cRGD-Peptide Modified Covalent Organic Frameworks for Precision Chemotherapy in Triple-Negative Breast Cancer.

This study presents the use of nanoscale covalent organic frameworks (nCOFs) conjugated with tumor-targeting peptides for the targeted therapy of triple-negative breast cancer (TNBC). While peptides have previously been used for targeted delivery, their conjugation with COFs represents an innovative approach in this field. In particular, we have developed alkyne-functionalized nCOFs chemically modified with cyclic RGD peptides (Alkyn-nCOF-cRGD). This configuration is designed to specifically target αvß3 integrins that are overexpressed in TNBC cells. These nCOFs exhibit excellent biocompatibility and are engineered to selectively disintegrate under acidic conditions, allowing for precise and localized drug release in tumor environment. Doxorubicin, a chemotherapeutic agent, has been encapsulated in these nCOFs with high loading efficiency. The therapeutic potential of Alkyn-nCOF-cRGD has been demonstrated in vitro and in vivo models. It shows significantly improved drug uptake and targeted cell death in TNBC, highlighting the efficacy of receptor-mediated endocytosis and pH-controlled drug release. This strategy leverages the unique properties of nCOFs with targeted drug delivery to achieve significant advances in personalized cancer therapy and set a new standard for precision chemotherapeutic delivery.

Highly functionalized pH-triggered supramolecular nanovalve for targeted cancer chemotherapy.

Chemotherapeutic drug delivery systems are commonly limited by their short half-lives, poor bioavailability, and unsuccessful targetability. Herein, pH-responsive hybrid NPs consist of benzimidazole-coated mesoporous silica nanoparticles (BZ-MSN) loaded with naturally occurring flavonoid quercetin (QUE-BZ-MSN). The NPs were further capped with beta-cyclodextrin (BCD) to obtain our desired BCD-QUE-BZMSN, with a zeta potential around 7.05 ± 2.37 mV and diameter about 115.2 ± 19.02 nm. The abundance of BZ onto the nanoparticles facilitates targeted quercetin chemotherapy against model lung and liver cancer cell lines. FTIR, EDX, and NMR analyses revealed evidence of possible surface functionalizations. Powder XRD analysis showed that our designed BCD-QUE-BZMSN formulation is amorphous in nature. The UV and SEM showed that our designed BCD-QUE-BZMSN has high drug entrapment efficiency and a nearly spherical morphology. In vitro, drug release assessments show controlled pH-dependent release profiles that could enhance the targeted chemotherapeutic response against mildly acidic regions in cancer cell lines. The obtained BCD-QUE-BZMSN nanovalve achieved significantly higher cytotoxic efficacy as compared to QUE alone, which was evaluated by in vitro cellular uptake against liver and lung cancer cell lines, and the cellular morphological ablation was further confirmed via inverted microscopy. The outcomes of the study imply that our designed BCD-QUE-BZMSN nanovalve is a potential carrier for cancer chemotherapeutics.

pH-responsive chitosan copolymer synthesized via click chemistry for design of polymeric nanoparticles for targeted drug delivery.

The polymeric nanoparticles (PNPs) loaded with prednisolone were developed to exhibit pH-responsive properties owing to the attachment of a hydrazone linkage between the copolymer chitosan and mPEG. In the diseased cellular environment, the hydrazone bond tends to break due to reduced pH, leading to the release of the drug from the PNPs at the required site of action. The fabricated PNPs exhibit spherical morphology, optimum size (∼200 nm), negative surface charge, and monodispersed particle size distribution. The encapsulation efficiency of the PNPs was determined to be 71.1 ± 0.79 % and two experiments (polymer weight loss and drug release) confirmed the pH-responsive properties of the PNPs. The cellular study cytotoxicity assay showed biocompatibility of PNPs and drug molecule-mediated toxicity to A549 cells. The ligand atrial natriuretic peptide-attached PNPs internalized into A549 cells via natriuretic peptide receptor-A to achieve target specificity. The PNPs cytotoxicity and pH-response medicated inflammation reduction functionality was studied in inflammation-induced RAW264.7 cell lines. The study observed the PNPs effectively reduced the inflammatory mediators NO and ROS levels in RAW264.7. The results showed that pH-responsive properties of PNPs and this novel fabricated delivery system effectively treat inflammatory and cancer diseases.

pH stimulus-responsive hybrid nanoparticles: A system designed for follicular delivery of brazilian plant-derived 5-alpha-reductase enzyme inhibitors.

The 5-alpha-reductase enzyme, present in pilosebaceous units, plays a crucial role in the appearance of cutaneous hyperandrogenism manifestations (hirsutism, acne, and androgenetic alopecia). Its inhibition is an excellent strategy to reverse these conditions. Given the limitations of existing treatments, with transient effects and delayed therapeutic response, as well as the possibility of causing undesirable side effects, this study sought to develop new drug delivery systems to overcome these limitations. In other words, innovative stimuli-responsive hybrid nanoparticles were synthesized using silica/natural polysaccharides, encapsulating 5-alpha-reductase enzyme inhibitors derived from the plant Stryphnodendron adstringens (Mart.) Coville (commonly known as 'Barbatimão'). Silica core was synthesized by the modified Stöber method. The pH responsive polysaccharides used to coat the porous silica cores were chitosan, and sodium alginate, this coating was carried out using the Layer-by-Layer technique. The hybrid nanoparticles were characterized at molecular and physical-chemical levels. Furthermore, encapsulation efficiency, pH-dependent release behavior, and cytotoxicity were evaluated. Amorphous mesoporous structure with adequate size for follicular delivery (between 300 and 600 nm) in addition to effective phytocompound loading capacity, above 80 % was obtained. Based on the release studies, it was possible to observe pH responsiveness. The ethyl acetate fraction (EAF) obtained from "Barbatimão" bark extract was released in a controlled and more efficient manner by the alginate-coated nanoparticle (SNP_EAF_SA) at pH 7.4, which corresponds to the pH at the deepest area of hair follicles. Furthermore, SNP_EAF_SA proved to be less cytotoxic compared to EAF and chitosan-coated hybrid nanoparticles (SNP_EAF_CH). Characterization, release, and cytotoxicity results indicate that SNP_EAF_SA is a promising system for on-demand follicular delivery of antiandrogenic actives contained in EAF.

pH-responsive shell-sheddable polymeric nanoparticles as the photodynamic drug carrier: synthesis, characterization, and in vitro studies.

Shell-sheddable nanoparticles, composed of amphiphilic blockpolymers, have emerged as an attractive vehicle for the site-specific delivery of therapeutic agents. In this study, pH-responsive sheddable copolymers bearing an orthoester linker were synthesized via the ring-opening polymerization between γ-benzyl-L-glutamate N-carboxyanhydride and orthoester-bearing poly (ethylene glycol) macroinitiator (PEG-pH-NH2). The obtained poly (ethylene glycol)-b-poly(γ-benzyl-L-glutamate) (PEG-PBLG) could form stable nanoparticles in aqueous solutions due to the amphiphilic nature of the block copolymers. The PEG-PBLG-based nanoparticle exhibited good stability in physiological conditions (pH 7.4), whereas the nanoparticle was disassembled under acidic conditions (pH 5.0). The nanoparticles could encapsulate a photosensitizer, protophorphyrin IX (PpIX), and deliver it into acidic environments. According to optical imaging test, it was found that quenched fluorescence signal of PpIX highly recovered under acidic conditions. Acid-responsive sheddable nanoparticles rapidly release the PpIX when they are incubated under acidic conditions (pH 5.0), and the PpIX release was remarkably reduced in physiological buffer (pH 7.4). In vitro cytotoxicity test showed that cells treated with pH-responsive sheddable nanoparticle became highly phototoxic upon irradiation. Microscopic observation demonstrated that PpIX-loaded nanoparticle rapidly degraded at the endosome of SCC7 cancer cells, which enabled PpIX release into the cancer cells. These results suggest that pH-responsive sheddable are a promising carrier for photodynamic agents.

Genome editing mRNA nanotherapies inhibit cervical cancer progression and regulate the immunosuppressive microenvironment for adoptive T-cell therapy.

CRISPR/Cas9-based genome editing is promising for therapy of cervical cancer by precisely targeting human papillomavirus (HPV). To develop CRISPR/Cas9-based genome editing nanotherapies, a pH-responsive hybrid nonviral nanovector was constructed for co-delivering Cas9 mRNA and guide RNAs (gRNAs) targeting E6 or E7 oncogenes. The pH-responsive nanovector was fabricated using an acetalated cyclic oligosaccharide (ACD), in combination with low molecular weight polyethyleneimine. Thus obtained hybrid ACD nanoparticles (defined as ACD NP) showed efficient loading for both Cas9 mRNA and E6 or E7 gRNA, giving rise to two pH-responsive genome editing nanotherapies E6/ACD NP and E7/ACD NP, respectively. Cellularly, ACD NP exhibited high transfection but low cytotoxicity in HeLa cervical carcinoma cells. Also, efficient genome editing of target genes was achieved in HeLa cells, with minimal off-target effects. In mice bearing HeLa xenografts, treatment with E6/ACD NP or E7/ACD NP afforded effective editing of target oncogenes and considerable antitumor activities. More importantly, treatment with E6/ACD NP or E7/ACD NP notably promoted CD8+ T cell survival by reversing the immunosuppressive microenvironment, thereby leading to synergistic antitumor effects by combination therapy using the gene editing nanotherapies and adoptive T-cell transfer. Consequently, our pH-responsive genome editing nanotherapies deserve further development for the treatment of HPV-associated cervical cancer, and they can also serve as promising nanotherapies to improve efficacies of other immune therapies against different advanced cancers by regulating the immunosuppressive tumor microenvironment.

Smartphone-based pH responsive 3-channel colorimetric biosensor for non-enzymatic multi-antibiotic residues.

Antibiotic residues in animal-derived food pose a risk to food safety and human health. Here, a smartphone-based pH-responsive 3-channel colorimetric biosensor is constructed for rapid detection of non-enzymatic multi-antibiotic residues in milk. In this system, a magnetic separation and enrichment approach is designed to specifically capture different antibiotic residues in complex environment. Indicators loaded on polydopamine-silver nanoparticles with excellently pH responsive visualization properties are utilized to ensure the high sensitivity of detection system. Moreover, smartphones are introduced to fulfill the demand for portable and on-site inspection of practical applications. It achieves simultaneous detection of oxytetracycline, kanamycin and streptomycin in the linear range of 1-105 pg/mL with detection limits of 0.085, 0.168, and 0.307 pg/mL, respectively. The practicality of the reported multi-antibiotic residues detection system is successfully demonstrated and evaluated challenging milk samples. Therefore, this system demonstrates the wide applications in multi-antibiotic residue analysis and food safety guarantee.

Stimuli-sensitive nano-drug delivery with programmable size changes to enhance accumulation of therapeutic agents in tumors.

Nano-based drug delivery systems hold significant promise for cancer therapies. Presently, the poor accumulation of drug-carrying nanoparticles in tumors has limited their success. In this study, based on a combination of the paradigms of intravascular and extravascular drug release, an efficient nanosized drug delivery system with programmable size changes is introduced. Drug-loaded smaller nanoparticles (secondary nanoparticles), which are loaded inside larger nanoparticles (primary nanoparticles), are released within the microvascular network due to temperature field resulting from focused ultrasound. This leads to the scale of the drug delivery system decreasing by 7.5 to 150 times. Subsequently, smaller nanoparticles enter the tissue at high transvascular rates and achieve higher accumulation, leading to higher penetration depths. In response to the acidic pH of tumor microenvironment (according to the distribution of oxygen), they begin to release the drug doxorubicin at very slow rates (i.e., sustained release). To predict the performance and distribution of therapeutic agents, a semi-realistic microvascular network is first generated based on a sprouting angiogenesis model and the transport of therapeutic agents is then investigated based on a developed multi-compartment model. The results show that reducing the size of the primary and secondary nanoparticles can lead to higher cell death rate. In addition, tumor growth can be inhibited for a longer time by enhancing the bioavailability of the drug in the extracellular space. The proposed drug delivery system can be very promising in clinical applications. Furthermore, the proposed mathematical model is applicable to broader applications to predict the performance of drug delivery systems.

Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle.

Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disulfiram (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenvironment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.

Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery.

Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.

Smart antimicrobial Pickering emulsion stabilized by pH-responsive cellulose-based nanoparticles.

Responsive antimicrobial materials can control and slow the release of antimicrobial agents smartly by responding to the stimulation of environmental conditions. In this study, we designed the pH-responsive cellulose-based nanoparticles (TOCNC-g-PEI) with amino and carboxyl groups by grafting polyethyleneimine (PEI) to carboxylated cellulose nanocrystals. Finally, the Pickering emulsion was endowed with smart antimicrobial properties by emulsifying the oregano essential oil (OEO) with nanoparticles. The TOCNC-g-PEI25000 had uniform size, greater dispersion, and excellent antimicrobial properties. The contact angles of nanoparticles were 78.70 ± 1.13°, 55.80 ± 1.58° and 55.35 ± 1.56° at neutral conditions, pH 4.0 and 8.0, respectively. The nanoparticles were responding to pH stimulation. The developed emulsion (4:6, 1.30 wt%) had exceptionally stabilized and encapsulated 98.56 ± 1.22 % of the oil phase. The OEO released rapidly within 0-12 h and slowly at 12-36 h. The cumulative release rates quickly reached 93.60 ± 3.73 % (pH 4.0) and 83.25 ± 0.36 % (pH 8.0) and stabilized gradually. The antimicrobial rates of emulsion stimulated for 4 h reached 100 % at pH 4.0, and both of them exceeded 96.10 ± 2.49 % at pH 8.0. The response of Pickering emulsion to pH stimulating controlled release antimicrobial agents and achieved smart antimicrobial.

pH-responsive Astragalus polysaccharide-loaded PLGA nanoparticles as an adjuvant system to improve immune responses.

Modern medical science believes that astragalus polysaccharides (APS) have the efficacy of strengthening immune system, while their peculiarities greatly reduced clinical applications. Poly(lactic-co-glycolic acid) (PLGA) is a synthetic carrier material with outstanding biochemical properties. In this study, PLGA materials were used to prepare the novel pH-responsive targeting drug delivery carriers which were encapsulated APS inside. The OVA-loaded pH-responsive APS-encapsulated PLGA Nanoparticles (OVA-loaded pH-responsive APSPs) and the OVA-loaded APSPs were constructed by multiple emulsion solvent evaporation method. Characterization and immunoenhancing activities of PLGA nanoparticles (NPs) were evaluated in vitro and in vivo. The size of NPs ranged from 142.6 to 194.6 nm, and all NPs were negatively charged. Additionally, pH-responsive APSPs shown violent release behaviors in an acidic environment. pH-responsive APSPs had low cytotoxicity, and significantly enhanced expression of MHC-II, CD80, CD86, and phagocytosis ability of macrophages. Both OVA-loaded NPs could stimulate greater Th1-biased immune responses compared with APS alone, and they could significantly promote proliferation, differentiation, and maturity of splenic lymphocytes and dendritic cells in mice respectively. NPs induced significantly greater antigen-specific IgG antibody responses and expression of IL-4, IL-6, IFN-γ, and TNF-α. Moreover, OVA-loaded pH-responsive APSPs had an aptitude for both cellular and humoral immunity reinforcement during early immunization, while OVA-loaded APSPs had advantages on later stages of immune responses.

Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy.

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.

Application of Fluconazole-Loaded pH-Sensitive Lipid Nanoparticles for Enhanced Antifungal Therapy.

Cryptococcus neoformans is a yeast-like fungus that can cause the life-threatening disease cryptococcal meningitis. Numerous reports have shown increased resistance of this fungus against antifungal treatments, such as fluconazole (Fluc), contributing to an 80% global mortality rate. This work presents a novel approach to improve the delivery of the antifungal agent Fluc and increase the drug's targetability and availability at the infection site. Exploiting the acidic environment surrounding a C. neoformans infected site, we have developed pH-sensitive lipid nanoparticles (LNP) encapsulating Fluc to inhibit the growth of resistant C. neoformans. The LNP-Fluc delivery system consists of a neutral lipid monoolein (MO) and a novel synthetic ionizable lipid 2-morpholinoethyl oleate (O2ME). At neutral pH, because of the presence of O2ME, the nanoparticles are neutral and exhibit a liquid crystalline hexagonal nanostructure (hexosomes). At an acidic pH, they are positively charged with a cubic nanostructure (cubosomes), which facilitates the interaction with the negatively charged fungal cell wall. This interaction results in the MIC50 and MIC90 values of the LNP-Fluc being significantly lower than that of the free-Fluc control. Confocal laser scanning microscopy and scanning electron microscopy further support the MIC values, showing fungal cells exposed to LNP-Fluc at acidic pH were heavily distorted, demonstrating efflux of cytoplasmic molecules. In contrast, fungal cells exposed to Fluc alone showed cell walls mostly intact. This current study represents a significant advancement in delivering targeted antifungal therapy to combat fungal antimicrobial resistance.

pH-Responsive Nanoparticles for Multidimensional Combined Chemo-Immunotherapy of Cancer.

Current research has demonstrated that tumor development and progression are dependent on a multi-cellular interactome, which forms the tumor microenvironment. Multiple components of this multi-cellular ecosystem need to be targeted simultaneously for successful cancer therapy. The objective of this study was to develop a multidimensional combined chemo-immunotherapeutic modality for effective breast cancer treatment. TLR 7/8 agonist resiquimod was identified as a potent macrophage stimulant in an initial screening. To deliver paclitaxel as a chemotherapeutic drug and resiquimod as an immune activator in a tumor-targeted fashion, two different pH-sensitive nanoparticles were synthesized using two different polymers, a linear PLGA and a multi-arm, star-shaped PLGA. The star-PLGA pH-responsive nanoparticles exhibited improved pH-dependent drug release and increased penetration in a complex breast cancer spheroid model (breast cancer cell + macrophage cell). Treatment with paclitaxel and resiquimod encapsulated in the pH-responsive nanoparticles resulted in increased cancer cell death and macrophage activation, as tested in an in-vitro breast cancer spheroid model. Altogether, the current study suggests that the paclitaxel and resiquimod combination has potent chemo-immunotherapeutic activity, and delivery using a pH-sensitive nanoparticle further improves its efficacy.

Threonine-Based Stimuli-Responsive Nanoparticles with Aggregation-Induced Emission-Type Fixed Cores for Detection of Amines in Aqueous Solutions.

Stimuli-responsive polymeric nanoparticles (NPs) exhibit reversible changes in the dispersion or aggregation state in response to external stimuli. In this context, we designed and synthesized core-shell NPs with threonine-containing weak polyelectrolyte shells and fluorescent cross-linked cores, which are applicable for the detection of pH changes and amine compounds in aqueous solution. Stable and uniform NP(dTh) and NP(Fl), consisting of fluorescent symmetric diphenyl dithiophene (dTh) and diphenyl fluorene (Fl) cross-linked cores, were prepared by site-selective Suzuki coupling reactions in self-assembled block copolymer. NP(Fl) with the Fl unit in the core showed a high fluorescence intensity in different solvents, which is regarded as an aggregation-induced emission-type NP showing strong emission in aggregated states in the cross-linked core. Unimodal NPs were observed in water at different pH values, and the diameter of NP(Fl) changed from 122 (pH = 2) to 220 nm (pH = 11). Furthermore, pH-dependent changes of the fluorescence peak positions and intensities were detected, which may be due to the core aggregation derived from the deprotonation of the threonine-based shell fragment. Specific interactions between the threonine-based shell of NP(Fl) and amine compounds (triethylamine and p-phenylenediamine) resulted in fluorescence quenching, suggesting the feasibility of fluorescent amine detection.

Targeted Cancer Therapy via pH-Functionalized Nanoparticles: A Scoping Review of Methods and Outcomes.

(1) Background: In recent years, several studies have described various and heterogenous methods to sensitize nanoparticles (NPs) to pH changes; therefore, in this current scoping review, we aimed to map current protocols for pH functionalization of NPs and analyze the outcomes of drug-loaded pH-functionalized NPs (pH-NPs) when delivered in vivo in tumoral tissue. (2) Methods: A systematic search of the PubMed database was performed for all published studies relating to in vivo models of anti-tumor drug delivery via pH-responsive NPs. Data on the type of NPs, the pH sensitization method, the in vivo model, the tumor cell line, the type and name of drug for targeted therapy, the type of in vivo imaging, and the method of delivery and outcomes were extracted in a separate database. (3) Results: One hundred and twenty eligible manuscripts were included. Interestingly, 45.8% of studies (n = 55) used polymers to construct nanoparticles, while others used other types, i.e., mesoporous silica (n = 15), metal (n = 8), lipids (n = 12), etc. The mean acidic pH value used in the current literature is 5.7. When exposed to in vitro acidic environment, without exception, pH-NPs released drugs inversely proportional to the pH value. pH-NPs showed an increase in tumor regression compared to controls, suggesting better targeted drug release. (4) Conclusions: pH-NPs were shown to improve drug delivery and enhance antitumoral effects in various experimental malignant cell lines.

pH-Responsive Nanoparticles for Delivery of Paclitaxel to the Injury Site for Inhibiting Vascular Restenosis.

A high incidence of restenosis has been reported at the site of inflammation following angioplasty and stent implantation. The anti-proliferative drug paclitaxel (PTX) could help to reduce inflammation and restenosis; however, it has poor water solubility and serious adverse side effects at high doses. Given the presence of metabolic acidosis at the site of inflammation, we hypothesized that nanoparticles that are responsive to low pH could precisely release the loaded drug at the target site. We successfully constructed pH-responsive poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with PTX and NaHCO3 as a pH-sensitive therapeutic agent (PTX-NaHCO3-PLGA NPs). The NPs exhibited remarkable pH sensitivity and a good safety profile both in vitro in rat vascular smooth muscle cells and in vivo in Sprague Dawley rats after tail vein injection. In the rat model, the PTX-NaHCO3-PLGA NPs treatment group showed suppressed intimal proliferation following balloon-induced carotid artery injury compared with that of the saline-treated control. Overall, these results demonstrate that our newly developed pH-responsive nanodrug delivery platform has the potential to effectively inhibit restenosis.

Preparation of Modified Chitosan-based Nanoparticles for Efficient Delivery of Doxorubicin and/or Cisplatin to Breast Cancer Cells.

PURPOSE: The aim is to develop a novel pH-responsive modified chitosan-based nanoparticles system for active loading of doxorubicin (DOX) and triggered intracellular release. METHODS: Nanoparticles were formed in an aqueous medium via ionic interaction between negatively charged chitosan derivative and positively charged DOX at neutral pH and then transformed in situ into cisplatin (CIS) cross-linked nanoparticles through cross-linking the formed micelles via chelation interaction between the negatively charged polymeric carrier and cisplatin. Nanoparticles were characterized in terms of particle size and zeta potential using DLS and TEM. Drug loading efficiency and encapsulation efficiency were determined based on the physio-chemical proprieties of the polymer and the amount of the cross-linking agent. In vitro release studies were performed using the dialysis method at different pHs. Finally, the cytotoxic effects of these nanoparticles were performed against the MCF-7 BrCA cell line under different pHs. RESULTS: The average particle size of polymer alone and DOX nanoparticles was 277.401 ± 13.50 nm and 290.20 ± 17.43 nm, respectively. The zeta potential was -14.6 ± 1.02 mV and -13.2 ± 0.55 mV, respectively, with a low polydispersity index. Drug loading and encapsulation deficiencies were determined, dependent on the amount of the cross-linking agent. In vitro release studies showed that the release of DOX from these nanoparticles was pH-dependent. Moreover, results showed that the cytotoxicity magnitude of DOX-loaded nanoparticles against MCF-7 BrCA cells was higher compared with free DOX. CONCLUSION: These novel pH-sensitive nanoparticles proved to be a promising Nano-drug delivery for tumor-targeted delivery of DOX.

In vitro cytotoxicity studies of smart pH-sensitive lamivudine-loaded CaAl-LDH magnetic nanoparticles against Mel-Rm and A-549 cancer cells.

In this study, an effective nano-drug delivery system was prepared by the co-precipitation method via two steps; the preparation of Fe3O4 magnetic nanoparticles and its surface modification with layered double hydroxide (LDH) and loading lamivudine on this nanocarrier (Fe3O4@CaAl-LDH@Lamivudine). The developed nanoparticles (NPs) were characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray analysis, Fourier-transformed infrared spectroscopy, vibrating-sample magnetometry, thermogravimetric analysis, X-ray photoelectron spectroscopy and Brunauer-Emmett-Teller. The prepared system demonstrated an average size of 130 nm. Also, the drug entrapment efficiency was estimated at ∼70%. In vitro, drug release investigations showed a controlled and pH-dependent lamivudine release over 300 min. The in vitro cytotoxic activity of Fe3O4@CaAl-LDH@Lamivudine NPs was explored against Mel-Rm and A-549 cancer cell lines in comparison with lamivudine and nanocarrier using lactate dehydrogenase colorimetric and MTT assay. The results of the MTT assay revealed that the Fe3O4@CaAl-LDH@Lamivudine NPs significantly inhibited the proliferation of Mel-Rm and A-549 cells in a dose-dependent manner. The influences of Fe3O4@CaAl-LDH@Lamivudine on the cancer cell lines by different therapeutic investigation illustrated the remarkable effect in comparison with free drug. Finally, the achieved consequences confirm the anticancer properties of Fe3O4@CaAl-LDH@Lamivudine and indicate that they may be a cost-effective substitute in the treatment of lung and skin cancer.Communicated by Ramaswamy H. Sarma.