Cationic Polymeric Nanoparticles Research Articles

Glomerulus-Targeted ROS-Responsive Polymeric Nanoparticles for Effective Membranous Nephropathy Therapy.

Membranous nephropathy (MN) is a common immune-mediated glomerular disease that requires the development of safe and highly effective therapies. Celastrol (CLT) has shown promise as a therapeutic molecule candidate, but its clinical use is currently limited due to off-target toxicity. Given that excess levels of reactive oxygen species (ROS) contributing to podocyte damage is a key driver of MN progression to end-stage renal disease, we rationally designed ROS-responsive cationic polymeric nanoparticles (PPS-CPNs) with a well-defined particle size and surface charge by employing poly(propylene sulfide)-polyethylene glycol (PPS-PEG) and poly(propylene sulfide)-polyethylenimine (PPS-PEI) to selectively deliver CLT to the damaged glomerulus for MN therapy. Experimental results show that PPS-CPNs successfully crossed the fenestrated endothelium, accumulated in the glomerular basement membrane (GBM), and were internalized by podocytes where rapid drug release was triggered by the overproduction of ROS, thereby outperforming nonresponsive CLT nanotherapy to alleviate subepithelial immune deposits, podocyte foot process effacement, and GBM expansion in a rat MN model. Moreover, the ROS-responsive CLT nanotherapy was associated with significantly lower toxicity to major organs than free CLT. These results suggest that encapsulating CLT into PPS-CPNs can improve efficacy and reduce toxicity as a promising treatment option for MN.

Croconaine conjugated cationic polymeric nanoparticles for NIR enhanced bacterial killing

Light-triggered treatment approach has been regarded as an effective option for sterilization due to noninvasiveness, limited drug resistance, and minimized adverse effects. Herein, we designed and synthesized a functionalized cationic polymer, CR-PQAC, with croconaine bridging agent and quaternary ammonium groups for photothermal enhanced antimicrobial therapy under near-infrared irradiation. The quaternary ammonium group on the pendent chain endowing CR-PQAC the ability to effectively bind to bacteria. The CR-PQAC could self-assembles into micellar nanoparticles in aqueous solution, which exhibited strong absorption in the near-infrared (NIR) region, excellent photostability, and photothermal conversion efficiency of up to 43.8 %. Notably, the CR-PQAC nanoparticles presented remarkable antibacterial activity against both methicillin-resistant Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) bacteria with 808 nm laser irradiation. Moreover, the developed CR-PQAC has negligible dark cytotoxicity and good hemolytic compatibility against mammalian cells. Both in vitro and in vivo studies have demonstrated that the desirable antibacterial efficacy of CR-PQAC was obtained. Therefore, the proposed CR-PQAC may be a promising antimicrobial agent for NIR-enhanced killing bacterial.

Antimicrobial polymer-loaded hydrogels for the topical treatment of multidrug-resistant wound biofilm infections

Integration of antimicrobial polymeric nanoparticles into hydrogel materials presents a promising strategy to address multidrug-resistant biofilm infections. Here we report an injectable hydrogel loaded with engineered cationic antimicrobial polymeric nanoparticles (PNPs) for the effective topical treatment of severe wound biofilm infections. The PNPs demonstrated biofilm penetration and disruption, resulting in the eradication of resistant and persister cells that reside within the biofilm. Significantly, PNPs did not elicit resistance development even after multiple exposures to sub-therapeutic doses. In vitro studies showed PNPs significantly reduced prolonged inflammation due to infection and promoted fibroblast migration. These PNPs were then incorporated into Poloxamer 407 (P407) hydrogels and utilized as an inert carrier for PNPs to provide a controlled and sustained topical release of the antimicrobial nanoparticles at the wound area. In vivo studies using a mature (4-day) wound biofilm infection in a murine model mimicking severe human wound infections demonstrated provided 99% bacterial biofilm clearance and significantly enhanced wound healing. Overall, this work demonstrated the efficacy and selectivity of the antimicrobial polymer-loaded hydrogel platform as a topical treatment for difficult-to-treat wound biofilm infections.

Extracellular Vesicles Facilitate the Transportation of Nanoparticles within and between Cells for Enhanced Tumor Therapy.

The interaction between nanoparticles and cells is closely associated with the therapeutic effects of nanomedicine. Nanoparticles could be transported among cells, but the process-related mechanism remains to be further explored. In this study, it was found that endocytosed cationic polymer nanoparticles (cNPs) could be excreted in an extracellular vesicle (EV)-coated form (cNP@EVs). It was deduced that cNPs may pass through early endosomes, multivesicular bodies (MVBs), and autophagic MVBs within cells. Moreover, a high level of autophagy facilitated the exocytosis process. Since EVs were the effective vehicles for conveying biological information and substances, cNP@EVs were proved to be efficient forms for the intercellular transportation of nanoparticles and have the potential as efficient biomimetic drug delivery systems. These properties endowed cNP@EVs with deep penetration and enhanced antitumor activity. Our findings provided a proof-of-concept for understanding the transfer process of nanoparticles among cells and may help us to further utilize EV-mediated transportation of nanoparticles, therefore, expanding its clinical application.

Cationic brush hybrid nanoparticles scavenge cell-free DNA to enhance rheumatoid arthritis treatment

Abnormally high level of cell-free DNA (cfDNA) is one of the important causes of autoimmune diseases, which aggravate the symptoms of rheumatoid arthritis (RA). Recently, the utilization of cationic polymeric nanoparticles for scavenging cfDNA has emerged as a promising therapeutic strategy for the treatment of RA. However, the intravenous introduction of cationic polymeric nanoparticles into the circulation carries a risk of dissociation, causing toxicity. To realize the potential clinical translation, we employed a series of silica particles grafted with poly(2-(dimethylamino) ethyl methacrylate) (PDMA) (SiNP@PDMA) brush, which possess adjustable PDMA content (100, 200, and 300 degree of polymerization (DP)) and particle size (50, 100, and 200 nm diameter), to selectively scavenge cfDNA in inflamed joint cavity. We demonstrate that the binding affinity for cfDNA, cytotoxicity, circulation time in vivo and retention in the inflamed joint cavity are influenced by the core-shell structure of SiNP@PDMA, ultimately impacting therapeutic efficacy. Among them, SiNP@PDMA with 100 nm size and 200 DP of PDMA exhibit enhanced accumulation and prolonged retention time in inflammatory joint cavity, resulting in superior therapeutic effect. Therefore, in this study, applying the precisely tuning size and cation content of SiNP@PDMA, we demonstrated the factors to matter the therapeutic effect of cationic nanoparticles, which deepened the understanding of the anti-inflammatory therapies based on cfDNA scavenger for RA. Statement of significanceInspired by the discovery that cfDNA would induce inappropriate immune responses to exacerbate the progress of RA, we innovatively employed SiNP@PDMA as a cfDNA scavenger to inhibit cfDNA-induced inflammation in RA. Increase in the cation content efficiently strengthened the binding between SiNP@PDMA and cfDNA, leading to an improvement in inhibitory effect of inflammation. In addition, we compared the behaviors of 50, 100 and 200 nm SiNP@PDMA in RA symptom suppression, local cfDNA scavenging and inflammation inhibition. The results demonstrated that SiNP100-PDMA200 outperformed other analogues, corresponding to their more favorable distribution in inflammatory articular cavity. Together, this study revealed the structure-property relationship of cfDNA scavengers for further development of safe and effective cfDNA scavenging system.

In-Situ Thermoresponsive Hydrogel Containing Resveratrol-Loaded Nanoparticles as a Localized Drug Delivery Platform for Dry Eye Disease.

Dry eye disease (DED) is a dynamic and complex disease that can cause significant damage to the ocular surface and discomfort, compromising the patient's quality of life. Phytochemicals such as resveratrol have received increasing attention due to their ability to interfere with multiple pathways related to these diseases. However, the low bioavailability and the poor therapeutic response of resveratrol hinder its clinical applications. Cationic polymeric nanoparticles, in combination with in situ gelling polymers, could represent a promising strategy to prolong drug corneal residence time reducing the frequency of administration and increasing the therapeutic response. Eyedrop formulations, based on acetylated polyethyleneimine-modified polylactic-co-glicolyc acid- (PLGA-PEI) nanoparticles loaded with resveratrol (RSV-NPs) were dispersed into poloxamer 407 hydrogel and characterized in terms of pH, gelation time, rheological properties, in vitro drugs release, and biocompatibility. Moreover, the antioxidant and anti-inflammatory effects of RSV were assessed in vitro by mimicking a DED condition through the exposition of epithelial corneal cells to a hyperosmotic state. This formulation exhibited sustained release of RSV for up to 3 days, exerting potent antioxidant and anti-inflammatory effects on corneal epithelial cells. In addition, RSV reversed the mitochondrial dysfunction mediated by high osmotic pressure, leading to upregulated sirtuin-1 (SIRT1) expression, an essential regulator of mitochondrial function. These results suggest the potential of eyedrop formulation as a platform to overcome the rapid clearance of current solutions for treating various inflammation- and oxidative stress-related diseases such as DED.

Thymol-Loaded Eudragit RS30D Cationic Nanoparticles-Based Hydrogels for Topical Application in Wounds: In Vitro and In Vivo Evaluation

Natural medicines formulated using nanotechnology-based systems are a rich source of new wound-treating therapeutics. This study aims to develop thymol-loaded cationic polymeric nanoparticles (CPNPs) to enhance the skin retention and wound healing efficacy of thymol. The developed materials exhibited entrapment efficiencies of 56.58 to 68.97%, particle sizes of 36.30 to 99.41 nm, and positively charged zeta potential. In Vitro sustained release of thymol up to 24 h was achieved. Selected thymol CPNPs (F5 and C2) were mixed with methylcellulose to form hydrogels (GF5 and GC2). An In Vivo skin-retention study revealed that GF5 and GC2 showed 3.3- and 3.6-fold higher retention than free thymol, respectively. An In Vitro scratch-wound healing assay revealed a significant acceleration in wound closure at 24 h by 58.09% (GF5) and 57.45% (GC2). The potential for free thymol hydrogel, GF5, and GC2 to combat MRSA in a murine skin model was evaluated. The bacterial counts, recovered from skin lesions and the spleen, were assessed. Although a significant reduction in the bacterial counts recovered from the skin lesions was shown by all three formulations, only GF5 and GC2 were able to reduce the bacterial dissemination to the spleen. Thus, our study suggests that Eudragit RS30D nanoparticles-based hydrogels are a potential delivery system for enhancing thymol skin retention and wound healing activity.

Green synthesis of chitosan nanoparticles, optimization, characterization and antibacterial efficacy against multi drug resistant biofilm-forming Acinetobacterbaumannii

Chitosan nanoparticles (CNPs) are promising versatile cationic polymeric nanoparticles, which have received growing interest over last few decades. The biocompatibility, biodegradability, environmental safety and non-toxicity of the chitosan nanoparticles makes it preferred for a wide range of biological applications including agriculture, medical and pharmaceutical fields. In this study, CNPs were biosynthesized by aqueous extract of Eucalyptusglobulus Labill fresh leaves as bio-reductant. Box–Behnken design in 29 experimental runs was used for optimization of different factors affecting the production of CNPs. The maximum yield of CNPs was 9.91 mg/mL at pH of 4.5, chitosan concentration of 1%, incubation time of 60 min and temperature of 50 °C. The crystallinity, particle size and morphology of the biosynthesized CNPs were characterized. The CNPs possess a positively charged surface of 31.1 mV. The SEM images of the CNPs confirms the formation of spherical form with smooth surface. The TEM images show CNPs were spherical in shape and their size range was between 6.92 and 10.10 nm. X-ray diffraction indicates the high degree of CNPs crystallinity. FTIR analysis revealed various functional groups of organic compounds including NH, NH2, C–H, C−O, C–N, O–H, C–C, C–OH and C–O–C. The thermogravimetric analysis results revealed that CNPs are thermally stable. The antibacterial activity of CNPs was determined against pathogenic multidrug-resistant bacteria, Acinetobacterbaumannii. The diameters of the inhibition zones were 12, 16 and 30 mm using the concentrations of 12.5, 25 and 50 mg/mL; respectively. When compared to previous studies, the biosynthesized CNPs produced using an aqueous extract of fresh Eucalyptusglobulus Labill leaves have the smallest particle sizes (with a size range between 6.92 and 10.10 nm). Consequently, it is a promising candidate for a diverse range of medical applications and pharmaceutical industries.

Cationic Polyethyleneimine (PEI)-Gold Nanocomposites Modulate Macrophage Activation and Reprogram Mouse Breast Triple-Negative MET-1 Tumor Immunological Microenvironment.

Nanomedicines based on inorganic nanoparticles have grown in the last decades due to the nanosystems’ versatility in the coating, tuneability, and physical and chemical properties. Nonetheless, concerns have been raised regarding the immunotropic profile of nanoparticles and how metallic nanoparticles affect the immune system. Cationic polymer nanoparticles are widely used for cell transfection and proved to exert an adjuvant immunomodulatory effect that improves the efficiency of conventional vaccines against infection or cancer. Likewise, gold nanoparticles (AuNPs) also exhibit diverse effects on immune response depending on size or coatings. Photothermal or photodynamic therapy, radiosensitization, and drug or gene delivery systems take advantage of the unique properties of AuNPs to deeply modify the tumoral ecosystem. However, the collective effects that AuNPs combined with cationic polymers might exert on their own in the tumor immunological microenvironment remain elusive. The purpose of this study was to analyze the triple-negative breast tumor immunological microenvironment upon intratumoral injection of polyethyleneimine (PEI)–AuNP nanocomposites (named AuPEI) and elucidate how it might affect future immunotherapeutic approaches based on this nanosystem. AuPEI nanocomposites were synthesized through a one-pot synthesis method with PEI as both a reducing and capping agent, resulting in fractal assemblies of about 10 nm AuNPs. AuPEI induced an inflammatory profile in vitro in the mouse macrophage-like cells RAW264.7 as determined by the secretion of TNF-α and CCL5 while the immunosuppressor IL-10 was not increased. However, in vivo in the mouse breast MET-1 tumor model, AuPEI nanocomposites shifted the immunological tumor microenvironment toward an M2 phenotype with an immunosuppressive profile as determined by the infiltration of PD-1-positive lymphocytes. This dichotomy in AuPEI nanocomposites in vitro and in vivo might be attributed to the highly complex tumor microenvironment and highlights the importance of testing the immunogenicity of nanomaterials in vitro and more importantly in vivo in relevant immunocompetent mouse tumor models to better elucidate any adverse or unexpected effect.

Gemcitabine cationic polymeric nanoparticles against ovarian cancer: formulation, characterization, and targeted drug delivery

This study focused on gemcitabine (GTB) delivery of cationic polymeric nanoparticles to treat ovarian cancer in order to promote effective localized delivery and drug retention during biological discharge. To begin, four GTB-loaded polymer nanoparticles were prepared: chitosan nanoparticles (CS-NPs), polysarcosin nanoparticles (PSar-NPs), poly-l-lysine & polysarcosin nanoparticles (PLL-PSar-NPs), and chitosan & polysarcosin nanoparticles (CS-PSar-NPs). Based on preliminary particle size, zeta potential, encapsulation efficiency, DSC, surface morphology, release profiling, and cellular internalization studies using rhodamine 123 and Nile red fluorescent markers, it was hypothesized that CS-PSar-NPs could be the best cationic formulation with strong biocompatibility and anticancer activity against the OVCAR-8 ovarian cancer cell line. To improve effective targeting, cellular penetration, and in vitro cytotoxicity, epidermal growth factor receptor variation III (EGFRvIII) is attached over all four polymeric nanoparticles. Confocal imaging revealed that EGFRvIII-conjugated cationic GTB polymeric nanoparticles had a greater cellular uptake and double internalization capabilities than unconjugated nanoparticles, as well as time-dependent cell entrance. GTB and EGFRvIII-conjugated polymer nanoparticles would have a stronger potential to infiltrate ovarian cancer cells during the first hour of incubation. According to TEM and FTIR findings, EGFRvIII conjugation across the non-target CS-PSar-NP surface was successful, making CS-PSar-NPS-EGFRvIII more target-specific and thus a safer drug delivery candidate for ovarian cancer treatment. Highlights GTB loaded non-target CS-PSar-NPs & active targeted CS-PSar-NPs-EGFRvII developed. SEM, AFM, DSC, particle size, zeta potential, internalization performed for CS-PSar-NPs. MTT & CLSM study confirmed CS-PSar-NPS-EGFRvII was binding specific to OVCAR-8 cells Fabrication of EGFRvII over nanoparticles confirmed by TEM. CS-PSar-NPS-EGFRvII safer candidate for ovarian cancer.

Injectable Tripeptide/Polymer Nanoparticles Supramolecular Hydrogel: A Candidate for the Treatment of Inflammatory Pathologies.

Supramolecular peptide-based hydrogels attract great attention in several fields, i.e., biomedicine, catalysis, energy, and materials chemistry, due to the noncovalent nature of the self-assembly and functional tunable properties defined by the amino acid sequence. In this work, we developed an injectable hybrid supramolecular hydrogel whose formation was triggered by electrostatic interactions between a phosphorylated tripeptide, Fmoc-FFpY (F: phenylalanine, pY: phosphorylated tyrosine), and cationic polymer nanoparticles made of vinylimidazole and ketoprofen (poly(HKT-co-VI) NPs). Hydrogel formation was assessed through inverted tube tests, and its fibrillary structure, around polymer NPs, was observed by transmission electron microscopy. Interestingly, peptide self-assembly yields the formation of nontwisted and twisted fibers, which could be attributed to β-sheets and α-helix structures, respectively, as characterized by circular dichroism and infrared spectroscopies. An increase of the elastic modulus of the Fmoc-FFpY/polymer NPs hybrid hydrogels was observed with peptide concentration as well as its injectability property, due to its shear thinning behavior and self-healing ability. After checking their stability under physiological conditions, the cytotoxicity properties of these hybrid hydrogels were evaluated in contact with human dermal fibroblasts (FBH) and murine macrophages (RAW 264.7). Finally, the Fmoc-FFpY/polymer NPs hybrid hydrogels exhibited a great nitric oxide reduction (∼67%) up to basal values of pro-inflammatory RAW 264.7 cells, thus confirming their excellent anti-inflammatory properties for the treatment of localized inflammatory pathologies.

Systemic immune responses to irradiated tumours via the transport of antigens to the tumour periphery by injected flagellate bacteria.

Because the tumour microenvironment is typically immunosuppressive, the release of tumour antigens mediated by radiotherapy or chemotherapy does not sufficiently activate immune responses. Here we show that, following radiotherapy, the intratumoural injection of a genetically attenuated strain of Salmonella coated with antigen-adsorbing cationic polymer nanoparticles caused the accumulation of tumour antigens at the tumour's periphery. This enhanced the crosstalk between the antigens and dendritic cells, and resulted in large increases in activated ovalbumin-specific dendritic cells in vitro and in systemic antitumour effects, and extended survival in multiple tumour models in mice, including a model of metastasis and recurrence. The antitumour effects were abrogated by the antibody-mediated depletion of CD8+ T cells, indicating that systemic tumour regression was caused by adaptive immune responses. Leveraging flagellate bacteria to transport tumour antigens to the periphery of tumours to potentiate the activation of dendritic cells may open up new strategies for in situ cancer vaccination.

Cationic Polymeric Nanoparticles for Improved Ocular Delivery and Antimycotic Activity of Terconazole

Terconazole (TCZ) is a broad-spectrum antifungal triazole that is particularly active against Candida species, but its poor water solubility hinders its ocular absorption and restricts its application. This study aims to fabricate TCZ-loaded cationic polymeric nanoparticles to enhance the ocular delivery and antimycotic activity of terconazole. TCZ-loaded nanoparticles were developed by nanoprecipitation method employing Eudragit RLPO®. They were characterized by entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), morphology, Fourier transform infrared spectroscopy (FT-IR), and X-ray powder diffraction (XRPD). In-vitro antimycotic activity was evaluated by measuring zone of inhibition (ZI), minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). The developed nanoparticles were spherical with moderate to high EE% (44.03–71.14%), a nanometric PS (49.41–78.72 nm), and a positively charged ZP (≥ +21.47). In-vitro release studies revealed sustained release of drug up to 24 h. FT-IR of TCZ-loaded nanoparticles revealed distinctive peaks for Eudragit RLPO® and Poloxamer-188, with disappearance of the TCZ characteristic peaks. XRPD revealed the amorphous state of TCZ within the polymer matrix. Mucoadhesive studies proved the mucoadhesive property of the developed TCZ nanoparticles. In-vitro antimycotic studies, assessed by ZI, MIC and MFC, revealed enhanced antimycotic activity of TCZ-loaded nanoparticles against Candida albicans, relative to plain TCZ. No irritation or abnormal changes to the rabbits’ eyes for plain and medicated polymeric nanoparticles were found by the in-vivo Draize test. These findings reveal that the cationic polymeric nanoparticles can be regarded as a potential drug delivery system for enhancing the ocular antimycotic activity of TCZ.

Topical cationic hairy particles targeting cell free DNA in dermis enhance treatment of psoriasis

Abnormal high level of cell free DNA (cfDNA) triggers chronic inflammation to exacerbate psoriasis symptoms. Scavenging cfDNA by topical cationic polymeric nanoparticles has been certified as an effective therapeutic strategy for treating psoriasis. However, cationic cfDNA scavengers have a great potential risk to organs after entering systemic circulation through skin barrier. For better transformation to clinical application, herein a series of poly(2-(dimethylamino)ethyl methacrylate) (PDMA) grafted hairy silica particles (cSPs) with tunable PDMA length and particle size are applied to scavenge cfDNA in dermis. We reveal that the structure of cSPs correlates with the permeation ability across stratum corneum, retention time in dermis, binding affinity to cfDNA, and toxicity tolerance, which in turn affect the therapeutic effect. Especially, the cSPs of 700 nm show more accumulation and longer retention in psoriatic lesions, leading to excellent treatment results. They also outperform the cSPs of 200 nm at a lower administration frequency. Thus, we address the issues of size, cationic content of cSPs to open a potential new avenue to topically treatment of psoriasis by targeting cfDNA in dermis.

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC

Dual pH-responsive charge-reversal and photo-crosslinkable polymer nanoparticles for controlled drug release

In this article, we introduce a pH-responsive charge-reversible and photo-crosslinkable polymer nanoparticle. It is prepared via typical self-assembly from a block copolymer poly((7-(4-vinyl-benzyloxyl)-4-methylcoumarin)-co-acrylicacid)-b-poly((2-dimethylamino) ethyl methacrylate)-co-styrene) (P(VBMC-co-AA)-b-P(DMAEMA-co-St)), whose two blocks have different ionizable moieties. In an aqueous solution of pH ≤ 4, the cationic polymer nanoparticles are formed due to the fully protonated PDMAEMA. At a pH ranging from 5.0 to 7.8, partially ionized PAA and protonated PDMAEMA lead to the formation of polymer nanoparticles with a mixed shell. In a pH range of 8–10, a large amount of precipitation is produced within the isoelectric point (IEP) region because of the weak hydrophilic two blocks. In an aqueous solution of pH ≥ 10, polymer nanoparticles are reformed with PAA shell and P(DMAEMA-co-St) core. The coumarin groups of polymer can undergo photo-crosslinking and photo-cleavage reactions under UV light irradiation at λ = 365 nm and λ = 254 nm, respectively. The reversible nature of the photo-reaction can regulate the reversal of polymer nanoparticles. Furthermore, the aggregation-induced fluorescence emission (AIFE) property of polymer nanoparticles at different pH is tested by fluorescence emission spectra. The results indicate that the aggregation state of coumarin blocks in solution also changes with the pH value. The DOX release experiment in vitro shows that the release behavior of DOX-loaded nanoparticles can be adjusted by pH and light to achieve significant control. The inhibitory effect on the growth of tumor cells is displayed by cellular uptake and cytotoxicity test in vitro. The self-assembly system of polymer nanoparticles can be cooperatively controlled by multiple stimulations and displays potential applications in controlled drug delivery.

Anti-tumor Effects of Chitosan-grafted Cationic Polymer Nanoparticles against Human Breast Cancer Cell Lines

Anti-tumor Effects of Chitosan-grafted Cationic Polymer Nanoparticles against Human Breast Cancer Cell Lines

A Nanoparticle Platform for Improved Potency, Stability, and Adjuvanticity of Poly(I:C)

AbstractCancer immunotherapies and prophylactic vaccines against infectious diseases often exploit adjuvants such as toll‐like receptor agonists (TLRa) to drive potent and directed immune responses. Unfortunately, a promising class of TLRa based on nucleic acid derivatives is susceptible to degradation by nucleases, cause life‐threatening systemic toxicities, and is difficult to target to specific cell populations or tissues within the body. In this study a library of cationic polymeric nanoparticles (NP) is developed for encapsulation and delivery of the double‐stranded RNA structural mimic, poly(I:C) (pIC), to address these limitations. Using a combinatorial library screening approach, pIC/poly(β‐amino ester) (PBAE) NPs are identified that skew activation resulting in enhanced potency (13‐fold increase in type I interferon [IFN] production) and negligible toxicity. These highly potent adjuvant NPs increase the magnitude, duration, and affinity maturation of antigen‐specific antibodies following vaccination with a model subunit vaccine. This NP platform provides an opportunity to alter the immune response to pIC, creating a potent type I IFN‐producing adjuvant capable of driving stronger humoral responses to immunization and improving affinity maturation more than 14‐fold. This platform can be applied generally to develop more effective vaccines and immunotherapies.

Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways

For decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity – especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complex in vivo systemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles – toxicity is a function of multiple pathophysiological responses - triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles – systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) ameliorates in vivo toxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluating in vivo toxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.

PLGA cationic nanoparticles, obtained from nano-emulsion templating, as potential DNA vaccines

Polymeric nanoparticles offer advantageous characteristics as gene-delivery vectors such as biocompatibility and biodegradability. With this aim, a smart and innovative strategy was followed here: Cationic PLGA nano-emulsions, prepared by a low energy method, were used as templates to obtain cationic nanoparticles (NPs) able to easily complex with nucleic acids (i.e. plasmid DNA) by electrostatic interactions. The strategy employed to produce stable positively-charged nanoparticles was the use of non-ionic/cationic surfactant mixtures to stabilize template nano-emulsions. This methodology allowed obtaining nanoparticles with reproducible nanometric sizes and positive zeta potential values, appropriate to successfully complex with nucleic acids, resulting in nanometric spherical polyplexes. Nanoparticles, plasmids and polyplexes proved to be biocompatible at the optimal concentration. Therefore, we can conclude that we have designed a novel strategy to efficiently obtain cationic polymeric nanoparticles that can be a promising approach to act as novel non-viral gene-delivery vectors, useful for many applications in gene therapy, such as gene vaccines.