Telnova, Andrey Terskov, Alexander Khorovodov, Daria Elovenko, Arina Evsukova, Maria Zhoy, Ilana Agranovich, Elena Vodovozova, Anna Alekseeva, Jürgen Kurths and Edik Rafailov

Pharmaceutics 2023, 15(2), 567; https://doi.org/10.3390/pharmaceutics15020567 - 08 Feb 2023

Cited by 10 | Viewed by 2308

Abstract

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level [...] Read more.

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level laser treatment (LLLT, 1268 nm) in the mouse cortex. LLLT-BBBO is accompanied by activation of the brain drainage system contributing effective delivery of liposomes into glioblastoma (GBM). The LLLT induces the generation of singlet oxygen without photosensitizers (PSs) in the blood endothelial cells and astrocytes, which can be a trigger mechanism of BBBO. LLLT-BBBO causes activation of the ABC-transport system with a temporal decrease in the expression of tight junction proteins. The BBB recovery is accompanied by activation of neuronal metabolic activity and stabilization of the BBB permeability. LLLT-BBBO can be used as a new opportunity of interstitial PS-free photodynamic therapy (PDT) for modulation of brain tumor immunity and improvement of immuno-therapy for GBM in infants in whom PDT with PSs, radio- and chemotherapy are strongly limited, as well as in adults with a high allergic reaction to PSs. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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12 pages, 2354 KiB

Open AccessArticle

New Insights into the Behavior of NHC-Gold Complexes in Cancer Cells

by Giuseppa Augello, Antonina Azzolina, Filomena Rossi, Filippo Prencipe, Giuseppe Felice Mangiatordi, Michele Saviano, Luisa Ronga, Melchiorre Cervello and Diego Tesauro

Pharmaceutics 2023, 15(2), 466; https://doi.org/10.3390/pharmaceutics15020466 - 31 Jan 2023

Cited by 7 | Viewed by 1603

Abstract

Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin [...] Read more.

Among the non-platinum antitumor agents, gold complexes have received increased attention owing to their strong antiproliferative effects, which generally occur through non-cisplatin-like mechanisms of action. Several studies have revealed that many cytotoxic gold compounds, such as N-heterocyclic carbene (NHC)-gold(I) complexes, are potent thioredoxin reductase (TrxR) inhibitors. Many other pathways have been supposed to be altered by gold coordination to protein targets. Within this frame, we have selected two gold(I) complexes based on aromatic ligands to be tested on cancer cells. Differently from bis [1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene]gold(I) bromide (Au4BC), bis [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) inhibited TrxR1 activity in vitro. Treatment of Huh7 hepatocellular carcinoma (HCC) cells, and MDA-MB-231 triple-negative breast cancer (TNBC) cells, with Au4BC inhibited cell viability, increased reactive oxygen species (ROS) levels, caused DNA damage, and induced autophagy and apoptosis. Notably, we found that, although Au3BC inhibited TrxR1 activity, no effect on the cell viabilities of HCC and BC cells was observed. At the molecular level, Au3BC induced a protective response mechanism in Huh7 and MDA-MB-231 cells, by inducing up-regulation of RAD51 and p62 protein expression, two proteins involved in DNA damage repair and autophagy, respectively. RAD51 gene knock-down in HCC cells increased cell sensitivity to Au3BC by significant reduction of cell viability, induction of DNA damage, and induction of apoptosis and autophagy. All together, these results suggest that the tested NHC-Gold complexes, Au3BC and Au4BC, showed different mechanisms of action, either dependent or independent of TrxR1 inhibition. As a result, Au3BC and Au4BC were found to be promising candidates as anticancer drugs for the treatment of HCC and BC. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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20 pages, 3520 KiB

Open AccessArticle

pH-Responsive Drug Delivery Nanoplatforms as Smart Carriers of Unsymmetrical Bisacridines for Targeted Cancer Therapy

by Joanna Pilch, Agnieszka Potęga, Agata Kowalczyk, Artur Kasprzak, Patrycja Kowalik, Piotr Bujak, Ewa Paluszkiewicz, Ewa Augustin and Anna M. Nowicka

Pharmaceutics 2023, 15(1), 201; https://doi.org/10.3390/pharmaceutics15010201 - 06 Jan 2023

Cited by 7 | Viewed by 1485

Abstract

Selective therapy and controlled drug release at an intracellular level remain key challenges for effective cancer treatment. Here, we employed folic acid (FA) as a self-navigating molecule in nanoconjugates containing quantum dots (QDs) and β-cyclodextrin (β-CD) for the delivery of [...] Read more.

Selective therapy and controlled drug release at an intracellular level remain key challenges for effective cancer treatment. Here, we employed folic acid (FA) as a self-navigating molecule in nanoconjugates containing quantum dots (QDs) and β-cyclodextrin (β-CD) for the delivery of antitumor unsymmetrical bisacridine compound (C-2028) to lung and prostate cancers as well as normal cells. The bisacridine derivative can form the inclusion complex with β-cyclodextrin molecule, due to the presence of a planar fragment in its structure. The stability of such a complex is pH-dependent. The drug release profile at different pH values and the mechanism of C-2028 release from QDs-β-CD-FA nanoconjugates were investigated. Next, the intracellular fate of compounds and their influence on lysosomal content in the cells were also studied. Confocal Laser Scanning Microscopy studies proved that all investigated compounds were delivered to acidic organelles, the pH of which promoted an increased release of C-2028 from its nanoconjugates. Since the pH in normal cells is higher than in cancer cells, the release of C-2028 from its nanoconjugates is decreased in these cells. Additionally, we obtained the concentration profiles of C-2028 in the selected cells treated with unbound C-2028 or nanoconjugate by the HPLC analysis. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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14 pages, 2824 KiB

Open AccessArticle

Development of an Antibody Delivery Method for Cancer Treatment by Combining Ultrasound with Therapeutic Antibody-Modified Nanobubbles Using Fc-Binding Polypeptide

by Yusuke Yano, Nobuhito Hamano, Kenshin Haruta, Tomomi Kobayashi, Masahiro Sato, Yamato Kikkawa, Yoko Endo-Takahashi, Rui Tada, Ryo Suzuki, Kazuo Maruyama, Motoyoshi Nomizu and Yoichi Negishi

Pharmaceutics 2023, 15(1), 130; https://doi.org/10.3390/pharmaceutics15010130 - 30 Dec 2022

Cited by 1 | Viewed by 2098

Abstract

A key challenge in treating solid tumors is that the tumor microenvironment often inhibits the penetration of therapeutic antibodies into the tumor, leading to reduced therapeutic efficiency. It has been reported that the combination of ultrasound-responsive micro/nanobubble and therapeutic ultrasound (TUS) enhances the [...] Read more.

A key challenge in treating solid tumors is that the tumor microenvironment often inhibits the penetration of therapeutic antibodies into the tumor, leading to reduced therapeutic efficiency. It has been reported that the combination of ultrasound-responsive micro/nanobubble and therapeutic ultrasound (TUS) enhances the tissue permeability and increases the efficiency of delivery of macromolecular drugs to target tissues. In this study, to facilitate efficient therapeutic antibody delivery to tumors using this combination system, we developed therapeutic antibody-modified nanobubble (NBs) using an Fc-binding polypeptide that can quickly load antibodies to nanocarriers; since the polypeptide was derived from Protein G. TUS exposure to this Herceptin^®-modified NBs (Her-NBs) was followed by evaluation of the antibody’s own ADCC activity, resulting the retained activity. Moreover, the utility of combining therapeutic antibody-modified NBs and TUS exposure as an antibody delivery system for cancer therapy was assessed in vivo. The Her-NBs + TUS group had a higher inhibitory effect than the Herceptin and Her-NBs groups. Overall, these results suggest that the combination of therapeutic antibody-modified NBs and TUS exposure can enable efficient antibody drug delivery to tumors, while retaining the original antibody activity. Hence, this system has the potential to maximize the therapeutic effects in antibody therapy for solid cancers. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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20 pages, 7739 KiB

Open AccessArticle

Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells

by Elena N. Komedchikova, Olga A. Kolesnikova, Ekaterina D. Tereshina, Polina A. Kotelnikova, Anna S. Sogomonyan, Alexey V. Stepanov, Sergey M. Deyev, Maxim P. Nikitin and Victoria O. Shipunova

Pharmaceutics 2023, 15(1), 52; https://doi.org/10.3390/pharmaceutics15010052 - 24 Dec 2022

Cited by 7 | Viewed by 2442

Abstract

Nanoparticle-based chemotherapy is considered to be an effective approach to cancer diagnostics and therapy in modern biomedicine. However, efficient tumor targeting remains a great challenge due to the lack of specificity, selectivity, and high dosage of chemotherapeutic drugs required. A two-step targeted drug [...] Read more.

Nanoparticle-based chemotherapy is considered to be an effective approach to cancer diagnostics and therapy in modern biomedicine. However, efficient tumor targeting remains a great challenge due to the lack of specificity, selectivity, and high dosage of chemotherapeutic drugs required. A two-step targeted drug delivery strategy (DDS), involving cancer cell pre-targeting, first with a first nontoxic module and subsequent targeting with a second complementary toxic module, is a solution for decreasing doses for administration and lowering systemic toxicity. To prove two-step DDS efficiency, we performed a direct comparison of one-step and two-step DDS based on chemotherapy loaded PLGA nanoparticles and barnase*barstar interface. Namely, we developed and thoroughly characterized the two-step targeting strategy of HER2-overexpressing cancer cells. The first targeting block consists of anti-HER2 scaffold polypeptide DARPin9_29 fused with barstar. Barstar exhibits an extremely effective binding to ribonuclease barnase with K_aff = 10¹⁴ M⁻¹, thus making the barnase*barstar protein pair one of the strongest known protein*protein complexes. A therapeutic PLGA-based nanocarrier coupled to barnase was used as a second targeting block. The PLGA nanoparticles were loaded with diagnostic dye, Nile Blue, and a chemotherapeutic drug, doxorubicin. We showed that the two-step DDS increases the performance of chemotherapy-loaded nanocarriers: IC50 of doxorubicin delivered via two-step DDS was more than 100 times lower than that for one-step DDS: IC50 = 43 ± 3 nM for two-step DDS vs. IC50 = 4972 ± 1965 nM for one-step DDS. The obtained results demonstrate the significant efficiency of two-step DDS over the classical one-step one. We believe that the obtained data will significantly change the direction of research in developing targeted anti-cancer drugs and promote the creation of new generation cancer treatment strategies. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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17 pages, 3572 KiB

Open AccessArticle

Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease

by Jingyi Ma, Virender Kumar and Ram I. Mahato

Pharmaceutics 2022, 14(9), 1894; https://doi.org/10.3390/pharmaceutics14091894 - 07 Sep 2022

Cited by 3 | Viewed by 1928

Abstract

The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, [...] Read more.

The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition. Therefore, we used a novel PDE4B inhibitor KVA-D88 as the therapeutic for ALD treatment. KVA-D88 inhibited inflammatory response, promoted β-oxidation, increased the level of antioxidants in the hepatocytes, and suppressed hepatic stellate cell (HSC) activation in vitro. To improve the solubility and availability in vivo, KVA-D88 was encapsulated into mPEG-b-P(CB-co-LA) nanoparticles (NPs) by solvent evaporation, with a mean particle size of 135 nm and drug loading of 4.2%. We fed the male C57BL/6 mice with a Lieber–DeCarli liquid diet containing 5% (v/v) ethanol for 6 weeks to induce ALD. Systemic administration of KVA-D88 free drug and KVA-D88-loaded NPs at 5 mg/kg significantly improved the ALD in mice. KVA-D88 significantly ameliorated alcohol-induced hepatic injury and inflammation. KVA-D88 also markedly reduced steatosis by promoting fatty acid β-oxidation. Liver fibrosis and reactive oxygen species (ROS)-caused cellular damage was observed to be alleviated by KVA-D88. KVA-D88-loaded NPs proved better efficacy than free drug in the animal study. In conclusion, the novel PDE4B inhibitor KVA-D88-loaded NPs have the potential to treat ALD in mice Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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10 pages, 2772 KiB

Open AccessArticle

Tumor Microenvironment-Responsive Polymeric iRGD and Doxorubicin Conjugates Reduce Spontaneous Lung Metastasis in an Orthotopic Breast Cancer Model

by Zheng-Hong Peng, Chinmay M. Jogdeo, Jing Li, Ying Xie, Yazhe Wang, Yuri M. Sheinin, Jindřich Kopeček and David Oupický

Pharmaceutics 2022, 14(8), 1725; https://doi.org/10.3390/pharmaceutics14081725 - 18 Aug 2022

Cited by 3 | Viewed by 2132

Abstract

Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate [...] Read more.

Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate P-DOX-iRGD that not only significantly suppressed primary tumor growth but also substantially inhibited pulmonary metastasis in an orthotopic mouse model of breast cancer. In addition, treatment with P-DOX-iRGD markedly reduced breast cancer-induced splenomegaly and liver hematopoiesis. Interestingly, contrasting results were seen for the free form and polymeric form of DOX in vitro and in vivo, which may be attributed to the enhanced permeability and retention (EPR) effect. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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23 pages, 3772 KiB

Open AccessEditor’s ChoiceArticle

Design and Validation of Nanofibers Made of Self-Assembled Peptides to Become Multifunctional Stimuli-Sensitive Nanovectors of Anticancer Drug Doxorubicin

by Valentina Del Genio, Annarita Falanga, Emilie Allard-Vannier, Katel Hervé-Aubert, Marilisa Leone, Rosa Bellavita, Rustem Uzbekov, Igor Chourpa and Stefania Galdiero

Pharmaceutics 2022, 14(8), 1544; https://doi.org/10.3390/pharmaceutics14081544 - 25 Jul 2022

Cited by 14 | Viewed by 2176

Abstract

Self-assembled peptides possess remarkable potential as targeted drug delivery systems and key applications dwell anti-cancer therapy. Peptides can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions (pH, temperature, ionic strength). Herein, we investigated the development of self-assembled [...] Read more.

Self-assembled peptides possess remarkable potential as targeted drug delivery systems and key applications dwell anti-cancer therapy. Peptides can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions (pH, temperature, ionic strength). Herein, we investigated the development of self-assembled peptide-based nanofibers (NFs) with the inclusion of a cell-penetrating peptide (namely gH625) and a matrix metalloproteinase-9 (MMP-9) responsive sequence, which proved to enhance respectively the penetration and tumor-triggered cleavage to release Doxorubicin in Triple Negative Breast Cancer cells where MMP-9 levels are elevated. The NFs formulation has been optimized via critical micelle concentration measurements, fluorescence, and circular dichroism. The final nanovectors were characterized for morphology (TEM), size (hydrodynamic diameter), and surface charge (zeta potential). The Doxo loading and release kinetics were studied in situ, by optical microspectroscopy (fluorescence and surface-enhanced Raman scattering–SERS). Confocal spectral imaging of the Doxo fluorescence was used to study the TNBC models in vitro, in cells with various MMP-9 levels, the drug delivery to cells as well as the resulting cytotoxicity profiles. The results confirm that these NFs are a promising platform to develop novel nanovectors of Doxo, namely in the framework of TNBC treatment. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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Review

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28 pages, 7993 KiB

Open AccessReview

Recent Advances in Targeted Drug Delivery Strategy for Enhancing Oncotherapy

by Jianmin Li, Qingluo Wang, Guoyu Xia, Nigela Adilijiang, Ying Li, Zhenqing Hou, Zhongxiong Fan and Jinyao Li

Pharmaceutics 2023, 15(9), 2233; https://doi.org/10.3390/pharmaceutics15092233 - 29 Aug 2023

Cited by 8 | Viewed by 4421

Abstract

Targeted drug delivery is a precise and effective strategy in oncotherapy that can accurately deliver drugs to tumor cells or tissues to enhance their therapeutic effect and, meanwhile, weaken their undesirable side effects on normal cells or tissues. In this research field, a [...] Read more.

Targeted drug delivery is a precise and effective strategy in oncotherapy that can accurately deliver drugs to tumor cells or tissues to enhance their therapeutic effect and, meanwhile, weaken their undesirable side effects on normal cells or tissues. In this research field, a large number of researchers have achieved significant breakthroughs and advances in oncotherapy. Typically, nanocarriers as a promising drug delivery strategy can effectively deliver drugs to the tumor site through enhanced permeability and retention (EPR) effect-mediated passive targeting and various types of receptor-mediated active targeting, respectively. Herein, we review recent targeted drug delivery strategies and technologies for enhancing oncotherapy. In addition, we also review two mainstream drug delivery strategies, passive and active targeting, based on various nanocarriers for enhancing tumor therapy. Meanwhile, a comparison and combination of passive and active targeting are also carried out. Furthermore, we discuss the associated challenges of passive and active targeted drug delivery strategies and the prospects for further study. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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63 pages, 5895 KiB

Open AccessEditor’s ChoiceReview

Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria

by Jason M. Roe, Kevin Seely, Caleb J. Bussard, Emily Eischen Martin, Elizabeth G. Mouw, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E. Brooks and Kaitlin M. Dailey

Pharmaceutics 2023, 15(7), 2004; https://doi.org/10.3390/pharmaceutics15072004 - 21 Jul 2023

Cited by 1 | Viewed by 3594

Abstract

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, [...] Read more.

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to “hijack” typical host–pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed “domestication”, of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria–host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as “prophylactic”, may even be able to prevent or “derail” tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria–host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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30 pages, 7401 KiB

Open AccessReview

Utilization of Functionalized Metal–Organic Framework Nanoparticle as Targeted Drug Delivery System for Cancer Therapy

by Vy Anh Tran, Van Thuan Le, Van Dat Doan and Giang N. L. Vo

Pharmaceutics 2023, 15(3), 931; https://doi.org/10.3390/pharmaceutics15030931 - 13 Mar 2023

Cited by 13 | Viewed by 3846

Abstract

Cancer is a multifaceted disease that results from the complex interaction between genetic and environmental factors. Cancer is a mortal disease with the biggest clinical, societal, and economic burden. Research on better methods of the detection, diagnosis, and treatment of cancer is crucial. [...] Read more.

Cancer is a multifaceted disease that results from the complex interaction between genetic and environmental factors. Cancer is a mortal disease with the biggest clinical, societal, and economic burden. Research on better methods of the detection, diagnosis, and treatment of cancer is crucial. Recent advancements in material science have led to the development of metal–organic frameworks, also known as MOFs. MOFs have recently been established as promising and adaptable delivery platforms and target vehicles for cancer therapy. These MOFs have been constructed in a fashion that offers them the capability of drug release that is stimuli-responsive. This feature has the potential to be exploited for cancer therapy that is externally led. This review presents an in-depth summary of the research that has been conducted to date in the field of MOF-based nanoplatforms for cancer therapeutics. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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26 pages, 1446 KiB

Open AccessReview

Injectable Nano Drug Delivery Systems for the Treatment of Breast Cancer

by Urmila Kafle, Satish Agrawal and Alekha K. Dash

Pharmaceutics 2022, 14(12), 2783; https://doi.org/10.3390/pharmaceutics14122783 - 13 Dec 2022

Cited by 13 | Viewed by 3281

Abstract

Breast cancer is the most diagnosed type of cancer, with 2.26 million cases and 685,000 deaths recorded in 2020. If left untreated, this deadly disease can metastasize to distant organs, which is the reason behind its incurability and related deaths. Currently, conventional therapies [...] Read more.

Breast cancer is the most diagnosed type of cancer, with 2.26 million cases and 685,000 deaths recorded in 2020. If left untreated, this deadly disease can metastasize to distant organs, which is the reason behind its incurability and related deaths. Currently, conventional therapies are used to treat breast cancer, but they have numerous shortcomings such as low bioavailability, short circulation time, and off-target toxicity. To address these challenges, nanomedicines are preferred and are being extensively investigated for breast cancer treatment. Nanomedicines are novel drug delivery systems that can improve drug stability, aqueous solubility, blood circulation time, controlled release, and targeted delivery at the tumoral site and enhance therapeutic safety and effectiveness. Nanoparticles (NPs) can be administered through different routes. Although the injectable route is less preferred than the oral route for drug administration, it has its advantages: it helps tailor drugs with targeted moiety, boosts payload, avoids first-pass metabolism, and improves the pharmacokinetic parameters of the active pharmaceutical ingredients. Targeted delivery of nanomedicine, closer to organelles such as the mitochondria and nuclei in breast cancer, reduces the dosage requirements and the toxic effects of chemotherapeutics. This review aims to provide the current status of the recent advances in various injectable nanomedicines for targeted treatment of breast cancer. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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19 pages, 1792 KiB

Open AccessReview

Topically Applied Resiquimod versus Imiquimod as a Potential Adjuvant in Melanoma Treatment

by Supreeda Tambunlertchai, Sean M. Geary and Aliasger K. Salem

Pharmaceutics 2022, 14(10), 2076; https://doi.org/10.3390/pharmaceutics14102076 - 29 Sep 2022

Cited by 9 | Viewed by 2235

Abstract

Melanoma is the most lethal form of skin cancer and surgery remains the preferred and most effective treatment. Nevertheless, there are cases where surgery is not a viable method and alternative treatments are therefore adopted. One such treatment that has been tested is [...] Read more.

Melanoma is the most lethal form of skin cancer and surgery remains the preferred and most effective treatment. Nevertheless, there are cases where surgery is not a viable method and alternative treatments are therefore adopted. One such treatment that has been tested is topical 5% imiquimod (IMQ) cream, which, although showing promise as a treatment for melanoma, has been found to have undesirable off-target effects. Resiquimod (RSQ) is an immunomodulatory molecule that can activate immune responses by binding to Toll-like receptors (TLR) 7 and 8 and may be more effective than IMQ in the context of melanoma treatment. RSQ can cross the stratum corneum (SC) easily without requiring pretreatment of the skin. In a gel formulation, RSQ has been studied as a monotherapy and adjuvant for melanoma treatment in pre-clinical studies and as an adjuvant in clinical settings. Although side effects of RSQ in gel formulation were also reported, they were never severe enough for the treatment to be suspended. In this review, we discuss the potential use of RSQ as an adjuvant for melanoma treatment. Full article

(This article belongs to the Special Issue Targeted Drug Delivery to Improve Cancer Therapy)

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