Pharmaceutics

Editorial

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4 pages, 187 KiB

Open AccessEditorial

Novel Anticancer Strategies

by Hassan Bousbaa

Pharmaceutics 2021, 13(2), 275; https://doi.org/10.3390/pharmaceutics13020275 - 18 Feb 2021

Cited by 11 | Viewed by 2344

Abstract

Cancer incidence and mortality continue to increase rapidly worldwide [...] Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

Research

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16 pages, 5356 KiB

Open AccessArticle

Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer

by Guillaume Sicard, Clément Paris, Sarah Giacometti, Anne Rodallec, Joseph Ciccolini, Palma Rocchi and Raphaëlle Fanciullino

Pharmaceutics 2020, 12(12), 1166; https://doi.org/10.3390/pharmaceutics12121166 - 29 Nov 2020

Cited by 17 | Viewed by 3656

Abstract

Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a [...] Read more.

Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option—however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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17 pages, 1669 KiB

Open AccessArticle

Low-Intensity Sonoporation-Induced Intracellular Signalling of Pancreatic Cancer Cells, Fibroblasts and Endothelial Cells

by Ragnhild Haugse, Anika Langer, Elisa Thodesen Murvold, Daniela Elena Costea, Bjørn Tore Gjertsen, Odd Helge Gilja, Spiros Kotopoulis, Gorka Ruiz de Garibay and Emmet McCormack

Pharmaceutics 2020, 12(11), 1058; https://doi.org/10.3390/pharmaceutics12111058 - 6 Nov 2020

Cited by 16 | Viewed by 3100

Abstract

The use of ultrasound (US) and microbubbles (MB), usually referred to as sonoporation, has great potential to increase the efficacy of chemotherapy. However, the molecular mechanisms that mediate sonoporation response are not well-known, and recent research suggests that cell stress induced by US [...] Read more.

The use of ultrasound (US) and microbubbles (MB), usually referred to as sonoporation, has great potential to increase the efficacy of chemotherapy. However, the molecular mechanisms that mediate sonoporation response are not well-known, and recent research suggests that cell stress induced by US + MBs may contribute to the treatment benefit. Furthermore, there is a growing understanding that the effects of US + MBs are beyond only the cancer cells and involves the tumour vasculature and microenvironment. We treated pancreatic cancer cells (MIA PaCa-2) and stromal cells, fibroblasts (BJ) and human umbilical vein endothelial cells (HUVECs), with US ± MB, and investigated the extent of uptake of cell impermeable dye (calcein, by flow cytometry), viability (cell count, Annexin/PI and WST-1 assays) and activation of a number of key proteins in important intracellular signalling pathways immediately and 2 h after sonoporation (phospho flow cytometry). Different cell types responded differently to US ± MBs in all these aspects. In general, sonoporation induces immediate, transient activation of MAP-kinases (p38, ERK1/2), and an increase in phosphorylation of ribosomal protein S6 together with dephosphorylation of 4E-BP1. The sonoporation stress-response resembles cellular responses to electroporation and pore-forming toxins in membrane repair and restoring cellular homeostasis, and may be exploited therapeutically. The stromal cells were more sensitive to sonoporation than tumoural cells, and further efforts in optimising sonoporation-enhanced therapy should be targeted at the microenvironment. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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15 pages, 4489 KiB

Open AccessArticle

Physicochemical, Pharmacokinetic, and Toxicity Evaluation of Soluplus^® Polymeric Micelles Encapsulating Fenbendazole

by Ik Sup Jin, Min Jeong Jo, Chun-Woong Park, Youn Bok Chung, Jin-Seok Kim and Dae Hwan Shin

Pharmaceutics 2020, 12(10), 1000; https://doi.org/10.3390/pharmaceutics12101000 - 21 Oct 2020

Cited by 27 | Viewed by 5222

Abstract

Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections; however, these are toxic. To [...] Read more.

Fenbendazole (FEN), a broad-spectrum benzimidazole anthelmintic, suppresses cancer cell growth through various mechanisms but has low solubility and achieves low blood concentrations, which leads to low bioavailability. Solubilizing agents are required to prepare poorly soluble drugs for injections; however, these are toxic. To overcome this problem, we designed and fabricated low-toxicity Soluplus^® polymeric micelles encapsulating FEN and conducted toxicity assays in vitro and in vivo. FEN-loaded Soluplus^® micelles had an average particle size of 68.3 ± 0.6 nm, a zeta potential of −2.3 ± 0.2 mV, a drug loading of 0.8 ± 0.03%, and an encapsulation efficiency of 85.3 ± 2.9%. MTT and clonogenic assays were performed on A549 cells treated with free FEN and FEN-loaded Soluplus^® micelles. The in vitro drug release profile showed that the micelles released FEN more gradually than the solution. Pharmacokinetic studies revealed lower total clearance and volume of distribution and higher area under the curve and plasma concentration at time zero of FEN-loaded Soluplus^® micelles than of the FEN solution. The in vivo toxicity assay revealed that FEN-loaded Soluplus^® micelle induced no severe toxicity. Therefore, we propose that preclinical and clinical safety and efficacy trials on FEN-loaded Soluplus^® micelles would be worthwhile. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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13 pages, 3524 KiB

Open AccessArticle

Anti-Cancer Activity of As₄O₆ and its Efficacy in a Series of Patient-Derived Xenografts for Human Cervical Cancer

by Joseph J. Noh, Myeong-Seon Kim, Young-Jae Cho, Soo-Young Jeong, Yoo-Young Lee, Ji-Yoon Ryu, Jung-Joo Choi, Illju Bae, Zhaoyan Wu, Byoung-Gie Kim, Jae Ryoung Hwang and Jeong-Won Lee

Pharmaceutics 2020, 12(10), 987; https://doi.org/10.3390/pharmaceutics12100987 - 19 Oct 2020

Cited by 6 | Viewed by 2892

Abstract

Purpose: To investigate the anti-cancer effects of tetraarsenic hexoxide (TAO, As₄O₆) in cervical cancer cell lines and in a series of patient-derived xenograft (PDX) mouse models. Methods: Human cervical cancer cell lines, including HeLa, SiHa and CaSki, and human [...] Read more.

Purpose: To investigate the anti-cancer effects of tetraarsenic hexoxide (TAO, As₄O₆) in cervical cancer cell lines and in a series of patient-derived xenograft (PDX) mouse models. Methods: Human cervical cancer cell lines, including HeLa, SiHa and CaSki, and human umbilical vein endothelial cells (HUVECs), were used to evaluate the anti-cancer activity of TAO. Cellular proliferation, apoptosis, and enzyme-linked immunosorbent assay (ELISA) for matrix metallopeptidase 2 (MMP-2) and 9 (MMP-9) were assessed. The tumor weights of the PDXs that were given TAO were measured. The PDXs included primary squamous cell carcinoma, primary adenocarcinoma, recurrent squamous cell carcinoma, and recurrent adenocarcinoma. Results: TAO significantly decreased cellular proliferation and increased apoptosis in cervical cancer cell lines and HUVEC. The functional studies on the cytotoxicity of TAO revealed that it inhibited the activation of Akt and vascular endothelial growth factor receptor 2 (VEGFR2). It also decreased the concentrations of MMP-2 in both cervical cancer cell lines and HUVECs. Active caspase-3 and p62 were both increased by the treatment of TAO, indicating increased rates of apoptosis and decreased rates of autophagy, respectively. In vivo studies with PDXs revealed that TAO significantly decreased tumor weight for both primary squamous cell carcinoma and adenocarcinoma of the cervix. However, this anti-cancer effect was not seen in PDXs with recurrent cancers. Nevertheless, the combination of TAO with cisplatin significantly decreased tumor weight in PDX models for both primary and recurrent cancers. Conclusions: TAO exerted inhibitory effects on angiogenesis, cellular migration, and autophagy, and it showed stimulatory effects on apoptosis. Overall, it demonstrated anti-cancer effects in animal models for human cervical cancer. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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17 pages, 2685 KiB

Open AccessArticle

Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer

by Ayman Abouzayed, Hanna Tano, Ábel Nagy, Sara S. Rinne, Fadya Wadeea, Sharmishtaa Kumar, Kristina Westerlund, Vladimir Tolmachev, Amelie Eriksson Karlström and Anna Orlova

Pharmaceutics 2020, 12(10), 977; https://doi.org/10.3390/pharmaceutics12100977 - 16 Oct 2020

Cited by 10 | Viewed by 4103

Abstract

The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂) to an [...] Read more.

The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC₅₀) of ^natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [¹¹¹In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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15 pages, 5099 KiB

Open AccessArticle

Deep Tumor Penetration of Doxorubicin-Loaded Glycol Chitosan Nanoparticles Using High-Intensity Focused Ultrasound

by Yongwhan Choi, Hyounkoo Han, Sangmin Jeon, Hong Yeol Yoon, Hyuncheol Kim, Ick Chan Kwon and Kwangmeyung Kim

Pharmaceutics 2020, 12(10), 974; https://doi.org/10.3390/pharmaceutics12100974 - 15 Oct 2020

Cited by 24 | Viewed by 3186

Abstract

The dense extracellular matrix (ECM) in heterogeneous tumor tissues can prevent the deep tumor penetration of drug-loaded nanoparticles, resulting in a limited therapeutic efficacy in cancer treatment. Herein, we suggest that the deep tumor penetration of doxorubicin (DOX)-loaded glycol chitosan nanoparticles (CNPs) can [...] Read more.

The dense extracellular matrix (ECM) in heterogeneous tumor tissues can prevent the deep tumor penetration of drug-loaded nanoparticles, resulting in a limited therapeutic efficacy in cancer treatment. Herein, we suggest that the deep tumor penetration of doxorubicin (DOX)-loaded glycol chitosan nanoparticles (CNPs) can be improved using high-intensity focused ultrasound (HIFU) technology. Firstly, we prepared amphiphilic glycol chitosan-5β-cholanic acid conjugates that can self-assemble to form stable nanoparticles with an average of 283.7 ± 5.3 nm. Next, the anticancer drug DOX was simply loaded into the CNPs via a dialysis method. DOX-loaded CNPs (DOX-CNPs) had stable nanoparticle structures with an average size of 265.9 ± 35.5 nm in aqueous condition. In cultured cells, HIFU-treated DOX-CNPs showed rapid drug release and enhanced cellular uptake in A549 cells, resulting in increased cytotoxicity, compared to untreated DOX-CNPs. In ECM-rich A549 tumor-bearing mice, the tumor-targeting efficacy of intravenously injected DOX-CNPs with HIFU treatment was 1.84 times higher than that of untreated DOX-CNPs. Furthermore, the deep tumor penetration of HIFU-treated DOX-CNPs was clearly observed at targeted tumor tissues, due to the destruction of the ECM structure via HIFU treatment. Finally, HIFU-treated DOX-CNPs greatly increased the therapeutic efficacy at ECM-rich A549 tumor-bearing mice, compared to free DOX and untreated DOX-CNPs. This deep penetration of drug-loaded nanoparticles via HIFU treatment is a promising strategy to treat heterogeneous tumors with dense ECM structures. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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17 pages, 3953 KiB

Open AccessArticle

A Tumor-Immune Interaction Model for Synergistic Combinations of Anti PD-L1 and Ionizing Irradiation Treatment

by Jong Hyuk Byun, In-Soo Yoon, Yong Dam Jeong, Sungchan Kim and Il Hyo Jung

Pharmaceutics 2020, 12(9), 830; https://doi.org/10.3390/pharmaceutics12090830 - 31 Aug 2020

Cited by 9 | Viewed by 3026

Abstract

Combination therapy with immune checkpoint blockade and ionizing irradiation therapy (IR) generates a synergistic effect to inhibit tumor growth better than either therapy does alone. We modeled the tumor-immune interactions occurring during combined IT and IR based on the published data from Deng [...] Read more.

Combination therapy with immune checkpoint blockade and ionizing irradiation therapy (IR) generates a synergistic effect to inhibit tumor growth better than either therapy does alone. We modeled the tumor-immune interactions occurring during combined IT and IR based on the published data from Deng et al. The mathematical model considered programmed cell death protein 1 and programmed death ligand 1, to quantify data fitting and global sensitivity of critical parameters. Fitting of data from control, IR and IT samples was conducted to verify the synergistic effect of a combination therapy consisting of IR and IT. Our approach using the model showed that an increase in the expression level of PD-1 and PD-L1 was proportional to tumor growth before therapy, but not after initiating therapy. The high expression level of PD-L1 in T cells may inhibit IT efficacy. After combination therapy begins, the tumor size was also influenced by the ratio of PD-1 to PD-L1. These results highlight that the ratio of PD-1 to PD-L1 in T cells could be considered in combination therapy. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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20 pages, 2660 KiB

Open AccessArticle

Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer

by Levente E. Dókus, Eszter Lajkó, Ivan Ranđelović, Diána Mező, Gitta Schlosser, László Kőhidai, József Tóvári and Gábor Mező

Pharmaceutics 2020, 12(6), 576; https://doi.org/10.3390/pharmaceutics12060576 - 22 Jun 2020

Cited by 25 | Viewed by 3732

Abstract

The Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most aggressive and dangerous cancerous diseases, leading to a high rate of mortality. Therefore, the development of new, more efficient treatment approaches is necessary to cure this illness. Peptide-based drug targeting provides a new [...] Read more.

The Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most aggressive and dangerous cancerous diseases, leading to a high rate of mortality. Therefore, the development of new, more efficient treatment approaches is necessary to cure this illness. Peptide-based drug targeting provides a new tool for this purpose. Previously, a hexapeptide Cys-Lys-Ala-Ala-Lys-Asn (CKAAKN) was applied efficiently as the homing device for drug-loaded nanostructures in PDAC cells. In this research, Cys was replaced by Ser in the sequence and this new SKAAKN targeting moiety was used in conjugates containing daunomycin (Dau). Five different structures were developed and tested. The results indicated that linear versions with one Dau were not effective on PANC-1 cells in vitro; however, branched conjugates with two Dau molecules showed significant antitumor activity. Differences in the antitumor effect of the conjugates could be explained with the different cellular uptake and lysosomal degradation. The most efficient conjugate was Dau=Aoa-GFLG-K(Dau=Aoa)SKAAKN-OH (conjugate 4) that also showed significant tumor growth inhibition on s.c. implanted PANC-1 tumor-bearing mice with negligible side effects. Our novel results suggest that peptide-based drug delivery systems could be a promising tool for the treatment of pancreatic cancers. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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16 pages, 8276 KiB

Open AccessArticle

Tumor-Homing pH-Sensitive Extracellular Vesicles for Targeting Heterogeneous Tumors

by Jaeduk Park, Hyuk Lee, Yu Seok Youn, Kyung Taek Oh and Eun Seong Lee

Pharmaceutics 2020, 12(4), 372; https://doi.org/10.3390/pharmaceutics12040372 - 17 Apr 2020

Cited by 26 | Viewed by 4040

Abstract

In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, [...] Read more.

In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, as a model antitumor drug). Consequently, HDEA/DOX anchored EVs (HDEA@EVs) can interact with origin tumor cells owing to EVs’ homing ability to origin cells. Therefore, EV blends of HDEA@BTEVs and HDEA@SKEVs demonstrate highly increased cellular uptake in both BT-474 and SK-N-MC cells: HDEA@BTEVs for BT-474 tumor cells and HDEA@SKEVs for SK-N-MC tumor cells. Furthermore, the hydrophobic HDEA present in HDEA@EVs at pH 7.4 can switch to hydrophilic HDEA at pH 6.5 as a result of acidic pH-induced protonation of 3-(diethylamino)propylamine (DEAP) moieties, resulting in an acidic pH-activated EVs’ disruption, accelerated release of encapsulated DOX molecules, and highly increased cell cytotoxicity. However, EV blends containing pH-insensitive HA grafted with deoxycholic acid (HDOC) (HDOC@BTEVs and HDOC@SKEVs) showed less cell cytotoxicity for both BT-474 and SK-N-MC tumor cells, because they did not act on EVs’ disruption and the resulting DOX release. Consequently, the use of these tumor-homing pH-sensitive EV blends may result in effective targeted therapies for various tumor cells. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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Review

Jump to: Editorial, Research

52 pages, 8206 KiB

Open AccessReview

Delivery of Natural Agents by Means of Mesoporous Silica Nanospheres as a Promising Anticancer Strategy

by Khaled AbouAitah and Witold Lojkowski

Pharmaceutics 2021, 13(2), 143; https://doi.org/10.3390/pharmaceutics13020143 - 22 Jan 2021

Cited by 35 | Viewed by 5194

Abstract

Natural prodrugs derived from different natural origins (e.g., medicinal plants, microbes, animals) have a long history in traditional medicine. They exhibit a broad range of pharmacological activities, including anticancer effects in vitro and in vivo. They have potential as safe, cost-effective treatments with [...] Read more.

Natural prodrugs derived from different natural origins (e.g., medicinal plants, microbes, animals) have a long history in traditional medicine. They exhibit a broad range of pharmacological activities, including anticancer effects in vitro and in vivo. They have potential as safe, cost-effective treatments with few side effects, but are lacking in solubility, bioavailability, specific targeting and have short half-lives. These are barriers to clinical application. Nanomedicine has the potential to offer solutions to circumvent these limitations and allow the use of natural pro-drugs in cancer therapy. Mesoporous silica nanoparticles (MSNs) of various morphology have attracted considerable attention in the search for targeted drug delivery systems. MSNs are characterized by chemical stability, easy synthesis and functionalization, large surface area, tunable pore sizes and volumes, good biocompatibility, controlled drug release under different conditions, and high drug-loading capacity, enabling multifunctional purposes. In vivo pre-clinical evaluations, a significant majority of results indicate the safety profile of MSNs if they are synthesized in an optimized way. Here, we present an overview of synthesis methods, possible surface functionalization, cellular uptake, biodistribution, toxicity, loading strategies, delivery designs with controlled release, and cancer targeting and discuss the future of anticancer nanotechnology-based natural prodrug delivery systems. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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24 pages, 1433 KiB

Open AccessReview

Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma

by Adriana G. Quiroz-Reyes, Jose F. Islas, Paulina Delgado-Gonzalez, Hector Franco-Villarreal and Elsa N. Garza-Treviño

Pharmaceutics 2021, 13(1), 103; https://doi.org/10.3390/pharmaceutics13010103 - 14 Jan 2021

Cited by 11 | Viewed by 3962

Abstract

Metastasis is the process of dissemination of a tumor, whereby cells from the primary site dislodge and find their way to other tissues where secondary tumors establish. Metastasis is the primary cause of death related to cancer. This process warrants changes in original [...] Read more.

Metastasis is the process of dissemination of a tumor, whereby cells from the primary site dislodge and find their way to other tissues where secondary tumors establish. Metastasis is the primary cause of death related to cancer. This process warrants changes in original tumoral cells and their microenvironment to establish a metastatic niche. Traditionally, cancer therapy has focused on metastasis prevention by systematic treatments or direct surgical re-sectioning. However, metastasis can still occur. More recently, new therapies direct their attention to targeting cancer stem cells. As they propose, these cells could be the orchestrators of the metastatic niche. In this review, we describe conventional and novel developments in cancer therapeutics for liver and lung metastasis. We further discuss the resistance mechanisms of targeted therapy, the advantages, and disadvantages of diverse treatment approaches, and future novel strategies to enhance cancer prognosis. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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49 pages, 1885 KiB

Open AccessReview

The Therapeutic Efficacy of Dendrimer and Micelle Formulations for Breast Cancer Treatment

by Sibusiso Alven and Blessing Atim Aderibigbe

Pharmaceutics 2020, 12(12), 1212; https://doi.org/10.3390/pharmaceutics12121212 - 15 Dec 2020

Cited by 51 | Viewed by 3664

Abstract

Breast cancer is among the most common types of cancer in women and it is the cause of a high rate of mortality globally. The use of anticancer drugs is the standard treatment approach used for this type of cancer. However, most of [...] Read more.

Breast cancer is among the most common types of cancer in women and it is the cause of a high rate of mortality globally. The use of anticancer drugs is the standard treatment approach used for this type of cancer. However, most of these drugs are limited by multi-drug resistance, drug toxicity, poor drug bioavailability, low water solubility, poor pharmacokinetics, etc. To overcome multi-drug resistance, combinations of two or more anticancer drugs are used. However, the combination of two or more anticancer drugs produce toxic side effects. Micelles and dendrimers are promising drug delivery systems that can overcome the limitations associated with the currently used anticancer drugs. They have the capability to overcome drug resistance, reduce drug toxicity, improve the drug solubility and bioavailability. Different classes of anticancer drugs have been loaded into micelles and dendrimers, resulting in targeted drug delivery, sustained drug release mechanism, increased cellular uptake, reduced toxic side effects of the loaded drugs with enhanced anticancer activity in vitro and in vivo. This review article reports the biological outcomes of dendrimers and micelles loaded with different known anticancer agents on breast cancer in vitro and in vivo. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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29 pages, 3628 KiB

Open AccessReview

Nanodelivery Systems Targeting Epidermal Growth Factor Receptors for Glioma Management

by Sathishbabu Paranthaman, Meghana Goravinahalli Shivananjegowda, Manohar Mahadev, Afrasim Moin, Shivakumar Hagalavadi Nanjappa, Nandakumar Dalavaikodihalli Nanjaiyah, Saravana Babu Chidambaram and Devegowda Vishakante Gowda

Pharmaceutics 2020, 12(12), 1198; https://doi.org/10.3390/pharmaceutics12121198 - 10 Dec 2020

Cited by 11 | Viewed by 3608

Abstract

A paradigm shift in treating the most aggressive and malignant form of glioma is continuously evolving; however, these strategies do not provide a better life and survival index. Currently, neurosurgical debulking, radiotherapy, and chemotherapy are the treatment options available for glioma, but these [...] Read more.

A paradigm shift in treating the most aggressive and malignant form of glioma is continuously evolving; however, these strategies do not provide a better life and survival index. Currently, neurosurgical debulking, radiotherapy, and chemotherapy are the treatment options available for glioma, but these are non-specific in action. Patients invariably develop resistance to these therapies, leading to recurrence and death. Receptor Tyrosine Kinases (RTKs) are among the most common cell surface proteins in glioma and play a significant role in malignant progression; thus, these are currently being explored as therapeutic targets. RTKs belong to the family of cell surface receptors that are activated by ligands which in turn activates two major downstream signaling pathways via Rapidly Accelerating Sarcoma/mitogen activated protein kinase/extracellular-signal-regulated kinase (Ras/MAPK/ERK) and phosphatidylinositol 3-kinase/a serine/threonine protein kinase/mammalian target of rapamycin (PI3K/AKT/mTOR). These pathways are critically involved in regulating cell proliferation, invasion, metabolism, autophagy, and apoptosis. Dysregulation in these pathways results in uncontrolled glioma cell proliferation, invasion, angiogenesis, and cancer progression. Thus, RTK pathways are considered a potential target in glioma management. This review summarizes the possible risk factors involved in the growth of glioblastoma (GBM). The role of RTKs inhibitors (TKIs) and the intracellular signaling pathways involved, small molecules under clinical trials, and the updates were discussed. We have also compiled information on the outcomes from the various endothelial growth factor receptor (EGFR)–TKIs-based nanoformulations from the preclinical and clinical points of view. Aided by an extensive literature search, we propose the challenges and potential opportunities for future research on EGFR–TKIs-based nanodelivery systems. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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38 pages, 4532 KiB

Open AccessReview

Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research

by Bárbara Pinto, Ana C. Henriques, Patrícia M. A. Silva and Hassan Bousbaa

Pharmaceutics 2020, 12(12), 1186; https://doi.org/10.3390/pharmaceutics12121186 - 6 Dec 2020

Cited by 238 | Viewed by 11040

Abstract

Most cancer biologists still rely on conventional two-dimensional (2D) monolayer culture techniques to test in vitro anti-tumor drugs prior to in vivo testing. However, the vast majority of promising preclinical drugs have no or weak efficacy in real patients with tumors, thereby delaying [...] Read more.

Most cancer biologists still rely on conventional two-dimensional (2D) monolayer culture techniques to test in vitro anti-tumor drugs prior to in vivo testing. However, the vast majority of promising preclinical drugs have no or weak efficacy in real patients with tumors, thereby delaying the discovery of successful therapeutics. This is because 2D culture lacks cell–cell contacts and natural tumor microenvironment, important in tumor signaling and drug response, thereby resulting in a reduced malignant phenotype compared to the real tumor. In this sense, three-dimensional (3D) cultures of cancer cells that better recapitulate in vivo cell environments emerged as scientifically accurate and low cost cancer models for preclinical screening and testing of new drug candidates before moving to expensive and time-consuming animal models. Here, we provide a comprehensive overview of 3D tumor systems and highlight the strategies for spheroid construction and evaluation tools of targeted therapies, focusing on their applicability in cancer research. Examples of the applicability of 3D culture for the evaluation of the therapeutic efficacy of nanomedicines are discussed. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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20 pages, 1792 KiB

Open AccessReview

Extracellular Vesicles as Drug Delivery Systems in Cancer

by Laia Hernandez-Oller, Joaquin Seras-Franzoso, Fernanda Andrade, Diana Rafael, Ibane Abasolo, Petra Gener and Simo Schwartz Jr.

Pharmaceutics 2020, 12(12), 1146; https://doi.org/10.3390/pharmaceutics12121146 - 26 Nov 2020

Cited by 27 | Viewed by 3364

Abstract

Within tumors, Cancer Stem Cell (CSC) subpopulation has an important role in maintaining growth and dissemination while preserving high resistance against current treatments. It has been shown that, when CSCs are eliminated, the surrounding Differentiated Cancer Cells (DCCs) may reverse their phenotype and [...] Read more.

Within tumors, Cancer Stem Cell (CSC) subpopulation has an important role in maintaining growth and dissemination while preserving high resistance against current treatments. It has been shown that, when CSCs are eliminated, the surrounding Differentiated Cancer Cells (DCCs) may reverse their phenotype and gain CSC-like features to preserve tumor progression and ensure tumor survival. This strongly suggests the existence of paracrine communication within tumor cells. It is evidenced that the molecular crosstalk is at least partly mediated by Extracellular Vesicles (EVs), which are cell-derived membranous nanoparticles that contain and transport complex molecules that can affect and modify the biological behavior of distal cells and their molecular background. This ability of directional transport of small molecules prospects EVs as natural Drug Delivery Systems (DDS). EVs present inherent homing abilities and are less immunogenic than synthetic nanoparticles, in general. Currently, strong efforts are focused into the development and improvement of EV-based DDS. Even though EV-DDS have already reached early phases in clinical trials, their clinical application is still far from commercialization since protocols for EVs loading, modification and isolation need to be standardized for large-scale production. Here, we summarized recent knowledge regarding the use of EVs as natural DDS against CSCs and cancer resistance. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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Open AccessReview

Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy

by Guillaume Sicard, Frédéric Fina, Raphaelle Fanciullino, Fabrice Barlesi and Joseph Ciccolini

Pharmaceutics 2020, 12(8), 758; https://doi.org/10.3390/pharmaceutics12080758 - 11 Aug 2020

Cited by 7 | Viewed by 3356

Abstract

Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than [...] Read more.

Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal time-window to combine immune checkpoint inhibitors with other drugs. In this review, we present the various putative markers that have been investigated as predictive tools with immune checkpoint inhibitors and could be used to help further combining treatments. Whereas none of the current biomarkers, such as the PDL1 expression of a tumor mutational burden, is suitable to identify the best way to combine treatments, monitoring circulating tumor DNA is a promising strategy, in particular to check whether the STING-cGAS pathway has been activated by cytotoxics. As such, circulating tumor DNA could help defining the best time-window to administrate immune checkpoint inhibitors after that cytotoxics have been given. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies)

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