Hima Bindu Ruttala

Smart chemistry-based nanosized drug delivery systems for systemic applications: A comprehensive review

This review focuses on the smart chemistry that has been utilized in developing polymer-based drug delivery systems over the past 10years. We provide a comprehensive overview of the different functional moieties and reducible linkages exploited in these systems, and outline their design, synthesis, and application from a therapeutic efficacy viewpoint. Furthermore, we highlight the next generation nanomedicine strategies based on this novel chemistry.

Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors

In this study, we report a facile method to construct a bioactive (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) polypeptide nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The smart pH-sensitive nanovehicle was fabricated with precisely tailored drug-to-carrier ratio that resulted in accelerated, sequential drug release. As a result of ratiometric loading, QUR could significantly enhance the cytotoxic potential of DOX, induced marked cell apoptosis; change cell cycle patterns, inhibit the migratory capacity of sensitive and resistant cancer cells. In particular, pro-oxidant QUR from DQ-NV remarkably reduced the GSH/GSSG ratio, indicating high oxidative stress and damage to cellular components. DQ-NV induced tumor shrinkage more effectively than the single drugs in mice carrying subcutaneous SCC-7 xenografts. DQ-NV consistently induced high expression of caspase-3 and PARP and low expression of Ki67 and CD31 immunomarkers. In summary, we demonstrate the development of a robust polypeptide-based intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy. STATEMENT OF SIGNIFICANCE In this study, we report a facile method to construct bioactive and biodegradable polypeptide nanovehicles as an advanced platform technology for application in cancer therapy. We designed a robust (poly(phenylalanine)-b-poly(l-histidine)-b-poly(ethylene glycol) nanoconstruct to co-load doxorubicin (DOX) and quercetin (QUR) (DQ-NV). The conformational changes of the histidine block at tumor pH resulted in accelerated, sequential drug release. QUR could significantly enhance the cytotoxic potential of DOX, induce marked cell apoptosis, change cell cycle patterns, and inhibit the migratory capacity of sensitive and resistant cancer cells. DQ-NV induced tumor shrinkage more effectively than the single drugs and the 2-drug cocktail in tumor xenografts. In summary, we demonstrate the development of an intracellular nanovehicle for synergistic delivery of DOX/QUR in cancer chemotherapy.

Eudragit-coated aceclofenac-loaded pectin microspheres in chronopharmacological treatment of rheumatoid arthritis

Abstract The aim of this study was to develop a pectin-based colon-specific multiparticulate delivery system. Aceclofenac was used as a model drug owing to its potential therapeutic efficacy in rheumatoid arthritis. Pectin microspheres were prepared using emulsion dehydration technique. These microspheres were coated with Eudragit S-100 using solvent evaporation method. The effect of different variables (polymer, emulsifier, stirring speed and stirring time) was investigated in terms of size, surface morphology, entrapment efficiency, in vitro release and in vivo studies. The size of uncoated microspheres ranged from 30 to 55 µm and exhibited 5–40% of drug release in the upper gastrointestinal tract; however, continuous high release of drug was observed at colonic pH. In addition, the release of drug from the microspheres was found to be higher in the presence of rat cecal contents with maximum release at the 8th hour. This is one of the prerequisites for the effective treatment of rheumatoid arthritis, indicating the effect of colonic enzymes on the pectin microspheres. In vivo studies suggest the maintenance of therapeutic concentration of drug for 24 h with significant anti-inflammatory effect. Therefore, these findings clearly suggest that the Eudragit-coated pectin microspheres offer an exciting mode of aceclofenac delivery to colon in the chronopharmacological treatment of rheumatoid arthritis.

Layer-by-layer assembly of hierarchical nanoarchitectures to enhance the systemic performance of nanoparticle albumin-bound paclitaxel.

Although protein-bound paclitaxel (PTX, Abraxane®) has been established as a standard PTX-based therapy against multiple cancers, its clinical success is limited by unfavorable pharmacokinetics, suboptimal biodistribution, and acute toxicities. In the present study, we aimed to apply the principles of a layer-by-layer (LbL) technique to improve the poor colloidal stability and pharmacokinetic pattern of nanoparticle albumin-bound paclitaxel (nab-PTX). LbL-based nab-PTX was successfully fabricated by the alternate deposition of polyarginine (pARG) and poly(ethylene glycol)-block-poly (L-aspartic acid) (PEG-b-PLD) onto an albumin conjugate. The presence of protective entanglement by polyamino acids prevented the dissociation of nab-PTX and improved its colloidal stability even at a 100-fold dilution. The combined effect of high nanoparticle internalization and controlled release of PTX from LbL-nab-PTX increased its cytotoxicity in MCF-7 and MDA-MB-231 breast cancer cells. LbL-nab-PTX consistently induced apoptosis in approximately 52% and 22% of MCF-7 and MDA-MB-231 cancer cells, respectively. LbL assembly of polypeptides effectively prevented exposure of PTX to the systemic environment and thereby inhibited drug-induced hemolysis. Most importantly, LbL assembly of polypeptides to nab-PTX effectively increased the blood circulation potential of PTX and improved therapeutic efficacy via a significantly higher area under the curve (AUC)0-∞. We report for the first time the application of LbL functional architectures for improving the systemic performance of nab-PTX with a view toward its clinical translation for cancer therapy.

Molecularly targeted co-delivery of a histone deacetylase inhibitor and paclitaxel by lipid-protein hybrid nanoparticles for synergistic combinational chemotherapy

In this study, a transferrin-anchored albumin nanoplatform with PEGylated lipid bilayers (Tf-L-APVN) was developed for the targeted co-delivery of paclitaxel and vorinostat in solid tumors. Tf-L-APVN exhibited a sequential and controlled release profile of paclitaxel and vorinostat, with an accelerated release pattern at acidic pH. At cellular levels, Tf-L-APVN significantly enhanced the synergistic effects of paclitaxel and vorinostat on the proliferation of MCF-7, MDA-MB-231, and HepG2 cancer cells. Vorinostat could significantly enhance the cytotoxic potential of paclitaxel, induce marked cell apoptosis, alter cell cycle patterns, and inhibit the migratory capacity of cancer cells. In addition, Tf-L-APVN showed prolonged circulation in the blood and maintained an effective ratio of 1:1 (for paclitaxel and vorinostat) throughout the study period. In HepG2 tumor-bearing mice, Tf-L-APVN displayed excellent antitumor efficacy and the combination of paclitaxel and vorinostat significantly inhibited the tumor growth. Taken together, dual drug-loaded Tf receptor-targeted nanomedicine holds great potential in chemotherapy of solid tumors.

Multiple polysaccharide–drug complex-loaded liposomes: A unique strategy in drug loading and cancer targeting

In the present study, a unique strategy was developed to develop nanocarriers containing multiple therapeutics with controlled release characteristics. In this study, we demonstrated the synthesis of dextran sulfate-doxorubicin (DS-DOX) and alginate-cisplatin (AL-CIS) polymer-drug complexes to produce a transferrin ligand-conjugated liposome. The targeted nanoparticles (TL-DDAC) were nano-sized and spherical. The targeted liposome exhibited a specific receptor-mediated endocytic uptake in cancer cells. The enhanced cellular uptake of TL-DDAC resulted in a significantly better anticancer effect in resistant and sensitive breast cancer cells compared to that of the free drugs. Specifically, DOX and CIS at a molar ratio of 1:1 exhibited better therapeutic performance compared to that of other combinations. The combination of an anthracycline-based topoisomerase II inhibitor (DOX) and a platinum compound (CIS) resulted in significantly higher cell apoptosis (early and late) in both types of cancer cells. In conclusion, treatment with DS-DOX and AL-CIS based combination liposomes modified with transferrin (TL-DDAC) was an effective cancer treatment strategy. Further investigation in clinically relevant animal models is warranted to prove the therapeutic efficacy of this unique strategy.

Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy

In this study, we developed pH and redox-responsive crosslinked polypeptide-based combination micelles for enhanced chemotherapeutic efficacy and minimized side effects. The stability and drug release properties of the polypeptide micelles were efficiency balanced by the corona-crosslinking of the triblock copolymer, poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr) with coordinated redox and pH dual-sensitivity by introducing disulfide crosslinkages. Because of the crosslinking of the middle shell of the triblock polypeptide micelles, their robust structure was maintained in strong destabilization conditions and exhibited excellent stability. GSH concentrations were significantly higher in tumor tissue than in normal tissue, which formed the basis for our design. Drug release was elevated under redox and low acidic conditions. Furthermore, crosslinked micelles showed a superior anticancer effect compared to that of non-crosslinked micelles. Incorporation of docetaxel (DTX) and lonidamine (LND) in crosslinked polypeptide micelles increased the intracellular reactive oxygen species (ROS) level and oxidative stress and caused damage to intracellular components that resulted in greater apoptosis of cancer cells than when DTX or LND was used alone. The combination of DTX and LND in crosslinked micelles exhibited efficacious inhibition of tumor growth with an excellent safety profile compared to that reported for drug cocktail combinations and non-crosslinked micelles. Overall, redox/pH-responsive polypeptide micelles could be an interesting platform for efficient chemotherapy. STATEMENT OF SIGNIFICANCE We have synthesized a biodegradable polypeptide block copolymer to construct a facile pH and redox-responsive polymeric micelle asan advanced therapeutic system for cancer therapy. We have designed a corona-crosslinked triblock copolymer (poly (ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr)) micelles co-loaded with docetaxel and lonidamine (cl-M/DL). The corona of triblock polymer was crosslinked to maintain its structural integrity in the physiological environment. The mitochondrial targeting LND is expected to generate ROS, oxidative stress and thereby synergize the chemotherapeutic efficacy of DTX in killing cancer cells. Consistently, cl-M/DL exhibited excellent antitumor efficacy in xenograft tumor model with remarkable tumor regression. Overall, we demonstrated the construction of bioreducible nanosystem for the effective synergistic delivery of DTX/LND in tumor tissues towards cancer treatment.

Multimodal selenium nanoshell-capped Au@mSiO 2 nanoplatform for NIR-responsive chemo-photothermal therapy against metastatic breast cancer

Multimodal therapeutic agents based on novel nanomaterials for multidrug resistance have attracted increasing attention in cancer therapy. In this study, we describe the construction of a programmed mesoporous silica-capped gold nanorod covered with nano-selenium overcoat (Se@Au@mSiO2) nanoparticles as a multifunctional nanoplatform to incorporate materials with specific chemotherapeutic, chemoprevention, and photoablation/hyperthermia functions that collectively contribute to enhance anticancer efficacy in multidrug-resistant breast cancer. The triple-combination-based nanosized Se@Au@mSiO2/DOX effectively accumulates in the tumor and the release of the therapeutic cargo could be remotely manipulated by mild near-infrared (NIR) irradiation. Se@Au@mSiO2/DOX notably enhances the cell killing effect through induction of cell apoptosis. In addition, Se@Au@mSiO2/DOX inhibits tumor cell growth through cell cycle arrest and induction of apoptosis via suppression of the Src/FAK/AKT signaling pathways. Synergistic Se-photothermal-chemotherapy combination exhibits significant tumor growth suppression and delayed tumor progression in vivo. Immunohistochemistry analysis shows elevated numbers of caspase-3 and PARP-immunolabeled cells and decreased Ki-67 +  and CD31 + cancer cells in the tumor mass. No noticeable signs of organ damage or toxicity are observed after treatment with Se@Au@mSiO2/DOX (NIR+), which is further supported by hematology and biochemical analyses. Thus, Se@Au@mSiO2/DOX has potential for the clinical treatment of metastatic breast cancers with little or no adverse effects.Nanomedicine: Delivering a triple blow to breast cancerMultidrug-resistant breast cancers can be overcome with a carrier containing chemotherapies and laser-active nanorods coated with selenium. Multimodal agents employing nanomaterials are attracting attention for treating multidrug-resistant cancer cells. In particular, recent studies suggest that anticancer agents combined with selenium could reduce toxic side-effects during treatment of stubborn, metastatic tumors. Jong Oh Kim at Korea’s Yeungnam University and colleagues have now added another cancer-killing technique to the co-delivery approach—using light-absorbing nanorods to heat tumor cells. The team used this laser sensitivity for on-demand release of doxorubicin drugs from a silica-nanoparticle carrier holding selenium-covered gold nanorods. Additional in vitro and mouse tests revealed that the nanomedicine enhanced tumor cell death, partly through suppressing critical signaling pathways. The absence of organ damage during animal testing bodes well for future clinical trials of selenium-based drug delivery.A novel nanoplatform was designed by assembling nano-Se on the surface of NIR-responsive Au@mSiO2/DOX nanoparticles for the effective treatment of metastatic breast cancer (Se@Au@mSiO2/DOX).

Emerging potential of stimulus-responsive nanosized anticancer drug delivery systems for systemic applications

The development of novel drug delivery systems based on well-defined polymer therapeutics has led to significant improvements in the treatment of multiple disorders. Advances in material chemistry, nanotechnology, and nanomedicine have revolutionized the practices of drug delivery. Stimulus-responsive material-based nanosized drug delivery systems have remarkable properties that allow them to circumvent biological barriers and achieve targeted intracellular drug delivery. Specifically, the development of novel nanocarrier-based therapeutics is the need of the hour in managing complex diseases. In this review, we have briefly described the fundamentals of drug targeting to diseased tissues, physiological barriers in the human body, and the mechanisms/modes of drug-loaded carrier systems. To that end, this review serves as a comprehensive overview of the recent developments in stimulus-responsive drug delivery systems, with focus on their potential applications and impact on the future of drug delivery.

Polyunsaturated fatty acid-based targeted nanotherapeutics to enhance the therapeutic efficacy of docetaxel

Abstract Since breast cancer is one of the most lethal malignancies, targeted strategies are urgently needed. In this study, we report the enhanced therapeutic efficacy of docetaxel (DTX) when combined with polyunsaturated fatty acids (PUFA) for effective treatment of multi-resistant breast cancers. Folic acid (FA)-conjugated PUFA-based lipid nanoparticles (FA-PLN/DTX) was developed. The physicochemical properties, in vitro uptake, in vitro cytotoxicity, and in vivo anticancer activity of FA-PLN/DTX were evaluated. FA-PLN/DTX could efficiently target and treat human breast tumor xenografts in vivo. They showed high payload carrying capacity with controlled release characteristics and selective endocytic uptake in folate receptor-overexpressing MCF-7 and MDA-MB-231 cells. PUFA synergistically improved the anticancer efficacy of DTX in both tested cancer cell lines by inducing a G2/M phase arrest and cell apoptosis. Combination of PUFA and DTX remarkably downregulated the expression levels of pro-apoptotic and anti-apoptotic markers, and blocked the phosphorylation of AKT signaling pathways. Compared to DTX alone, FA-PLN/DTX showed superior antitumor efficacy, with no signs of toxic effects in cancer xenograft animal models. We propose that PUFA could improve the therapeutic efficacy of anticancer agents in cancer therapy. Further studies are necessary to fully understand these findings and achieve clinical translation.