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Molecular pharmaceutics [journal]
- Efficacy of PolyMPC-DOX Prodrugs in 4T1 Tumor-Bearing Mice. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 21.
We report the in vivo efficacy, in tumor-bearing mice, of cancer prodrugs consisting of poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) conjugated to doxorubicin (DOX). Our synthesis of polyMPC-DOX conjugates established prodrugs with tunable drug loading, pH sensitive release kinetics, and a maximum tolerated dose in the range of 30-50 mg/kg (DOX equivalent) in healthy mice. Here we show prolonged circulation of polyMPC-DOX, with a measured in vivo half-life (t1/2) 8 times greater than that of the free drug. We observed reduced drug uptake in healthy tissue, and 2-3 times enhanced drug accumulation in tumors for polyMPC-DOX prodrugs compared to free DOX, using BALB/c mice bearing 4T1 tumors. Prolonged survival and reduced tumor growth were observed in mice receiving the polyMPC-DOX prodrug treatment. Moreover, we evaluated immunogenicity of polyMPC-DOX prodrugs by examining complete blood count (CBC) and characteristic cytokine responses, demonstrating no apparent innate or adaptive immune system response.
- AN INSIGHT INTO THE BINDING MECHANISM OF IMIPENEM TO HUMAN SERUM ALBUMIN BY SPECTROSCOPIC AND COMPUTATIONAL APPROACHES. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 17.
The mechanism of interaction between imipenem and HSA was investigated by various techniques like fluorescence, UV-Vis absorbance, FRET, circular dichroism, urea denaturation, enzyme kinetics, ITC and molecular docking. We found that imipenem binds to HSA at a high affinity site located in sub-domain IIIA (Sudlow's site I) and a low affinity site located in sub-domain IIA-IIB. Electrostatic interactions played a vital role along with hydrogen bonding and hydrophobic interactions in stabilizing imipenem-HSA complex at sub-domain IIIA, while only electrostatic and hydrophobic interactions were present at sub-domain IIA-IIB. The binding and thermodynamic parameters obtained by ITC showed that the binding of imipenem to HSA was a spontaneous process ( = -32.31 kJ mol-1 for high affinity site and = -23.02 kJ mol-1 for low affinity site) with binding constants in the range of 104-105 M-1. Spectroscopic investigation revealed only one binding site of imipenem on HSA (Ka~104 M-1). FRET analysis showed that the binding distance between imipenem and HSA (Trp-214) was optimal (r = 4.32 nm) for quenching to occur. Decrease in esterase-like activity of HSA in the presence of imipenem showed that Arg-410 and Tyr-411 of sub-domain IIIA (Sudlow's site II) were directly involved in the binding process. CD spectral analysis showed altered conformation of HSA upon imipenem binding. Moreover, the binding of imipenem to sub-domain IIIA (Sudlow's site II) of HSA also affected its folding pathway as clear from urea-induced denaturation studies.
- MicroRNAs and Drug Resistance in Prostate Cancer. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 17.
Prostate cancer is the second leading cause of cancer related death in American men. Androgen deprivation therapy (ADT) is used to treat patients with aggressive prostate cancers. After androgen deprivation therapy, prostate cancers slowly progress to an androgen-independent status. Taxanes (e.g. docetaxel) are used as standard treatments for androgen-independent prostate cancers. However, these chemotherapeutic agents will eventually become ineffective due to the development of drug resistance. A microRNA (miRNA) is a small non-coding RNA molecule which can regulate gene expression at the post-transcription level. miRNAs elicit their effects by binging to the 3'-untranslated region (3'-UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNAs. miRNAs have received increasing attention as targets for cancer therapy, as they can target multiple signaling pathways related to tumor progression, metastasis, invasion, and chemoresistance. Emerging evidence suggests that aberrant expression of miRNAs can lead to the development of resistant prostate cancers. Here, we discuss the roles of miRNAs in the development of resistant prostate cancers and their involvement in various drug resistant mechanisms including androgen signaling, apoptosis avoidance, MDR transporters, epithelialmesenchymal transition (EMT), and cancer stem cells (CSCs). In addition, we also discuss strategies for treating resistant prostate cancers by targeting specific miRNAs. Different delivery strategies are also discussed with focus on those have been successfully used in human clinical trials.
- Lyotropic Liquid Crystalline Nanoparticles of CoQ10: Implication of Lipase Digestibility on Oral Bioavailability, in Vivo antioxidant activity, and in Vitro-in Vivo Relationships. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 17.
The present investigation reports implications of the lipase digestibility of lyotropic liquid crystalline nanoparticles (LCNPs) on the oral bioavailability, in vivo antioxidant potential, and in vitro-in vivo relationship (IVIVR) of CoQ10 loaded LCNPs prepared from glyceryl monooleate (GLCQ) and phytantriol (PLCQ). Exhaustive optimization of the process variables was carried out, and optimized lyophilized formulations were found to have particle sizes of 140.45 ± 5.47 nm and 238.42 ± 8.35 nm and a polydispersity index (PDI) of 0.15 ± 0.01 and 0.22 ± 0.03 for GLCQ and PLCQ, respectively. The entrapment efficiency at 10% theoretical loading was found to be >90% in both the cases. The morphological characteristics of the developed formulations were assessed using high resolution transmission electron microscopy and small-angle X-ray scattering analysis, which showed hexagonal (HII) structure. The developed formulations were also found to be stable in simulated gastrointestinal fluids for the stipulated period of time. The in vitro drug release studies revealed a bimodal sustained release drug profile with Higuchi type release kinetics as the best fit release model for both the formulations. The best fit release models were found to be of the Hixson Crowell type in the case of GLCQ when carried out in lipase rich media, suggestive of matrix erosion and subsequent formation of secondary structures, which was further corroborated by carrier degradation studies. Furthermore, 9.1- and 10.67-fold increase in Caco-2 cell uptake was observed in the case of GLCQ and PLCQ, respectively, attributed to the formation of the virtual channel pathway as a probable absorption mechanism. Consequently, 7.09- and 8.67-fold increase in oral bioavailability was observed in the case of GLCQ and PLCQ, respectively. The IVIVR was also established with r(2) values in the order of 0.996 and 0.999 for GLCQ and PLCQ, respectively, in contrast to that of 0.484 for free CoQ10. Finally, in vivo prophylactic antioxidant efficacy against the STZ-treated rats using various markers such as GSH, LDH, SOD, MDA, glucose level, and body weight showed significantly higher antioxidant activity of CoQ10-LCNPs as compared to that of free CoQ10. In a nutshell, the developed formulation strategy poses great potential in improving the oral bioavailability of difficult-to-deliver drugs such as CoQ10.
- Aptamer-targeted DNA nanostructures for therapeutic delivery. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 16.
DNA-based nanostructures have been widely used in various applications due to their structural diversity, programmability, and uniform structures. Their intrinsic biocompatibility and biodegradability further motivates the investigation of DNA-based nanostructures as delivery vehicles. Incorporating AS1411 aptamers into DNA pyramids leads to enhanced intracellular uptake and selectively inhibits the growth of cancer cells, achieved without the use of transfection reagents. Furthermore, aptamer-displaying pyramids are found to be substantially more resistant to nuclease degradation than single-stranded aptamers. These findings, along with their modularity, reinforce the potential of DNA-based nanostructures for therapeutic applications.
- The design and applications of bispecific heterodimers: molecular imaging and beyond. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 16.
Ligand-based molecular imaging probes have been designed with high affinity and specificity for monitoring biological process and responses. Single target recognition by traditional probes can limit their applicability for disease detection and therapy as synergistic action between disease mediators and different receptors are often involved in disease progression. Consequently, probes that can recognize multiple targets should demonstrate higher targeting efficacy and specificity than their mono-specific peers. This concept has been validated by multiple bispecific heterodimer-based imaging probes with promising results in several animal models. This review summarizes the design strategies for bispecific peptide and antibody-based heterodimers and their applications in molecular targeting and imaging. The design and application of bispecific heterodimer-conjugated nanomaterials are also discussed.
- Enhanced humoral and cell-mediated immune responses generated by cationic polymer-coated PLA microspheres with adsorbed HBsAg. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 16.
Surface-engineered particulate delivery systems for vaccine administration have been widely investigated in experimental and clinical studies. However, little is known about charge-coated microspheres as potential recombinant subunit protein antigen delivery systems in terms of adsorption and related immune responses. In the present study, cationic polymers, including chitosan (CS), chitosan chloride (CSC), and polyethylenimine (PEI), were used to coat PLA microspheres to build positively charged surfaces. Antigen adsorption capacity was enhanced with increased surface charge of coated microspheres. In macrophages, HBsAg adsorbed on the surface of cationic microspheres specifically enhanced antigen uptake and augmented CD86, MHC I, and MHC II expression and IL-1β, IL-6, TNF-α, and IL-12 release. Antigens were more likely to localize independent of lysosomes after phagocytosis in antigen-attached cationic microsphere formulations. After intraperitoneal immunization, cationic microsphere-based vaccine formulations generated a rapid and efficient humoral immune response and cytokine release as compared with aluminum-adsorbed vaccine and free antigens in vivo. Moreover, microspheres coated with cationic polymers with relatively high positive charges and higher antigen adsorption exhibited strong stimulation of the Th1 response. In conclusion, PLA microspheres coated with cationic polymers may be a potential recombinant antigen delivery system to induce strong cell and humoral immune responses.
- A Tumor Environment Responsive Doxorubicin-loaded Nanoparticle for Targeted Cancer Therapy. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 15.
Doxorubicin (DOX) is a potent cancer chemotherapeutic agent but its clinical use is severely limited by potentially lethal cardiotoxicity. Delivery of DOX by particulate carriers can be an effective way to reduce its distribution in cardiac tissue. In the present study, we developed a self-assembled, tumor-microenvironment-responsive delivery system for DOX. The core of the carrier was built upon the DOX/DNA intercalation, which was further combined with cationic gelatin (C-gel) to form the complex GDD. GDD was then packaged into a complex, namely HDD, based on the electrostatic interactions between the positively charged C-gel and negatively charged human serum albumin (HSA). The HSA molecules on the surface of the complex HDD effectively helped the particle evade the filtration of the body when injected into the circulation and passively accumulate into the tumor sites. After entering the tumor tissue, where albumin is rapidly consumed, GDD was release from HDD and the C-gel was then digested by the tumor-specific matrix metalloproteinase (MMPs) to free the DOX/DNA intercalation. Deoxyribonucleases (DNases) in the tissue could completely destroy the DNA molecules to release DOX into the microenvironments. After a series of in vitro optimization tests, we evaluated the anti-cancer capacity and cardiac toxicity of HDD in two animal models with cancer. The results suggested that HDD had a higher anti-cancer efficacy and a significantly lower cardiotoxicity than free DOX. Additionally, the main components of the carrier are all clinically approved materials. Taken together, our present delivery system is safe, efficient and has high potential for further clinical trials.
- Hepatic-targeted gene delivery using cationic mannan vehicle. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 15.
The incidence of hepatic diseases continuously increases worldwide and causes significant mortality because of inefficient pharmacotherapy. Gene therapy is a new strategy in the treatment of hepatic diseases, but the disadvantages of insufficient retention in the liver and undesirable side effects hinder its application. In this study, we developed a novel non-viral vehicle targeted to liver. Mannan was cationized with spermine at varying grafted ratios to deliver the gene and was optimized in cytotoxicity and transfection in vitro. Spermine-mannan (SM)-based delivery system was proven to be hepatic targeted and was capable of prolonging the gene retention period in the liver. Moreover, SM at N/P of 20 was confirmed to be less interfered by the serum. Optimized SM vehicle has relatively high hepatic transfection with almost no toxicity induction in the liver, which highlighted its potential in the treatment of hepatic diseases.
- A novel doxorubicin-loaded in situ forming gel based high concentration of phospholipid for intratumoral drug delivery. [JOURNAL ARTICLE]
- Mol Pharm 2014 Apr 15.
The purpose of the study was to develop a safe and effective drug delivery system for local chemotherapy. A novel injectable in situ forming gel system was prepared using small molecules materials, including phospholipid, medium chain triglycerides and ethanol. Thus, this new sustained release system was named as PME (first letter of phospholipid, MCT and ethanol). PME has a well-defined molecule structure, a high degree of safety and better biocompatible characters. It was in sol state with low viscosity in vitro and turned into a solid or semi-solid gel in situ after injection. When loaded with Doxorubicin (Dox), PME-D (doxorubicin-loaded PME) exhibited notably antitumor efficiency in S180 sarcoma tumors bearing mice after a single intratumoral injection. In vitro, PME-D had remarkable anti-proliferative efficacies against MCF-7 breast cancer cells for over 5 days. Moreover, initial burst effect can hardly be observed from PME system, which was different from many other in situ forming gels. In vivo biodistribution study showed the high Dox concentration in tumor compared with other major organs after PME-D intratumoral administration. The strong signal in tumor retained for more than 14 days after one single injection. The high concentration of Dox in tumor and long-term retention may explain the superior therapeutic efficacy and reduced side effect. The PME-D in situ-forming gel system is a promising drug delivery system for local chemotherapy.