Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles

Abstract

Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH-ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH-ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH-ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH-ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.

Taraxacum Officinale (Dandelion) Roots Extract Mitigates Doxorubicin-Induced HematoCardiotoxicity in Male Albino Rats

“…Treatment with dandelion significantly lowered serum level of these peptides (ANP, BNP) and this may illuminate and prove cardioprotective effect of dandelion as an antioxidant against DXR-induced oxidative myocardial damage. The results of our study recorded a significant increment in cardiac tissues content of MDA (lipid peroxide) with a depletion of enzymatic and non-enzymatic antioxidants (SOD and GSH) of DXR-treated rats which may reflect and confirm the oxidative stress status evoked through the treatment with DXR (Yu et al, 2013;Chen et al, 2015;Sun et al, 2015;Zhang et al, 2015;Khafaga and El-Sayed, 2017). Remarkably, treatment with dandelion effectively decreased cardiac MDA content and boosted the activity and/or content of different evaluated cardiac antioxidants, the eventual mechanism by which dandelion attenuated DXR-induced cardiotoxicity may be concluded in its powerful antioxidant effect in scavenging of the free radicals which mediate lipid peroxidation and tissues antioxidant exhaustion (Choi et al, 2010;Kenny et al, 2014;Tan et al, 2017).…”

“…The proved mitigation in hematological results upon combination of dandelion with doxorubicin may be due to the potent antioxidant effect of dandelion (Choi et al, 2010;Kenny et al, 2014;Tan et al, 2017) which may stabilize erythrocytic membranes preventing its destruction and preventing lymphocytic DNA damage. Also, dandelion can stimulate production of inteleukin-1 (IL-1) (Koo et al, 2004) which can ameliorate doxorubicin hematotoxicity (Eppstein et al, 1989) through its ability to increase colony stimulating factors (CSFs) (Ridgway et al, 1988;Schwartz et al, 1989), enhancing the marrow cells to enter into S, G2 and M phases and increase the reactivity of the precursor cells to GM-CSF (Neta et al, 1987) which collectively increase marrow leukocytic production.Serum level of CK-MB, LDH enzymes and trponin-I is considered as highly specific biomarkers for assessment of cardiac function as the magnitude of its elevation may reflect the severity of myocardiocytes membrane damage and loss of integrity (Latimar et al, 2003;Rohilla et al, 2012).The indicated oxidative stress generated by administration of DXR is supposed to be implicated in mycocardial damage and release of these enzymes which in turn increased their level in serum of DXR-treated rats (Nagi and Mansour, 2000;Yu et al, 2013;Chen et al, 2015;Zhang et al, 2015;Khafaga and El-Sayed, 2017). In contrast, co-administration of dandelion with DXR to the rats significantly decreased the elevated serum level of the assessed mycordial enzymes and tropnin-1, this cardioprotective action of dandelion may be owed to its previously proved antioxidant effect.…”

Nanoparticle-Mediated Combination Therapy: Two-in-One Approach for Cancer

“…Administration of autophagy inhibitors such as 3-methyladenine and chloroquine via cholic acid-conjugated NPs of poly (lactic-co-glycolic acid) (PLGA NPs) induces autophagy of the cancer, which is the alternative method for clinical applications [ 79 ]. The newly synthesized amphiphilic low molecular-weight heparin LMHA-ATRA conjugate, encapsulating the DOX NPs, exhibited significant loading capacities for DOX with excellent physico-chemical properties, bio-compatibility and remarkable differentiation-inducing activity and anti-angiogenic activity in human breast cancer cells [ 80 ]. Recently, NPs engineered with an average size of 50 nm-diameter containing diblock copolymer NPs were used to sequentially release WOR and DTX to cancer cells.…”

“…The combination of a PTX-PEG-ALN conjugate was designed to exploit active targeting by the ALN molecule and passive targeting through the EPR effect. The resultant complex conjugate, PTX-PEG-ALN, exhibited an improved pharmacokinetic profile compared with the free drugs, based on the marked increase in their half-lives [ 80 ]. Thomas et al (2013) designed multivalent dendrimers known as methotrexates as a folate-targeting anticancer therapeutic agent to serve as both a cancer cell-specific targeting ligand and as a therapeutic cytotoxic agent [ 117 ].…”

Heparin-Based Nanoparticles: An Overview of Their Applications

“…Zhang et al developed an interesting system which comprises two anticancer drugs, ATRA (all trans retinoic acid) and DOX (doxorubicin), the first one being conjugated to LMWH (low molecular weight heparin) and the second one loaded physically, such system was named as DOX-loaded LMWH-ATRA. The most relevant assets in this work are that the cytotoxicity effect on epithelial MCF-7 cells used was maintained and they possessed much higher anticancer activity compared to the free drugs in solution and side effects were reduced [46]. Kim et al conjugated LMWH (low molecular weight heparin) to (SA) stearylamine in order to create, first, a polymer that was used to synthesize self-assembled nanoparticles, and then, docetaxel was loaded within them.…”