ABSTRACT
Rapidly growing evidence suggests a strong dependence of a polyol pathway enzyme Aldose Reductase (AR) in cancer progression and invasion. Thus, inhibiting the AR through therapeutic inhibitors has a potential application in cancer treatment. Epalrestat (EPR) is the only marketed AR inhibitor with proven safety and efficacy in the management of complications like diabetic neuropathy. However, its short half-life and highly hydrophobic nature restrict its use as an anticancer agent. In the present study, we first developed a redox-sensitive prodrug of EPR by conjugating Tocopherol Polyethylene Glycol Succinate (TPGS) which can form a self-assembled micellar prodrug (EPR-SS-TPPGS). Subsequently, to achieve synergistic chemotherapeutic efficacy Doxorubicin (Dox) was co-loaded into the EPR-SS-TPGS micelles where the system is disrupted in a tumor redox environment and co-delivers Dox and EPR in a ratiometric manner. We then employed TPGS conjugated vitamin-B6 as a targeting moiety and prepared the mixed micelles to facilitate VTC receptor-mediated uptake. The encapsulation of Dox and EPR with the developed prodrug approach showed significant synergies with increased intracellular accumulation and redox triggered release in MDA-MB-231 and 4T1 cell lines leading to superior cell cycle arrest, mitochondrial membrane potential, and apoptosis. Prolonged circulation half-life and tumor site bioavailability were achieved for both the drugs with the developed approach. Surprisingly, EPR and Dox combination significantly down-regulated the CD44 receptor expression which is the main contributing factor of tumor metastasis. Furthermore, in vivo evaluation demonstrated a significant reduction in Dox-induced cardiotoxicity. In summary, this nanoencapsulation paradigm of AR inhibitors with chemotherapeutic agents lays the foundation of new opportunities in combination chemotherapy.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Doxorubicin/metabolism , Doxorubicin/pharmacology , Drug Carriers/chemistry , Prodrugs/metabolism , Rhodanine/analogs & derivatives , Thiazolidines/metabolism , Thiazolidines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Doxorubicin/chemistry , Drug Carriers/pharmacokinetics , Drug Liberation , Drug Synergism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Female , Humans , Intracellular Space/metabolism , Mice , Micelles , Oxidation-Reduction , Rhodanine/chemistry , Rhodanine/metabolism , Rhodanine/pharmacology , Thiazolidines/chemistry , Tissue Distribution , Vitamin B 6/chemistry , Vitamin E/chemistryABSTRACT
The combination of metabolic modulators with chemotherapy holds vast promise for effective inhibition of tumor progression and invasion. Herein, a ratiometric codelivery platform is developed for metformin (MET), a known metabolic modulator and topotecan (TPT), a chemotherapeutic drug, by engineering lipid bilayer-camouflaged mesoporous silica nanoparticles (LB-MSNs). In an attempt to deliver and maintain high tumor site concentrations of MET and TPT, a novel ion pairing-assisted loading procedure is developed using pamoic acid (PA) as an in situ trapping agent. PA, a hydrophobic counterion, increases the hydrophobicity of MET and TPT and facilitates MSNs with exceptionally high payload capacity (>40 and 32 wt%, respectively) and controlled release profile. Further, the synergy between MET and TPT determined by a modeling approach helps to afford synchronized delivery of both the drugs. Coloaded MET and TPT LB-MSNs present synergistic cytotoxicity against MDA-MB-231/4T1 cells and effectively promote apoptosis via mitochondrial membrane depolarization and cell cycle arrest. Extended pharmacokinetic profiles in preclinical models with fourfold to sevenfold longer circulation half-life and 7.5-100 times higher tumor site concentrations correspond to a significant increase in pharmacodynamic efficacy. Taken together, the developed codelivery approach effectively addresses the challenges in the chemotherapeutic efficacy of MET and TPT collectively.
Subject(s)
Drug Carriers/chemistry , Metformin/therapeutic use , Nanoparticles/chemistry , Silicon Dioxide/chemistry , Topotecan/therapeutic use , Animals , Breast Neoplasms/drug therapy , Cell Line, Tumor , Drug Delivery Systems/methods , Female , Humans , Kaplan-Meier Estimate , Lipid Bilayers/chemistry , Metformin/administration & dosage , Mice , Mice, Inbred BALB C , Porosity , Topotecan/administration & dosageABSTRACT
This study reports the development of Vitamin B6 (VitB6) modified pH sensitive charge reversal nanoparticles for efficient intracellular delivery of Doxorubicin (DOX). Herein, VitB6 was conjugated to stearic acid, and the nanoparticles of the lipid were formulated by solvent injection method (DOX-B6-SA-NP). Because of the pKa (5.6) of VitB6, DOX-B6-SA-NP showed positive charge and enhanced release of DOX at pH 5. Confocal microscopy illustrated that DOX-B6-SA-NP treatment kept higher DOX accumulation inside the cells than conventional pH insensitive lipid nanoparticles (DOX-SA-NP). The cationic charge of nanoparticles subsequently facilitated the endosomal escape and promoted the nuclear accumulation of DOX. Furthermore, in vitro cytotoxicity, apoptosis, cell cycle arrest, and mitochondrial membrane depolarization studies supported the enhanced efficacy of DOX-B6-SA-NP in comparison to free DOX and DOX-SA-NP. Intravenous pharmacokinetics and biodistribution investigations indicated that pH sensitive nanoparticles can significantly prolong the blood circulation time of DOX in biological system and increase the drug accumulation to tumor site. Consequent to this, DOX-B6-SA-NP also exhibited much enhanced therapeutic efficacy and lower toxicity in tumor-bearing rats compared to free DOX. The reduction in toxicity was confirmed by histological and survival analysis. In conclusion, these results suggest that the VitB6 modified charge reversal nanoparticles can be a novel platform for the successful delivery of anticancer drugs.
