scholarly journals A Mathematical Model for Thermosensitive Liposomal Delivery of Doxorubicin to Solid Tumour

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Wenbo Zhan ◽  
Xiao Yun Xu
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Solid Tumour ◽  
Transport Processes ◽  
Direct Infusion ◽  
Biochemical Processes ◽  
Normal Tissues ◽  
Thermosensitive Liposome ◽  
Anticancer Treatment

The effectiveness of anticancer treatments is often hampered by the serious side effects owing to toxicity of anticancer drugs and their undesirable uptake by healthy cells in vivo. Thermosensitive liposome-mediated drug delivery has been developed as part of research efforts aimed at improving therapeutic efficacy while reducing the associated side effect. Since multiple steps are involved in the transport of drug-loaded liposomes, drug release, and its uptake, mathematical models become an indispensible tool to analyse the transport processes and predict the outcome of anticancer treatment. In this study, a computational model is developed which incorporates the key physical and biochemical processes involved in drug delivery and cellular uptake. The model has been applied to idealized tumour geometry, and comparisons are made between continuous infusion of doxorubicin and thermosensitive liposome-mediated delivery. Results show that thermosensitive liposome-mediated delivery performs better in reducing drug concentration in normal tissues, which may help lower the risk of associated side effects. Compared with direct infusion over a 2-hour period, thermosensitive liposome delivery leads to a much higher peak intracellular concentration of doxorubicin, which may increase cell killing in tumour thereby enhancing the therapeutic effect of the drug.

Cancer Nanotheranostics: A Nanomedicinal Approach for Cancer Therapy and Diagnosis

2020 ◽  
Vol 20 (11) ◽  
pp. 1288-1299
Author(s):  
Paromita Kundu ◽  
Deepika Singh ◽  
Abhalaxmi Singh ◽  
Sanjeeb K. Sahoo
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Cancer Diagnosis ◽  
Specific Drug ◽  
Novel Therapies ◽  
Future Directions ◽  
Normal Tissues ◽  
Cancer Management ◽  
Single Probe ◽  
Therapy And Diagnosis

The panorama of cancer treatment has taken a considerable leap over the last decade with the advancement in the upcoming novel therapies combined with modern diagnostics. Nanotheranostics is an emerging science that holds tremendous potential as a contrivance by integrating therapy and imaging in a single probe for cancer diagnosis and treatment thus offering the advantage like tumor-specific drug delivery and at the same time reduced side effects to normal tissues. The recent surge in nanomedicine research has also paved the way for multimodal theranostic nanoprobe towards personalized therapy through interaction with a specific biological system. This review presents an overview of the nano theranostics approach in cancer management and a series of different nanomaterials used in theranostics and the possible challenges with future directions.

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

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1212
Author(s):  
Sibusiso Alven ◽  
Blessing Atim Aderibigbe
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Drug Resistance ◽  
Side Effects ◽  
Anticancer Drugs ◽  
Drug Toxicity ◽  
Multi Drug Resistance ◽  
Drug Bioavailability

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.

scholarly journals SCIDOT-28. TARGETED NANOPARTICLES FOR IMPROVED DRUG DELIVERY TO MEDULLOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi277-vi277
Author(s):  
Joelle P Straehla ◽  
Natalie Boehnke ◽  
Tamara G Dacoba ◽  
Paula T Hammond
Keyword(s):  
Drug Delivery ◽  
Endothelial Cells ◽  
Side Effects ◽  
Tumor Cells ◽  
Chemical Engineering ◽  
Xenograft Model ◽  
In Vivo Studies ◽  
Layer By Layer

Abstract Platinum-based agents remain a key component of therapy for children with medulloblastoma, despite significant systemic side effects and only modest blood-brain barrier (BBB) penetration. Cisplatin has a cerebrospinal fluid-to-plasma ratio <5% and dose-limiting side effects of nephrotoxicity, ototoxicity, and myelosuppression. Improving delivery of cisplatin across the BBB and selectively accumulating in tumors could improve its therapeutic index. To this end, we are leveraging chemical engineering techniques to rationally design cisplatin nanoparticles (NPs) to cross the BBB and preferentially enter medulloblastoma tumor cells. Using the layer-by-layer (LbL) platform to ‘wrap’ polyelectrolytes around a NP core by iterative electrostatic adsorption, we screened six negatively charged polypeptide and polysaccharide outer layers in medulloblastoma cell lines. Poly-L-aspartic acid (PLD) layered NPs had significant accumulation in tumor cells after 24 hours incubation, with an uptake index of 18±4 over unlayered control NPs. Next, we generated propargyl-functionalized PLD and used click chemistry to covalently conjugate the BBB shuttle ligands glutathione, angiopep-2, and transferrin, which have been shown to mediate transcytosis across brain endothelial cells. PLD layered NPs functionalized with angiopep-2 and transferrin had enhanced uptake in medulloblastoma tumor cells and NPs functionalized with glutathione were non-inferior to PLD layered NPs. After incubation with endothelial cells in vitro, all three BBB shuttle ligands enhanced uptake of PLD layered NPs over unlayered and non-functionalized control NPs. We then incorporated cisplatin into the nanoparticle core of this platform. Cisplatin-loaded NPs with PLD layering and ligand functionalization were more effective than free cisplatin as measured by IC50 over 72 hours in culture, and led to faster apoptosis as assessed by flow cytometry with annexin V and propidium iodide staining. In summary, functionalized nanoparticles are a promising platform to modulate drug delivery to medulloblastoma. In vivo studies using an orthotopic xenograft model are underway to investigate biodistribution, efficacy, and toxicity.

Anti-CD38 Targeted Nanoparticles for Drug Delivery in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2135-2135 ◽  
Author(s):  
Pilar De La Puente ◽  
Abbey Jin ◽  
Micah John Luderer ◽  
Barbara Muz ◽  
Justin A King ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Delivery ◽  
Therapeutic Efficacy ◽  
Research Funding ◽  
Free Drug ◽  
Targeted Nanoparticles ◽  
Normal Tissues ◽  
Kinetics Of

Abstract INTRODUCTION: The main limiting factor for the treatment with chemotherapies in multiple myeloma (MM) is the lack of specificity of the drugs. We propose the use of chitosan nanoparticles (cNPS) as specific and targeted drug delivery in MM using CD38 as targeting moiety. CD38 has been used as a therapeutic target in MM; anti-CD38 monoclonal antibodies are showing promising results of selective and efficient treatment of MM in preclinical studies and in early clinical trials. Moreover, we have recently shown that while the expression of several plasma cell markers such as CD138, CD56, and CD20 changed in different stages of the disease, CD38 is constantly expressed on all forms of MM cells. We hypothesize that the anti-CD38 targeted nanoparticles (CD38-NPs) will specifically deliver therapeutic agents to MM cells, thus improve therapeutic efficacy and reduce side effects. METHODS & RESULTS: cNPs were developed by ionic crosslinking and characterized by dynamic light scattering. A successful method to detect Bortezomib (Btz) by HPLC was developed and the encapsulation efficiency of Btz in cNPs was high (85%) after direct dispersion previous crosslinking. Stability (>30mV) and size (50nm) were not affected by drug loading and were constant for over a 2 month period at 4°C. The release kinetics of Btz from cNPs in different environments was investigated and found that our deliver system preferentially release drugs in tumor microenvironments; the tumor-like acidic pH (6.5-7.1) in MM conditioned media induced faster drug release (2.7-4.5 fold) than neutral pH representing blood and normal tissues. Then, the specificity and the kinetics of the binding of CD38-NPs to MM cells were investigated in vitro. The binding of CD38-NPs was significantly higher in MM cell lines and primary MM cells compared to normal mononuclear cells (MNCs) from peripheral blood and bone marrow. We further confirmed that CD38-NPs bind through CD38 within 2-3 hours, and the nanoparticles did not dissociate at least up to 24h after binding. Moreover, we tested the biodistribution and specificity of fluorescently labeled CD38-NPs in MM tumors models in vivo compared to the free dye and non-targeted cNPs; we found that free dye and non-targeted particles had random biodistribution in different normal tissues; while the CD38-NPs specifically bind the MM cells. Finally, the therapeutic efficacy of Btz-loaded CD38-NPs was assessed in vitro in the treatment of MM compared to free drug. Btz-loaded CD38-NPs induced significantly more killing and downregulation of pAKT in MM cell lines compared to free drug, while it did not affect MNCs. While 2.5nM free Btz induced almost no effect on MM cells, equivalent 2.5nM Btz-loaded CD38-NPs induced a profound killing of more than 50% of the MM cells. Btz-loaded CD38-NPs also led to the induction of a sub-G1 cell cycle arrest, which indicated accumulating apoptotic cells, decreased the percentage of cells in G2/M compared to free drug, and the effect was confirmed by specific signaling with reduced transition cell cycle proteins (pRb). We also found that Btz-loaded CD38-NPs significantly increased apoptosis and cell death (using Annexin/ PI assay) compared to free drug, which was confirmed by increased cleavage of caspase-3 and PARP. We also corroborated that empty (not drug loaded) CD38-NPs had no effect on survival, cell cycle, and apoptosis. Therefore, Btz-loaded CD38-NPs affected proliferation, cell cycle and apoptosis more profoundly compared to free Btz. Moreover, in vivo experiments to evaluate the efficacy and the toxicity of the Btz-loaded CD38-NPs compared with free Btz are ongoing. CONCLUSIONS: CD38-NPs were prepared, characterized, and showed to be stable over at least 2 months after preparation. The particles had preferential Btz release in tumor-microenvironment compared to blood and normal tissue microenvironment, due to differences in acidity of the medium. CD38-NPs were shown to specifically bind to MM cells through surface CD38 receptors in vitro and in vivo. Moreover, Btz-loaded CD38-NPs reduced MM proliferation, inhibited cell cycle, and induced apoptosis more robustly than equivalent concentrations of free drug, but not in MNCs. These results confirmed that CD38-NPs specifically delivered therapeutic agents to MM cells improving therapeutic efficacy. Therefore, CD38-NPs will reduce side effects and could be used as a new drug delivery approach in myeloma. Disclosures De La Puente: Cellatrix LLC: Other: Co-founder. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Karyopharma: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Amgen: Consultancy, Research Funding. Azab:Selexys: Research Funding; Vasculox: Research Funding; Cellatrix LLC: Other: Founder and owner; Karyopharm: Research Funding; Glycomimetics: Research Funding; Cleave Bioscience: Research Funding; Verastem: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner; Cell Works: Research Funding.

Bioinspired Drug Delivery Carrier for Enhanced Tumor-Targeting in Melanoma Mice Model

2019 ◽  
Vol 15 (7) ◽  
pp. 1482-1491 ◽  
Author(s):  
Xu Wang ◽  
Gao-Feng Liang ◽  
Xue-Qin Hao ◽  
Shu-Ying Feng ◽  
Lu Dai ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Near Infrared ◽  
Imaging System ◽  
Morphological Changes ◽  
The Body ◽  
Control Group ◽  
Mice Model ◽  
Normal Tissues ◽  
Specific Distribution

As a widely used first-line chemotherapy drug for tumor, Doxorubicin (DOX) can induce various side effects on normal tissues because of its non-specific distribution in the body. Emerging evidence has shown that platelets have the capability to recognize and interact with tumor cells. Inspired by this, the platelet-based drug delivery system was constructed by loading of DOX in platelet cytoplasm and modification of transferrin on the surface of platelet (Tf-P-DOX). The encapsulation efficiency of DOX in platelet was the highest at the DOX concentration of 0.05 mM, and reached to 64.9%. Fluorescence microscopy showed that the Tf-P-DOX facilitated cell uptakes and enhanced intracellular drug accumulation in B16F10 cells. Compared with free DOX, Tf-P-DOX exhibited an enhanced effect on cell apoptosis at the same concentration of DOX. In vivo imaging system showed that the near-infrared fluorescence of B16F10 tumor-bearing mice was mainly accumulated in the tumor site, which caused the inhibition of tumor growth in mice. The morphological changes of tumor tissue in Tf-P-DOX group was significant in comparison with those of the control group, including the small nucleus, the insufficiency of cancerous nest, and the infiltration of inflammatory cells, while Tf-P-DOX did not show significant adverse effects on normal tissues. Compared with the control group, the levels of caspase 9 and caspase 3 protein expressions were increased significantly in Tf-P-DOX group. Our studies suggest platelets can be repurposed as promising carriers for efficient targeting and treatment of solid tumors.

Targeted Chemotherapy for Breast Cancer Using an Intelligent Doxorubicin-Loaded Hexapeptide Hydrogel

2020 ◽  
Vol 16 (6) ◽  
pp. 842-852
Author(s):  
Shiyao Luo ◽  
Ying Zhu ◽  
Yiping Li ◽  
Li Chen ◽  
Shunzhong Lv ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Solid Phase ◽  
Synthesis Method ◽  
High Water ◽  
High Water Content ◽  
Normal Tissues ◽  
Self Assembling ◽  
Peptide Hydrogel

Self-assembling peptide hydrogels have a high water content, good biocompatibility and have become a competitive research object in the fields of tissue engineering, cancer treatment and drug delivery. In our research, a hexapeptide with high pH sensitivity was designed and synthesized by utilizing a solid-phase synthesis method. Under physiological conditions, the peptide could self-assemble into a hydrogel. When it reached the tumor acidic microenvironment, the peptide was degraded and doxorubicin was released to exert its antitumor effect. A series of physicochemical properties were investigated, including gelling ability, secondary structure, micromorphology, rheological properties and drug release studies. The results illustrated that PIDO peptide hydrogel has good pH responsiveness and injectability. In vitro cytotoxicity experiments and in vivo antitumor experiments showed that PIDO peptide hydrogel has a highly effective therapeutic effect on tumor cells and is less toxic to normal tissues. Our research provides a promising option for targeted drug delivery and sustainable release.

Ellipticine, its Derivatives: Re-evaluation of Clinical Suitability with the Aid of Drug Delivery Systems

2020 ◽  
Vol 20 (1) ◽  
pp. 33-46 ◽  
Author(s):  
Vipin Mohan Dan ◽  
Thania Sara Varghese ◽  
Gayathri Viswanathan ◽  
Sabulal Baby
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Drug Delivery Systems ◽  
Large Body ◽  
Delivery Systems ◽  
Clinical Settings ◽  
Therapeutic Drugs ◽  
Recent Developments

Targeted drug delivery systems gave newer dimensions for safer and more effective use of therapeutic drugs, thus helping in circumventing the issues of toxicity and unintended drug accumulation. These ongoing developments in delivery systems can, in turn, bring back drugs that suffered various limitations, Ellipticine (EPT) being a candidate. EPT derivatives witnessed entry into clinical settings but failed to survive in clinics citing various toxic side effects. A large body of preclinical data deliberates the potency of drug delivery systems in increasing the efficiency of EPT/derivatives while decreasing their toxic side effects. Recent developments in drug delivery systems provide a platform to explore EPT and its derivatives as good clinical candidates in treating tumors. The present review deals with delivery mechanisms of EPT/EPT derivatives as antitumor drugs, in vitro and in vivo, and evaluates the suitability of EPT-carriers in clinical settings.

scholarly journals Improved Safety and Anti-Glioblastoma Efficacy of CAT3-Encapsulated SMEDDS through Metabolism Modification

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 484
Author(s):  
Hongliang Wang ◽  
Lin Li ◽  
Jun Ye ◽  
Wujun Dong ◽  
Xing Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Gastrointestinal Tract ◽  
Side Effects ◽  
Drug Delivery System ◽  
Delivery System ◽  
Lymphatic Transport ◽  
Pharmacokinetic Parameters ◽  
Gastrointestinal Side Effects ◽  
The Brain

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood–brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats’ plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15–30 nm), positive charge (5–9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2–6-fold and 1.3–7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.

A tumor-sensitive biological metal–organic complex for drug delivery and cancer therapy

2020 ◽  
Vol 8 (32) ◽  
pp. 7189-7196 ◽  
Author(s):  
Zelei Jiang ◽  
Tong Wang ◽  
Shuai Yuan ◽  
Mengfan Wang ◽  
Wei Qi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Side Effects ◽  
Cancer Therapy ◽  
Cancer Drug ◽  
Organic Complex ◽  
Anti Cancer ◽  
Metal Organic Complex ◽  
Metal Organic ◽  
Inhibition Of Tumor Growth

Tumor-sensitive bioMOC-Zn(Cys) was developed using an endogenous Zn2+ ion and l-cystine for the delivery of anti-cancer drug DOX. In vivo application of DOX@bioMOC-Zn(Cys) shows the increased inhibition of tumor growth and prevented side effects.

scholarly journals Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy

2019 ◽  
Vol 11 (484) ◽  
pp. eaar5012 ◽  
Author(s):  
Marie-Eve Beaulieu ◽  
Toni Jauset ◽  
Daniel Massó-Vallés ◽  
Sandra Martínez-Martín ◽  
Peter Rahl ◽  
...  
Keyword(s):  
Side Effects ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Dominant Negative ◽  
Transgenic Expression ◽  
Normal Tissues ◽  
Oncogenic Mutation ◽  
Dominant Negative Form

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non–small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.

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