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19 pages, 2252 KiB

Open AccessArticle

Mitoxantrone-Loaded Nanoparticles for Magnetically Controlled Tumor Therapy–Induction of Tumor Cell Death, Release of Danger Signals and Activation of Immune Cells

by Teresa Ratschker, Laura Egenberger, Magdalena Alev, Lisa Zschiesche, Julia Band, Eveline Schreiber, Benjamin Frey, Anja Derer, Christoph Alexiou and Christina Janko

Pharmaceutics 2020, 12(10), 923; https://doi.org/10.3390/pharmaceutics12100923 - 27 Sep 2020

Cited by 7 | Viewed by 2349

Abstract

Stimulating the patient’s immune system represents a promising therapeutic strategy to fight cancer. However, low immunogenicity of the tumor cells within an immune suppressive milieu often leads to weak anti-tumor immune responses. Additionally, the immune system may be impaired by accompanying aggressive chemotherapies. [...] Read more.

Stimulating the patient’s immune system represents a promising therapeutic strategy to fight cancer. However, low immunogenicity of the tumor cells within an immune suppressive milieu often leads to weak anti-tumor immune responses. Additionally, the immune system may be impaired by accompanying aggressive chemotherapies. We show that mitoxantrone, bound to superparamagnetic iron oxide nanoparticles (SPIONs) as the transport system, can be magnetically accumulated in adherent HT-29 colon carcinoma cells, thereby inducing the same cell death phenotype as its soluble counterpart, a chemotherapeutic agent and prototypic inductor of immunogenic cell death. The nanoparticle-loaded drug induces cell cycle stop, apoptosis and secondary necrosis in a dose- and time-dependent manner comparable to the free drug. Cell death was accompanied by the release of interleukin-8 and damage-associated molecular patterns (DAMPs) such as HSP70 and ATP, which fostered chemotactic migration of monocytes and maturation of dendritic cells. We furthermore ensured absence of endotoxin contaminations and compatibility with erythrocytes and platelets and investigated the influence on plasma coagulation in vitro. Summarizing, with magnetic enrichment, mitoxantrone can be accumulated at the desired place, sparing healthy peripheral cells and tissues, such as immune cells. Conserving immune competence in cancer patients in the future might allow combined therapeutic approaches with immune therapies (e.g., checkpoint inhibitors). Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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14 pages, 2514 KiB

Open AccessArticle

Optimized Polyethylene Glycolylated Polymer–Lipid Hybrid Nanoparticles as a Potential Breast Cancer Treatment

by Salam Massadeh, Mustafa E Omer, Asmaa Alterawi, Rizwan Ali, Fayez H Alanazi, Fares Almutairi, Wejdan Almotairi, Faris F Alobaidi, Khulud Alhelal, Mansour S Almutairi, Abdulaziz Almalik, Aiman A. Obaidat, Manal Alaamery and Alaa Eldeen Yassin

Pharmaceutics 2020, 12(7), 666; https://doi.org/10.3390/pharmaceutics12070666 - 15 Jul 2020

Cited by 20 | Viewed by 3882

Abstract

Purpose: The aim of this work is to optimize a polyethylene glycolated (PEGylated) polymer–lipid hybrid nanoparticulate system for the delivery of anastrozole (ANS) to enhance its biopharmaceutical attributes and overall efficacy. Methods: ANS loaded PEGylated polymer–lipid hybrid nanoparticles (PLNPs) were prepared by a [...] Read more.

Purpose: The aim of this work is to optimize a polyethylene glycolated (PEGylated) polymer–lipid hybrid nanoparticulate system for the delivery of anastrozole (ANS) to enhance its biopharmaceutical attributes and overall efficacy. Methods: ANS loaded PEGylated polymer–lipid hybrid nanoparticles (PLNPs) were prepared by a direct emulsification solvent evaporation method. The physical incorporation of PEG was optimized using variable ratios. The produced particles were evaluated to discern their particle size and shape, zeta-potential, entrapment efficiency, and physical stability. The drug-release profiles were studied, and the kinetic model was analyzed. The anticancer activity of the ANS PLNPs on estrogen-positive breast cancer cell lines was determined using flow cytometry. Results: The prepared ANS-PLNPs showed particle sizes in the range of 193.6 ± 2.9 to 218.2 ± 1.9 nm, with good particle size uniformity (i.e., poly-dispersity index of around 0.1). Furthermore, they exhibited relatively low zeta-potential values ranging from −0.50 ± 0.52 to 6.01 ± 4.74. The transmission electron microscopy images showed spherical shape of ANS-PLNPs and the compliance with the sizes were revealed by light scattering. The differential scanning calorimetry DSC patterns of the ANS PLNPs revealed a disappearance of the characteristic sharp melting peak of pure ANS, supporting the incorporation of the drug into the polymeric matrices of the nanoparticles. Flow cytometry showed the apoptosis of MCF-7 cell lines in the presence of ANS-PLNPs. Conclusion: PEGylated polymeric nanoparticles presented a stable encapsulated system with which to incorporate an anticancer drug (ANS) with a high percentage of entrapment efficiency (around 80%), good size uniformity, and induction of apoptosis in MCF-7 cells. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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16 pages, 8806 KiB

Open AccessArticle

Evaluation of Novel Doxorubicin-Loaded Magnetic Wax Nanocomposite Vehicles as Cancer Combinatorial Therapy Agents

by Julia Jiménez-López, Lorena García-Hevia, Consolación Melguizo, Jose Prados, Manuel Bañobre-López and Juan Gallo

Pharmaceutics 2020, 12(7), 637; https://doi.org/10.3390/pharmaceutics12070637 - 07 Jul 2020

Cited by 6 | Viewed by 2934

Abstract

The development of nanotechnology-based solutions for cancer at a preclinical level advances at an astounding pace. So far, clinical translation of these new developments has not been able to keep the pace due to a range of different reasons. One of them is [...] Read more.

The development of nanotechnology-based solutions for cancer at a preclinical level advances at an astounding pace. So far, clinical translation of these new developments has not been able to keep the pace due to a range of different reasons. One of them is the mismatch between in vitro and in vivo results coming from the expected difference in complexity. To overcome this problem, extensive characterisation using advanced in vitro models can lead to stronger preliminary data to face in vivo tests. Here, a comprehensive in vitro validation of a combinatorial therapy nanoformulation against solid tumours is presented. The information extracted from the different in vitro models highlights the importance of advanced 3D models to fully understand the potential of this type of complex drugs. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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14 pages, 3331 KiB

Open AccessArticle

Tumor-Targeting Glycol Chitosan Nanoparticles for Image-Guided Surgery of Rabbit Orthotopic VX2 Lung Cancer

by Kyeong Cheol On, Jiyun Rho, Hong Yeol Yoon, Hyeyoun Chang, Ji Young Yhee, Jun Sik Yoon, Seo Young Jeong, Hyun Koo Kim and Kwangmeyung Kim

Pharmaceutics 2020, 12(7), 621; https://doi.org/10.3390/pharmaceutics12070621 - 03 Jul 2020

Cited by 14 | Viewed by 3075

Abstract

Theranostic nanoparticles can deliver therapeutic agents as well as diverse imaging agents to tumors. The enhanced permeation and retention (EPR) effect is regarded as a crucial mechanism for the tumor-targeted delivery of nanoparticles. Although a large number of studies of the EPR effect [...] Read more.

Theranostic nanoparticles can deliver therapeutic agents as well as diverse imaging agents to tumors. The enhanced permeation and retention (EPR) effect is regarded as a crucial mechanism for the tumor-targeted delivery of nanoparticles. Although a large number of studies of the EPR effect of theranostic nanoparticles have been performed, the effect of the change in the body size of the host on the EPR effect is not fully understood. In this regard, comparative research is needed on the behavior of nanoparticles in large animals for developing the nanoparticles to the clinical stage. In this study, we prepared fluorophore (indocyanine green (ICG) or cyanine 5.5 (Cy5.5))–conjugated glycol chitosan nanoparticles (CNPs) for comparing the tumor-targeting efficacy in VX2 tumor-bearing mouse and rabbit models. As expected, the CNPs formed nano-sized spherical nanoparticles and were stable for 8 days under aqueous conditions. The CNPs also exhibited dose-dependent cellular uptake into VX2 tumor cells without cytotoxicity. The half-life of the near-infrared fluorescence (NIRF) signals in the blood were 3.25 h and 4.73 h when the CNPs were injected into mice and rabbits, respectively. Importantly, the CNPs showed excellent tumor accumulation and prolonged biodistribution profiles in both the VX2 tumor-bearing mouse and rabbit models, wherein the tumor accumulation was maximized at 48 h and 72 h, respectively. Based on the excellent tumor accumulation of the CNPs, finally, the CNPs were used in the image-guided surgery of the rabbit orthotopic VX2 lung tumor model. The lung tumor tissue was successfully removed based on the NIRF signal from the CNPs in the tumor tissue. This study shows that CNPs can be potentially used for tumor theragnosis in small animals and large animals. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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20 pages, 3901 KiB

Open AccessArticle

Biomimetic Magnetoliposomes as Oxaliplatin Nanocarriers: In Vitro Study for Potential Application in Colon Cancer

by Beatriz Garcia-Pinel, Ylenia Jabalera, Raul Ortiz, Laura Cabeza, Concepción Jimenez-Lopez, Consolación Melguizo and Jose Prados

Pharmaceutics 2020, 12(6), 589; https://doi.org/10.3390/pharmaceutics12060589 - 24 Jun 2020

Cited by 28 | Viewed by 3471

Abstract

Current chemotherapy for colorectal cancer (CRC) includes the use of oxaliplatin (Oxa), a first-line cytotoxic drug which, in combination with irinotecan/5-fluorouracil or biologic agents, increases the survival rate of patients. However, the administration of this drug induces side effects that limit its application [...] Read more.

Current chemotherapy for colorectal cancer (CRC) includes the use of oxaliplatin (Oxa), a first-line cytotoxic drug which, in combination with irinotecan/5-fluorouracil or biologic agents, increases the survival rate of patients. However, the administration of this drug induces side effects that limit its application in patients, making it necessary to develop new tools for targeted chemotherapy. MamC-mediated biomimetic magnetic nanoparticles coupled with Oxa (Oxa-BMNPs) have been previously demonstrated to efficiently reduce the IC₅₀ compared to that of soluble Oxa. However, their strong interaction with the macrophages revealed toxicity and possibility of aggregation. In this scenario, a further improvement of this nanoassembly was necessary. In the present study, Oxa-BMNPs nanoassemblies were enveloped in phosphatidylcholine unilamellar liposomes (both pegylated and non-pegylated). Our results demonstrate that the addition of both a lipid cover and further pegylation improves the biocompatibility and cellular uptake of the Oxa-BMNPs nanoassemblies without significantly reducing their cytotoxic activity in colon cancer cells. In particular, with the pegylated magnetoliposome nanoformulation (a) hemolysis was reduced from 5% to 2%, being now hematocompatibles, (b) red blood cell agglutination was reduced, (c) toxicity in white blood cells was eliminated. This study represents a truly stepforward in this area as describes the production of one of the very few existing nanoformulations that could be used for a local chemotherapy to treat CRC. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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18 pages, 4757 KiB

Open AccessArticle

Injectable SN-38-embedded Polymeric Microparticles Promote Antitumor Efficacy against Malignant Glioma in an Animal Model

by Yuan-Yun Tseng, Tao-Chieh Yang, Shu-Mei Chen, Shun-Tai Yang, Ya-Ling Tang and Shih-Jung Liu

Pharmaceutics 2020, 12(5), 479; https://doi.org/10.3390/pharmaceutics12050479 - 24 May 2020

Cited by 7 | Viewed by 2894

Abstract

Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of [...] Read more.

Malignant glioma (MG) is extremely aggressive and highly resistant to chemotherapeutic agents. Using electrospraying, the potent chemotherapeutic agent 7-ethyl-10-hydroxycamptothecia (SN-38) was embedded into 50:50 biodegradable poly[(d,l)-lactide-co-glycolide] (PLGA) microparticles (SMPs). The SMPs were stereotactically injected into the brain parenchyma of healthy rats and intratumorally injected into F98 glioma-bearing rats for estimating the pharmacodynamics and therapeutic efficacy. SN-38 was rapidly released after injection and its local (brain tissue) concentration remained much higher than that in the blood for more than 8 weeks. Glioma-bearing rats were divided into three groups—group A (n = 13; stereotactically injected pure PLGA microparticles), group B (n = 12; stereotactically injected Gliadel wafer and oral temozolomide), and group C (n = 13; stereotactic and intratumoral introduction of SMPs). The SMPs exhibited significant therapeutic efficacy, with prolonged survival, retarded tumor growth, and attenuated malignancy. The experimental results demonstrated that SMPs provide an effective and potential strategy for the treatment of MG. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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24 pages, 5239 KiB

Open AccessArticle

Targeting the Tumor Microenvironment with Fluorescence-Activatable Bispecific Endoglin/Fibroblast Activation Protein Targeting Liposomes

by Felista L. Tansi, Ronny Rüger, Ansgar M. Kollmeier, Markus Rabenhold, Frank Steiniger, Roland E. Kontermann, Ulf K. Teichgräber, Alfred Fahr and Ingrid Hilger

Pharmaceutics 2020, 12(4), 370; https://doi.org/10.3390/pharmaceutics12040370 - 17 Apr 2020

Cited by 12 | Viewed by 3735

Abstract

Liposomes are biocompatible nanocarriers with promising features for targeted delivery of contrast agents and drugs into the tumor microenvironment, for imaging and therapy purposes. Liposome-based simultaneous targeting of tumor associated fibroblast and the vasculature is promising, but the heterogeneity of tumors entails a [...] Read more.

Liposomes are biocompatible nanocarriers with promising features for targeted delivery of contrast agents and drugs into the tumor microenvironment, for imaging and therapy purposes. Liposome-based simultaneous targeting of tumor associated fibroblast and the vasculature is promising, but the heterogeneity of tumors entails a thorough validation of suitable markers for targeted delivery. Thus, we elucidated the potential of bispecific liposomes targeting the fibroblast activation protein (FAP) on tumor stromal fibroblasts, together with endoglin which is overexpressed on tumor neovascular cells and some neoplastic cells. Fluorescence-quenched liposomes were prepared by hydrating a lipid film with a high concentration of the self-quenching near-infrared fluorescent dye, DY-676-COOH, to enable fluorescence detection exclusively upon liposomal degradation and subsequent activation. A non-quenched green fluorescent phospholipid was embedded in the liposomal surface to fluorescence-track intact liposomes. FAP- and murine endoglin-specific single chain antibody fragments were coupled to the liposomal surface, and the liposomal potentials validated in tumor cells and mice models. The bispecific liposomes revealed strong fluorescence quenching, activatability, and selectivity for target cells and delivered the encapsulated dye selectively into tumor vessels and tumor associated fibroblasts in xenografted mice models and enabled their fluorescence imaging. Furthermore, detection of swollen lymph nodes during intra-operative simulations was possible. Thus, the bispecific liposomes have potentials for targeted delivery into the tumor microenvironment and for image-guided surgery. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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20 pages, 2498 KiB

Open AccessArticle

Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells

by Gamal-Eldein Fathy Abd-Ellatef, Elena Gazzano, Daniela Chirio, Ahmed Ragab Hamed, Dimas Carolina Belisario, Carlo Zuddas, Elena Peira, Barbara Rolando, Joanna Kopecka, Mohamed Assem Said Marie, Simona Sapino, Sohair Ramadan Fahmy, Marina Gallarate, Abdel-Hamid Zaki Abdel-Hamid and Chiara Riganti

Pharmaceutics 2020, 12(2), 96; https://doi.org/10.3390/pharmaceutics12020096 - 24 Jan 2020

Cited by 82 | Viewed by 5435

Abstract

Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest [...] Read more.

Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5–10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-β/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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22 pages, 7141 KiB

Open AccessArticle

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study

by Wenbo Zhan

Pharmaceutics 2020, 12(1), 69; https://doi.org/10.3390/pharmaceutics12010069 - 15 Jan 2020

Cited by 7 | Viewed by 3885

Abstract

Focused ultrasound (FUS) coupled with microbubbles (MB) has been found to be a promising approach to disrupt the blood-brain barrier (BBB). However, how this disruption affects drug transport remains unclear. In this study, drug transport in combination therapy of liposomes and FUS-MB-induced BBB [...] Read more.

Focused ultrasound (FUS) coupled with microbubbles (MB) has been found to be a promising approach to disrupt the blood-brain barrier (BBB). However, how this disruption affects drug transport remains unclear. In this study, drug transport in combination therapy of liposomes and FUS-MB-induced BBB disruption (BBBD) was investigated based on a multiphysics model. A realistic 3D brain tumour model extracted from MR images was applied. The results demonstrated the advantage of liposomes compared to free doxorubicin injection in further improving treatment when the BBB is opened under the same delivery conditions using burst sonication. This improvement was mainly due to the BBBD-enhanced transvascular transport of free doxorubicin and the sustainable supply of the drug by long-circulating liposomes. Treatment efficacy can be improved in different ways. Disrupting the BBB simultaneously with liposome bolus injection enables more free drug molecules to cross the vessel wall, while prolonging the BBBD duration could accelerate liposome transvascular transport for more effective drug release. However, the drug release rate needs to be well controlled to balance the trade-off among drug release, transvascular exchange and elimination. The results obtained in this study could provide suggestions for the future optimisation of this FUS-MB–liposome combination therapy against brain cancer. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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Review

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23 pages, 996 KiB

Open AccessReview

Hyperthermia and Temperature-Sensitive Nanomaterials for Spatiotemporal Drug Delivery to Solid Tumors

by Mohamadreza Amin, Wenqiu Huang, Ann L. B. Seynhaeve and Timo L. M. ten Hagen

Pharmaceutics 2020, 12(11), 1007; https://doi.org/10.3390/pharmaceutics12111007 - 22 Oct 2020

Cited by 42 | Viewed by 3769

Abstract

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using [...] Read more.

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli. Among different stimuli, interests for application of external heat, hyperthermia, is growing. Advanced technology, ease of application and most importantly high level of control over applied heat, and as a result triggered release, and the adjuvant effect of hyperthermia in enhancing therapeutic response of chemotherapeutics, i.e., thermochemotherapy, make hyperthermia a great stimulus for triggered drug release. Therefore, a variety of temperature sensitive nano-carriers, lipid or/and polymeric based, have been fabricated and studied. Importantly, in order to achieve an efficient therapeutic outcome, and taking the advantages of thermochemotherapy into consideration, release characteristics from nano-carriers should fit with applicable clinical thermal setting. Here we introduce and discuss the application of the three most studied temperature sensitive nanoparticles with emphasis on release behavior and its importance regarding applicability and therapeutic potentials. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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21 pages, 4946 KiB

Open AccessReview

Mesoporous Silica Nanoparticles for Co-Delivery of Drugs and Nucleic Acids in Oncology: A Review

by Juan L. Paris and María Vallet-Regí

Pharmaceutics 2020, 12(6), 526; https://doi.org/10.3390/pharmaceutics12060526 - 08 Jun 2020

Cited by 57 | Viewed by 5346

Abstract

Mesoporous silica nanoparticles have attracted much attention in recent years as drug and gene delivery systems for biomedical applications. Among their most beneficial features for biomedicine, we can highlight their biocompatibility and their outstanding textural properties, which provide a great loading capacity for [...] Read more.

Mesoporous silica nanoparticles have attracted much attention in recent years as drug and gene delivery systems for biomedical applications. Among their most beneficial features for biomedicine, we can highlight their biocompatibility and their outstanding textural properties, which provide a great loading capacity for many types of cargos. In the context of cancer nanomedicine, combination therapy and gene transfection/silencing have recently been highlighted as two of its most promising fields. In this review, we aim to provide an overview of the different small molecule drug-nucleic acid co-delivery combinations that have been developed using mesoporous silica nanoparticles as carriers. By carefully selecting the chemotherapeutic drug and nucleic acid cargos to be co-delivered by mesoporous silica nanoparticles, different therapeutic goals can be achieved by overcoming resistance mechanisms, combining different cytotoxic mechanisms, or providing an additional antiangiogenic effect. The examples here presented highlight the great promise of this type of strategies for the development of future therapeutics. Full article

(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)

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