Localized doxorubicin chemotherapy with a biopolymeric nanocarrier improves survival and reduces toxicity in xenografts of human breast cancer (original) (raw)
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ACS Omega
Doxorubicin hydrochloride (DOX) is currently used to treat orthotropic and metastatic breast cancer. Because of its side effects, the use of DOX in cancer patients is sometimes limited; for this reason, several scientists tried designing drug delivery systems which can improve drug therapeutic efficacy and decrease its side effects. In this study, we designed, prepared, and physiochemically characterized nonionic surfactant vesicles (NSVs) which are obtained by selfassembling different combinations of hydrophilic (Tween 20) and hydrophobic (Span 20) surfactants, with cholesterol. DOX was loaded in NSVs using a passive and pH gradient remote loading procedure, which increased drug loading from ∼1 to ∼45%. NSVs were analyzed in terms of size, shape, size distribution, zeta potential, long-term stability, entrapment efficiency, and release kinetics, and nanocarriers having the best physiochemical parameters were selected for further in vitro tests. NSVs with and without DOX were stable and showed a sustained drug release up to 72 h. In vitro studies, with MCF-7 and MDA MB 468 cells, demonstrated that NSVs, containing Span 20, were better internalized in MCF-7 and MDA MB 468 cells than NSVs with Tween 20. NSVs increased the anticancer effect of DOX in MCF-7 and MDA MB 468 cells, and this effect is time and dose dependent. In vitro studies using metastatic and nonmetastatic breast cancer cells also demonstrated that NSVs, containing Span 20, had higher cytotoxicity than NSVs with Tween 20. The resulting data suggested that DOX-loaded NSVs could be a promising nanocarrier for the potential treatment of metastatic breast cancer. ■ INTRODUCTION Cancer is one of the principal causes of death in the world. Breast cancer has a high incidence and frequency and represents the second leading cause of cancer deaths in the female population worldwide, with an estimated 2.1 million new cases and 626,679 deaths reported in 2018. 1 It shows a higher incidence rate in high-income countries than in lowincome and middle-income countries. 2 Nowadays, there are more than 3.5 million breast cancer survivors, which include women still being treated and those who have completed treatment. 2 Breast cancer has been considered for a long time as the most aggressive cancer form affecting worldwide populations, particularly female, with an increased incidence and high mortality. 3 Early-stage breast cancer is treated using surgery, which is often combined with radio-and chemotherapies to decrease the risk of recurrence; while metastasis are treated early by systemically injecting drugs, such as chemotherapeutics, targeted molecules, hormones, and, recently, immune modulators. 4 Conventional therapies, such as surgery, radiotherapy, chemotherapy, and modern treatments, including immunotherapy, biological and differentiating drugs, anti-angionic compounds, signal transduction inhibitors, vaccines, targeted therapy, hormonal therapy, and gene therapy, showed a lack of efficacy for treating cancer and its resistance, as well as side effects, which occur quickly after several and multiple administrations because of scheduled protocols. 3,5 Anthracyclines, such as doxorubicin and epirubicin, taxanes, including paclitaxel and docetaxel, along with fluorouracil and cyclophosphamide, are the current therapeutic options used as the combination adjuvant for breast cancer treatment. The therapeutic protocol for breast cancer treatment in the United States includes 4 cycles of doxorubicin and cyclophosphamide plus 4 cycles of paclitaxel (AC-T). 6 Currently, clinical trials demonstrated that combination therapies, that is, immunotherapy, chemotherapy, and targeted therapies, can improve survival in breast cancer patients. 7 Physicochemical and biological properties of these chemotherapeutic drugs, for example, poor water solubility and
Macromolecular Bioscience, 2014
Releasibility of doxorubicin from drug-conjugates is believed to be a prerequisite for its anticancer activity. Here, a new glyco-drug approach that circumvents the releasibility restriction is reported, opening a new possibility to design efficient, target specific drug delivery system. It is discovered that stable amide coupling of doxorubicin (DOX) tohyaluronan (HA) shows dose dependent cytotoxicity to CD44 positive human coloncancer cells (HCT116) as compared to human breast cancer cells(MCF-7) and mouse fibroblast cells (NIH-3T3), which express less CD44 receptor. This direct conjugation approach is an easy scalable strategy that could be adopted to design innocuous anti-tumor nanoparticle formulations.
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.
Biomaterials, 2012
Polyethylene glycol (PEG)-conjugated hyaluronic acid-ceramide (HACE) was synthesized for the preparation of doxorubicin (DOX)-loaded HACE-PEG-based nanoparticles, 160 nm in mean diameter with a negative surface charge. Greater uptake of DOX from these HACE-PEG-based nanoparticles was observed in the CD44 receptor highly expressed SCC7 cell line, compared to results from the CD44negative cell line, NIH3T3. A strong fluorescent signal was detected in the tumor region upon intravenous injection of cyanine 5.5-labeled nanoparticles into the SCC7 tumor xenograft mice; the extended circulation time of the HACE-PEG-based nanoparticle was also observed. Pharmacokinetic study in rats showed a 73.0% reduction of the in vivo clearance of DOX compared to the control group. The antitumor efficacy of the DOX-loaded HACE-PEG-based nanoparticles was also verified in a tumor xenograft mouse model. DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction and by passive targeting due to its small mean diameter (<200 nm). Moreover, PEGylation resulted in prolonged nanoparticle circulation and reduced DOX clearance rate in an in vivo model. These results therefore indicate that PEGylated HACE nanoparticles represent a promising anticancer drug delivery system for cancer diagnosis and therapy. Biomaterials j o u r n a l h o m e p a g e : w w w . e l s e v i e r. co m/ lo ca t e / b i o m a t e ri a l s 0142-9612/$ e see front matter Ó
Biomaterials, 2010
The purpose of this study was to develop polymeric nano-carriers of doxorubicin (DOX) that can increase the therapeutic efficacy of DOX for sensitive and resistant cancers. Towards this goal, two polymeric DOX nano-conjugates were developed, for which the design was based on the use of multi-functionalized poly(ethylene oxide)-block-poly(3-caprolactone) (PEO-b-PCL) micelles decorated with avb3 integrintargeting ligand (i.e. RGD4C) on the micellar surface. In the first formulation, DOX was conjugated to the degradable PEO-b-PCL core using the pH-sensitive hydrazone bonds, namely RGD4C-PEO-b-P(CL-Hyd-DOX). In the second formulation, DOX was conjugated to the core using the more stable amide bonds, namely RGD4C-PEO-b-P(CL-Ami-DOX). The pH-triggered drug release, cellular uptake, intracellular distribution, and cytotoxicity against MDA-435/LCC6 WT (a DOX-sensitive cancer cell line) and MDA-435/ LCC6 MDR (a DOX-resistant clone expressing a high level of P-glycoprotein) were evaluated. Following earlier in vitro results, SCID mice bearing MDA-435/LCC6 WT and MDA-435/LCC6 MDR tumors were treated with RGD4C-PEO-b-P(CL-Hyd-DOX) and RGD4C-PEO-b-P(CL-Ami-DOX), respectively. In both formulations, surface decoration with RGD4C significantly increased the cellular uptake of DOX in MDA-435/ LCC6 WT and MDA-435/LCC6 MDR cells. In MDA-435/LCC6 WT , the best cytotoxic response was achieved using RGD4C-PEO-b-P(CL-Hyd-DOX), that correlated with the highest cellular uptake and preferential nuclear accumulation of DOX. In MDA-435/LCC6 MDR , RGD4C-PEO-b-P(CL-Ami-DOX) was the most cytotoxic, and this effect correlated with the accumulation of DOX in the mitochondria. Studies using a xenograft mouse model yielded results parallel to those of the in vitro studies. Our study showed that RGD4C-decorated PEO-b-P(CL-Hyd-DOX) and PEO-b-P(CL-Ami-DOX) can effectively improve the therapeutic efficacy of DOX in human MDA-435/LCC6 sensitive and resistant cancer, respectively, pointing to the potential of these polymeric micelles as the custom-designed drug carriers for clinical cancer therapy.
Biodegradable star HPMA polymer conjugates of doxorubicin for passive tumor targeting
European Journal of Pharmaceutical Sciences, 2011
New biodegradable star polymer-doxorubicin (Dox) conjugates designed for passive tumor targeting were investigated and the present study described their synthesis, physico-chemical characterization, drug release and biodegradation. In the conjugates the core formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin attached by hydrazone bonds, which enabled intracellular pH-controlled drug release, or by a GFLG sequence, which was susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of biodegradable polymer conjugates in a broad range of molecular weights (110-295 kDa) while still maintaining low polydispersity (∼1.7). The polymer grafts were attached to the dendrimers either through stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high molecular weight polymer carrier to products that were able to be excreted from the body by glomerular filtration. Biodegradability tests showed that the rate of degradation was much faster for reductively degradable conjugates (completed within 4 h) than the degradation of conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (within 72 h). This finding was likely due to the difference in steric hindrance for the small molecule glutathione and the enzyme cathepsin B. As for drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin either under mild acidic conditions or in the presence of lysosomal enzyme cathepsin B, both of which modeled the tumor cell microenvironment.
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.
Molecules
The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin’s efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 °C). The developed drug vehicle is composed of the following: a cell penetrating peptide (SynB1) to promote tumor and cellular uptake; thermally responsive Elastin-like polypeptide (ELP); and the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH) containing a pH-sensitive hydrazone linker that releases doxorubicin in the acidic tumor environment. We used the in vivo imaging system, IVIS, to determine biodistribution of doxorubicin-del...
Journal of Pharmaceutical Investigation
Purpose Natural materials have been extensively studied for oral drug delivery due to their biodegradability and other unique properties. In the current research, we fabricated sodium caseinate nanomicelles (NaCNs) using casein as a natural polymer to develop a controlled-release oral delivery system that would improve the therapeutic potential of doxorubicin (DOX) and reduce its toxicity. Methods DOX-loaded NaCNs were synthesized and thoroughly characterized, then subjected to in vivo anti-tumor evaluation and bio-distribution analysis in a 4T1-induced breast cancer model. Results Our findings indicated that the tumor would shrink by eight-fold in the group orally treated with DOX-NaCNs when compared to free DOX. The tumor accumulated drug 1.27-fold more from the orally administered DOX-NaCNs compared to the intravenously administered DOX-NaCNs, 6.8-fold more compared to free DOX, and 8.34-times more compared to orally administered free DOX. In comparison, the orally administered D...