Enhanced tumor uptake and activity of nanoplex-loaded doxorubicin (original) (raw)
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Advances in nano delivery systems for doxorubicin an updated insight.pdf
Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet V R ) and pegylated liposomal (Doxil V R ) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems.
Background and Aims: Doxorubicin is a potent anticancer drug and a major limiting factor that hinders therapeutic use as its high levels of systemic circulation often associated with various off-target effects, particularly cardiotoxicity. The present study focuses on evaluation of the efficacy of doxorubicin when it is loaded into the protein nanoparticles and delivered intravenously in rats bearing Hepatocellular carcinoma (HCC). The proteins selected as carrier were Apotransferrin and Lactoferrin, since the receptors for these two proteins are known to be over expressed on cancer cells due to their iron transport capacity.
Advances in nano-delivery systems for doxorubicin: an updated insight
2018
Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumors, transplantable leukemias and lymphomas. Conventional DOX induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet®) and pegylated liposomal (Doxil®) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of doxorubicin in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimizing its toxicity with increased half life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumor resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on doxorubicin nanoformulations, in this article we for the first time have given an updated insight on doxorubicin nano delivery systems. Key words: Doxorubicin; Myocet®; Doxil®; Cardiotoxicity; Nano delivery systems
Targeted doxorubicin nanotherapy strongly suppressing growth of multidrug resistant tumor in mice
The rational design of nanomedicine to treat multidrug resistant (MDR) tumors in vivo is described in the study. We prepared multifunctionalized Pluronic micelles that are already well-established to be responsive to low pH and redox in order to systemically deliver doxorubicin (DOX) to MDR tumors. Folic acids (FAs) were introduced on the micelle surface as tumor-targeting molecules. In vitro, the DOX-loaded micelles exerted high cytotoxicity in the DOX-resistant cells by bypassing MDR efflux. Cellular uptake studies clearly demonstrated that FA-conjugated DOX micelles (FA/DOX micelles) were efficiently internalized and accumulated in the MDR cells. In vivo studies indicated significant efficacy of FA/DOX micelles for MDR tumors in mice, and that the volume of tumors was 3 times smaller in this group than that of tumors in the free DOX group, and 8 times smaller than the tumors in the saline group. To the best of our knowledge, this methodology has been recognized to have significantly high efficacy, compared to previously reported DOX nanoparticle formulations. This superior anti-tumor efficacy of FA/DOX micelles in MDR tumor-bearing mice can be attributed to FA-targeted and-mediated endocytosis, inhibition of MDR effect, and subsequent DOX release triggered by dual stimuli (low pH and redox) inside the tumor. Given the promise of the multifunctional micelle mediated delivery on inhibition of MDR tumor growth, FA/DOX micelle platform is a much sought after goal for cancer chemotherapy, especially for cancers resistant to anticancer drugs.
Drug Delivery Approaches for Doxorubicin in the Management of Cancers
Current Cancer Therapy Reviews, 2019
Aim: We aimed to review the drug delivery approaches including a novel drug delivery system of doxorubicin as an important anticancer drug. Background: Doxorubicin (DOX) is widely used against breast, uterine, ovarian, lung and cervical cancer. It is listed among the essential medicines by WHO and is thus a very important drug that can be used to fight against cancer. Despite its effectiveness, the use of the drug is limited due to its dose-dependent toxicity. Several studies based on the DOX have suggested the need for novel drug delivery formulations in the treatment of malignant and cancerous diseases due to its cytotoxic nature. Objective: This review focuses on the different formulations of DOX which is a useful drug in the management of cancers, but associated with toxicity thus these approaches found applicability in the reduction of its toxicity. Methods: We searched the scientific database using cancer, DOX, and different formulations as the keywords. Here in only peer-reviewed research articles collected which were useful to our current work. Results: This study is based on an examination of the recent advancements of its novel drug delivery formulations. DOX hydrochloride is the first liposomal anticancer drug, administered via the intravenous route, and also clinically approved for the treatment of lymphomas, leukemias, and solid tumors. DOX is prepared into a liposomal formulation that contains polyethylene glycol (PEG) layer around DOX containing liposome made by pegylation process. DOX also formulated in nano-formulations which is also discussed herein led to reduced toxicity and increased efficacy. Conclusion: In the review, we described the significance of DOX in the form of different delivery approaches in the management of cancers with a reduction in the associated toxicity.
Cancer Nanomedicine: A New Era of Successful Targeted Therapy
Journal of Nanomaterials, 2019
Cancer is considered as one of the most challenging health care problems. Though there are many approved drugs that can be used for cancer therapy, drug resistance and delivery are among of the barriers of the treatment. In addition, pathological characteristics of tumors and their abnormal blood vessel architecture and function also reduce the efficiency of the conventional cancer treatment. Therefore, looking for techniques that can increase the efficacy of the therapy such as nanoparticles (NPs) is vital. NPs have many properties such as their small size, ability to load various drugs and large surface area, and ability to increase the absorption of conjugated. Therefore, the NPs have been considered as excellent tumor-targeting vehicles. The recent nanoscale vehicles include liposomes, polymeric nanoparticles, magnetic nanoparticles, dendrimers, and nanoshells; lipid-based NPs have been used as conjugates. There are few examples of approved conjugated anticancer NPs including AmBisome® (amphotericin B liposomal) and Doxil® (liposomal doxorubicin). There are many other conjugated anticancer drugs at different stages of clinical trials for treatment of various cancers. This review will discuss the properties of different NPs in cancer treatment and their benefits of overcoming multidrug resistance. In addition, recent advances of using nanomedicine in different approaches of cancer treatment such as chemotherapy, radiotherapy, and immunotherapy will be highlighted in this review.
Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells
Scientific Reports, 2016
Successful chemotherapeutic intervention for management of lung cancer requires an efficient drug delivery system. Gold nanoparticles (GNPs) can incorporate various therapeutics; however, GNPs have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (Exo) can ferry GNPtherapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel Exo-GNP-based therapeutic delivery system-'nanosomes'-for lung cancer therapy. This system consists of GNPs conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (Exo-GNP-Dox). The therapeutic efficacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fibroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). The enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved ROS-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efficient delivery of therapeutics to cancer cells. Extensive research in the area of cancer therapeutics has resulted in the discovery and synthesis of many potent small molecule inhibitors with excellent anti-cancer activity 1,2. Despite such tremendous progress, many of these therapeutic molecules have remained at the investigational level, and could not be used for clinical interventions 3. Conventional therapeutic molecules, such as synthetic drugs, compounds extracted from natural resources, or biomolecules like inhibitory RNA/DNA, do not bear any targeting signals specific to proliferating tumor cells, and produce off-target cytotoxicity 4. In addition, many of molecules of therapeutic importance are hydrophobic and/or negatively charged, which results in their poor bioavailability to cancer cells 5,6. To circumvent these drawbacks, recent advances in nanotechnology have resulted in the development of various drug delivery vehicles, such as liposomes, polymer-based and inorganic nanoparticles that can be conjugated to signaling molecules and used for targeted tumor therapy 7-10. Current delivery systems for anticancer therapeutics are plagued by numerous disadvantages related to low efficiency, poor bio-distribution, and immune response, limiting their application in clinical settings 11. Exosomes are submicron-sized cellular vesicles released by cells and can be isolated from all bodily fluids and from the medium of growing cells 12. Recently, it has been recognized that exosomes can ferry biomolecules, such
Nature Materials, 2009
New strategies to self-assemble biocompatible materials into nanoscale, drug-loaded packages with improved therapeutic efficacy are needed for nanomedicine. To address this need, we developed artificial recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into sub-100 nm size, near monodisperse nanoparticles upon conjugation of diverse hydrophobic molecules, including chemotherapeutics. These CPs consist of a biodegradable polypeptide that is attached to a short Cys-rich segment. Covalent modification of the Cys residues with a structurally diverse set of hydrophobic small molecules, including chemotherapeutics leads to spontaneous formation of nanoparticles over a range of CP compositions and molecular weights. When used to deliver chemotherapeutics to a murine cancer model, CP nanoparticles have a four-fold higher maximum tolerated dose than free drug, and induce nearly complete tumor regression after a single dose. This simple strategy can promote co-assembly of drugs, imaging agents, and targeting moieties into multifunctional nanomedicines.
Nanoparticle formulation improves doxorubicin efficacy by enhancing host antitumor immunity
Strategies that enhance the host antitumor immune response promise to revolutionize cancer therapy. Optimally mobilizing the immune system will likely require a multi-pronged approach to overcome the resistance developed by tumors to therapy. Recently, it has become recognized that doxorubicin can contribute to re-establishing host antitumor immunity through the generation of immunogenic cell death. However, the potential for delivery strategies to further enhance the immunological effects of doxorubicin has not been adequately examined. We report herein that Chimeric Polypeptide Doxorubicin (CP-Dox), a nanoparticle formulation of doxorubicin, enhances antitumor immunity. Compared to free doxorubicin, a single intravenous (IV) administration of CP-Dox at the maximum tolerated dose increases the infiltration of leukocytes into the tumor, slowing tumor growth and preventing metastasis in poorly immunogenic 4T1 mammary carcinoma. We demonstrate that the full efficacy of CP-Dox is dependent on CD8 + T cells and IFN-γ. CP-dox treatment also repolarized intratumoral myeloid cells towards an antitumor phenotype. These findings demonstrate that a nanoparticle drug is distinct from the free drug in its ability to productively stimulate antitumor immunity. Our study strongly argues for the use of antitumor immunotherapies combined with nanoparticle-packaged chemotherapy.
Biomedicine & Pharmacotherapy, 2017
In metastatic breast cancer (MBC), the conventional doxorubicin (DOX) has various problems due to lack of selectivity with subsequent therapeutic failure and adverse effects. DOX-induced cardiotoxicity is a major problem that necessitates the presence of new forms to decrease the risk of associated morbidity. Nanoparticles (NPs) are considered an important approach to selectively increase drug accumulation inside tumor cells and thus decreasing the associated side effects. Tumor cells develop resistance to chemotherapeutic agents through multiple mechanisms, one of which is over expression of efflux transporters. Various NPs have been investigated to overcome efflux mediated resistance. To date, only liposomal doxorubicin (LD) and pegylated liposomal doxorubicin (PLD) have entered phase II and III clinical trials and FDA-approved for clinical use in MBC. This review addresses the effects of LD and PLD on the hematological and palmar-plantar erythrodysesthesia (PPE) in anthracycline naïve and pretreated MBC patients. For evidence, studies to be included in this review were identified through PubMed, Cochrane and Google scholar databases. The results derived from: four phase III clinical trials that compared LD with the conventional DOX in naïve MBC patients, and ten non-comparative clinical trials investigated LD and PLD as monotherapy or combination in pretreated MBC. This work confirmed the cardiac tolerability profile of LD and PLD versus DOX, while hematological and skin toxicities were more common. Other DOX-NPs in preclinical trials were discussed in a chronological order. Finally, the modern preclinical development framework for DOX includes exosomal DOX (exo-DOX). Exosomal NPs are non-toxic, non-immunogenic, and can be engineered to have high cargo loading capacity and targeting specificity. These NPs have not been investigated clinically. Our study shows that the full clinical potentiality of DOX-NPs remains to be addressed to move the field forward.