pH-responsive Nanogels Research Articles

Radiation synthesis and characterization of pH-Responsive sodium Alginate/Poly(acrylic acid) nanogel loaded with ferulic acid for anticancer drug delivery

This study focuses on the synthesis and characterization of a pH-responsive nanogel system composed of sodium alginate (NaAlg) and poly(acrylic acid) loaded with ferulic acid. The mechanism of nanogel formation by gamma irradiation was elucidated, highlighting the role of polymer interactions and crosslinking agents. The pHdependent release of ferulic acid from the nanogel carrier was investigated, revealing a controlled release behavior in response to pH variations. The zeta potential values remained slightly negative across the pH range, indicating the presence of surface functional groups. Transmission electron microscopy confirmed the nanogel's formation and uniform particle size at pH 1. This nanogel was considered for controlled drug delivery applications, exhibiting high physical and chemical stability of ferulic acid. Our nanogel compound 5 decreased IC50 against HepG2, A549, MCF-7 and HCT-116 by 58.22 %, 78.35 %, 45.81 %, and 47.94 % respectively. Additionally, it decreased IC50 against VEGFR2 and EGFRT790 M by 41.94 %, and 70.59 % respectively.

Formulation and In Vitro Assessment of Polymeric pH-Responsive Nanogels of Chitosan for Sustained Delivery of Madecassoside.

Madecassoside, a triterpenoid saponin compound mainly isolated from the gotu kola herb (Centella asiatica), shows an extensive range of biological activities, including antiapoptotic, antioxidant, anti-inflammatory, moisturizing, neuroprotective, and wound healing effects. It has been highly used in the management of eczema, skin wounds, and other diseases. Due to poor oral bioavailability, membrane permeability, and intestinal absorption, the clinical application of the madecassoside is limited. Hence, a drug carrier system is needed that not only sustains the release of the madecassoside but also overcomes the drawbacks associated with its administration. Therefore, the authors prepared novel pH-responsive chitosan-based nanogels for the sustained release of madecassoside. Free radical polymerization technique was used for cross-linking of polymer chitosan and monomer methacrylic acid in the presence of cross-linker N',N'-methylene bis(acrylamide). The decrease in polymer crystallinity after polymerization and development of nanogels was demonstrated by XRD and FTIR analysis. The effects of nanogel contents on polymer volume, sol-gel analysis, swelling, drug loading, and release were investigated. Results indicated that high swelling and maximum release of the drug occurred at pH 7.4 compared to pH 1.2 and 4.6, indicating the excellent pH-sensitive nature of the engineered nanogels. High swelling and drug release were perceived with the integration of a high quantity of chitosan, while a decline was observed with the high integration of N',N'-methylene bis(acrylamide) and methacrylic acid contents. The same effects of nanogel contents were shown for drug loading too. Sol fraction was reduced, while gel fraction was enhanced by increasing the chitosan load, N',N'-methylene bis(acrylamide), and methacrylic acid. The Korsmeyer-Peppas model of kinetics was trailed by all nanogel formulations with non-Fickian diffusion. The results demonstrated that prepared nanogels can be employed for sustained release of the madecassoside.

PH-Responsive Nanogels Generated by Polymerization-Induced Self-Assembly of a Succinate-Functional Monomer.

Colloidal nanogels formed from a pH-responsive poly(succinate)-functional core and a poly(sulfonate)-functional corona were prepared via a previously unreported reversible addition-fragmentation chain-transfer (RAFT)-mediated aqueous emulsion polymerization-induced self-assembly (PISA) route. Specifically, a poly(potassium 3-sulfopropyl methacrylate) (PKSPMA50) macromolecular chain-transfer agent (macro-CTA) was synthesized via RAFT solution polymerization followed by chain-extension with a hydrophobic, carboxylic acid-functional, 2-(methacryloyloxy) ethyl succinate (MES) monomer at pH 2. Colloidal nanoparticles with tunable diameters between 66 to 150 nm, depending on the core composition, and narrow particle size distributions were obtained at 20% w/w solids. Well-defined pH-responsive nanogels that swell on increasing the pH could be prepared even without the addition of a cross-linking comonomer, and introducing an additional cross-linker to the core led to smaller nanogels with lower swelling ratios. These nanogels could reversibly change in size on cycling the pH between acidic and basic conditions and remain colloidally stable over a wide pH range and at 70 °C.

Investigating the Impact of Network Functionalization on Protein Adsorption to Polymer Nanogels.

This study explores the impact of network functionalization and chemical composition on the pH-responsive behavior of polymer nanogels and their adsorption of proteins. Using a thermodynamic theory informed by a molecular model, this work evaluates the interactions of three proteins with varying isoelectric points (insulin, myoglobin, and cytochrome c) and pH-responsive nanogels based on methacrylic acid or allylamine motifs. Three different functionalization strategies are considered, with pH-responsive segments distributed randomly, at the center, or on the surface of the polymer network. Our results show that the spatial distribution of functional units affects both the nanogels' mechanical response to pH changes and the level and localization of adsorbed proteins. The dependence of protein adsorption on the salt concentration is also investigated, with the conclusion that it is best to encapsulate proteins at low salt concentrations and aim for release at high salt concentrations. These results provide valuable information for the design of pH-responsive nanogels as vehicles for protein encapsulation, transport, and administration.

Multi-Stimuli-Responsive and Cell Membrane Camouflaged Aggregation-Induced Emission Nanogels for Precise Chemo-photothermal Synergistic Therapy of Tumors.

Targeted and controllable drug release at lesion sites with the aid of visual navigation in real-time is of great significance for precise theranostics of cancers. Benefiting from the marvelous features (e.g., bright emission and phototheranostic effects in aggregates) of aggregation-induced emission (AIE) materials, constructing AIE-based multifunctional nanocarriers that act as all-arounders to integrate multimodalities for precise theranostics is highly desirable. Here, an intelligent nanoplatform (P-TN-Dox@CM) with homologous targeting, controllable drug release, and in vivo dual-modal imaging for precise chemo-photothermal synergistic therapy is proposed. AIE photothermic agent (TN) and anticancer drug (Dox) are encapsulated in thermo-/pH-responsive nanogels (PNA), and the tumor cell membranes are camouflaged onto the surface of nanogels. Active targeting can be realized through homologous effects derived from source tumor cell membranes, which advantageously elevates the specific drug delivery to tumor sites. After being engulfed into tumor cells, the nanogels exhibit a burst drug release at low pH. The near-infrared (NIR) photoinduced local hyperthermia can activate severe cytotoxicity and further accelerate drug release, thus generating enhanced synergistic chemo-photothermal therapy to thoroughly eradicate tumors. Moreover, P-TN-Dox@CM nanogels could achieve NIR-fluorescence/photothermal dual-modal imaging to monitor the dynamic distribution of therapeutics in real-time. This work highlights the great potential of smart P-TN-Dox@CM nanogels as a versatile nanoplatform to integrate multimodalities for precise chemo-photothermal synergistic therapy in combating cancers.

PH-responsive nanogels with enhanced antioxidant and antitumor activities on drug delivery and smart drug release

pH-responsive nanogels have played an increasingly momentous role in tumor treatment. The focus of this study is to design and develop pH-responsive benzimidazole-chitosan quaternary ammonium salt (BIMIXHAC) nanogels for the controlled release of doxorubicin hydrochloride (DOX) while enhancing its hydrophilicity. BIMIXHAC is crosslinked with carboxymethyl chitosan (CMC), hyaluronic acid sodium salt (HA), and sodium alginates (SA) using an ion crosslinking method. The chemical structure of chitosan derivatives was verified by 1H NMR and FT-IR techniques. Compared to hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-based nanogels, BIMIXHAC-based nanogels exhibit better drug encapsulation efficiency and loading capacity (BIMIXHAC-D-HA 91.76 %, and 32.23 %), with pH-responsive release profiles and accelerated release in vitro. The series of nanogels formed by crosslinking with three different polyanionic crosslinkers have different particle size potentials and antioxidant properties. BIMIXHAC-HA, BIMIXHAC-SA and BIMIXHAC-CMC demonstrate favorable antioxidant capability. In addition, cytotoxicity tests showed that BIMIXHAC-based nanogels have high biocompatibility. BIMIXHAC-based nanogels exhibit preferable anticancer effects on MCF-7 and A549 cells. Furthermore, the BIMIXHAC-D-HA nanogel was 2.62 times less toxic than DOX to L929 cells. These results suggest that BIMIXHAC-based nanogels can serve as pH-responsive nanoplatforms for the delivery of anticancer drugs.

Chitosan-Biotin-Conjugated pH-Responsive Ru(II) Glucose Nanogel: A Dual Pathway of Targeting Cancer Cells and Self-Drug Delivery.

The current study paves the way for improved chemotherapy by creating pH-responsive nanogels (NGs) (GC1 and GC2) loaded with synthetic ruthenium(II) arene complexes to increase biological potency. NGs are fabricated by the conjugation of chitosan (CTS)-biotin biopolymers that selectively target the cancer cells as CTS has the pH-responsive property, which helps in releasing the drug in cancer cells having pH ∼ 5.5, and biotin provides the way to target the cancer cells selectively due to the overexpression of integrin. The synthesized compounds and NGs were thoroughly characterized using various spectroscopic and analytical techniques such as NMR, electrospray ionization-mass spectrometry, Fourier transform infrared, UV-vis, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, rheology, Brunauer-Emmett-Teller, and others. NGs displayed exceptional increased efficacy toward cancerous cells with IC50 values ranging from 7.50 to 18.86 μM via induced apoptosis in three human cancer cell lines. Apart from its potency, NGs were found to be highly selective toward cancer cells. Moreover, based on the results of immunoblot analysis, it was observed that the synthesized compounds exhibit a significant increase in the expression of cleaved caspase-3 and a decrease in the expression of the antiapoptotic protein BCL-XL. Interestingly, the complexes were discovered to have the additional capability of catalyzing the conversion of NADH to NAD+, leading to the generation of radical oxygen species within the cells. Additionally, it was discovered that NG-induced apoptosis depends on ROS production and DNA binding. A narrower range of LD50 values (1185.93 and 823.03 μM) was seen after administering NGs to zebrafish embryos in vivo. The results support the use of drug-loaded NGs as potential chemotherapeutic and chemopreventive agents for human cancer cells.

Topically applied pH-responsive nanogels for alkyl radical-based therapy against psoriasiform hyperplasia

Phototherapy is a conventional antipsoriatic approach based on oxygen-relevant generation of oxidative stress to inhibit keratinocyte hyperproliferation. However, this therapy can be restricted due to local hypoxia in psoriatic lesions. The generation of alkyl radicals is oxygen-independent and suppresses hyperproliferation. Herein, we established alkyl radical-based therapy to treat psoriatic hyperplasia. Because alkyl radicals are short-lived compounds, we loaded 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) as a precursor of alkyl radicals into the chitosan nanogels to improve stability. The present study presented a topically applied nanogel that led to a pH-responsive network sensitive to skin pH. This pH responsiveness of the nanogels allowed fast alkyl radical release in the target site. The physicochemical properties of the prepared nanogels were determined through size, zeta potential, scanning electron microscopy, and absorption spectroscopy. The antipsoriatic activity was examined with keratinocyte- and animal-based studies. The nanogels displayed a smooth and spherical morphology with a hydrodynamic diameter of 215 nm. This size was largely increased as the environmental pH increased to 6. The nanogels heated at 44 °C produced alkyl radicals to induce keratinocyte death through the necrosis pathway. Bioimaging demonstrated that topically applied nanogels could deliver alkyl radicals into the epidermis. This targeting was accompanied by the accumulation of free radicals in the epidermis according to the 2′,7′-dichlorodihydrofluorescein diacetate assay. The imiquimod-stimulated psoriasiform animal model indicated a remarkable reduction in erythema, scaling, and overexpressed cytokines upon topical treatment of the nanogels. The transepidermal water loss of the psoriasiform skin was inhibited from 51.7 to 27.0 g/m2/h, suggesting barrier function recovery by the nanocarriers. The nanogels lowered hyperplasia by decreasing the epidermal thickness from 212 to 89 μm. The incorporation of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) as a pH-sensitive fluorescence dye in the nanogels could be used to diagnose the severity of the psoriasiform plaque due to the stronger fluorescence of HPTS in skin with lower pH (psoriasiform skin pH = 4.4) than in healthy skin (pH = 4.9). It was possible to deliver the prepared nanogels into the epidermis to restrain hyperplasia without causing cutaneous irritation.

Design and development of pH-responsive alginate-based nanogel carriers for etoposide delivery

Recently, pH-responsive nanogels are playing progressively important roles in cancer treatment. The present study focuses on designing and developing pH-responsive alginate-based nanogels to achieve a controlled release of etoposide (Et) while enhancing its hydrophilicity. Alginate (ALG) is grafted with 2-hydroxypropyl methacrylamide (HPMA) through a microwave-supported method, and the chemical structure of the graft copolymer (ALG-g-PHPMA) was verified by 1H/13C NMR and FTIR techniques. The ALG-g-PHPMA and anticancer drug-loaded ALG-g-PHPMA@Et nanogels were obtained using an emulsion method, and their structures were characterized through FTIR, TG/DSC, AFM/TEM, BET, and DLS analyses. The ALG-g-PHPMA nanogels demonstrated a good drug encapsulation efficiency (79.60 %), displaying a pH-dependent release profile and an in vitro accelerated release of Et compared to the ALG nanogels. Thermal and BET analyses revealed enhanced stability, surface area, and porosity volume of the alginate nanogels. The grafting of PHPMA chains onto alginate altered the surface topology of the ALG nanogels, resulting in lower surface roughness. Furthermore, cytotoxicity tests showed the high biocompatibility of the ALG-g-PHPMA copolymer and its nanogels. The ALG-g-PHPMA@Et nanogels exhibited a higher anticancer effect on lung cancer (H1299) cells than free etoposide. These results suggest that the ALG-g-PHPMA nanogels can be applied as a pH-dependent nanoplatform for delivering anticancer drugs.

NIR light, pH, and redox-triple responsive nanogels for controlled release.

Herein we report a novel spiropyran (SP)-based organic-inorganic composite nanogel (NG), which was prepared using upconverting nanoparticles, spiropyran, acrylic acid and N,N'-bis(acryloyl)cystamine (BAC) compounds under emulsion polymerisation. Compared with other polymer nanoparticles, the crosslinked multi-stimulus responsive nanogels can adjust the release rate by altering more of the parameters and this can meet the needs of a complex biological environment to control the release of drugs. Doxorubicin hydrochlorides were used as a simulated drug to test the drug loading performance and controllable drug release performance of the composite NGs. Under near-infrared light (NIR) irradiation, an acidic environment or a reducing agent, the delivery of the loaded drugs was by controlled release over 24 hours. Under mild triple stimulation (NIR light, pH 6, and 4 mM reducing agent), the loaded drug could be released more efficiently. The organic-inorganic composite NGs with highly-efficient and controllable release performance for loaded drugs provide many choices for novel stimulus responsive nanocarriers.

Preparation of polymer nanoparticle-based complex coacervate hydrogels using polymerisation-induced self-assembly derived nanogels.

This paper reports a generic method to prepare polymer nanoparticle-based complex coacervate (PNCC) hydrogels by employing rationally designed nanogels synthesised by reversible addition-fragmentation chain-transfer (RAFT)-mediated polymerisation-induced self-assembly (PISA). Specifically, a poly(potassium 3-sulfopropyl methacrylate) (PKSPMA) macromolecular chain-transfer agent (macro-CTA) was synthesised via RAFT solution polymerisation followed by chain-extension with a statistical copolymer of benzyl methacrylate (BzMA) and methacrylic acid (MAA) at pH 2. Thus, pH-responsive nanoparticles (NPs) comprising a hydrophobic polyacid core-forming block and a sulfonate-functional stabiliser block were formed. With the introduction of methacrylic acid into the core of the NPs, they become swollen with increasing pH, as judged by dynamic light scattering (DLS), indicating nanogel-type behaviour. PNCC hydrogels were prepared by simply mixing the PISA-derived nanogels and cationic branched polyethyleneimine (bPEI) at 20% w/w. In the absence of MAA in the core of the NPs, gel formation was not observed. The mass ratio between the nanogels and bPEI affected resulting hydrogel strength and a mixture of bPEI and PKSPMA68-P(BzMA0.6-stat-MAA0.4)300 NPs with a mass ratio of 0.14 at pH ∼7 resulted in a hydrogel with a storage modulus of approximately 2000 Pa, as determined by oscillatory rheology. This PNCC hydrogel was shear-thinning and injectable, with recovery of gel strength occurring rapidly after the removal of shear.

Functionalized Moringa oleifera Gum as pH-Responsive Nanogel for Doxorubicin Delivery: Synthesis, Kinetic Modelling and In Vitro Cytotoxicity Study

Environment-responsive-cum-site-specific delivery of therapeutic drugs into tumor cells is a foremost challenge for chemotherapy. In the present work, Moringa oleifera gum-based pH-responsive nanogel (MOGN) was functionalized as a doxorubicin (DOX) carrier. It was synthesized via free radical polymerization through the γ-irradiation method using acrylamide and N,N'-MBA followed by hydrolysis, sonication, and ultracentrifugation. The swelling behavior of MOGN as a function of pH was assessed using a gravimetric method that revealed its superabsorbent nature (365.0 g/g). Furthermore, MOGN showed a very high loading efficiency (98.35 %L) of DOX by MOGN. In vitro release studies revealed that DOX release from DOX-loaded MOGN was 91.92% at pH 5.5 and 12.18% at 7.4 pH, thus favorable to the tumor environment. The drug release from nanogel followed Korsmeyer-Peppas model at pH 5.5 and 6.8 and the Higuchi model at pH 7.4. Later, the efficient DOX release at the tumor site was also investigated by cytotoxicity study using Rhabdomyosarcoma cells. Thus, the synthesized nanogel having high drug loading capacity and excellent pH-triggered disintegration and DOX release performance in a simulated tumor environment could be a promising candidate drug delivery system for the targeted and controlled release of anticancer drugs.

Multifunctional pH-responsive nanogel for malaria and cancer treatment: Hitting two targets with one arrow

Malaria and cancer have been considered deadly diseases around the world. Cancer and malaria both have high incidence rates despite numerous research efforts to develop effective strategies for mitigating the burden of these two distinct ailments. Herein, pH-responsive nanogel based on methacrylic acid-functionalized with bovine serum albumin (PMAA-BSA) with an average diameter of ∼75 nm was fabricated for smart delivery of chloroquine (CQ). These nanoplatforms exhibited high drug loading efficacy (26.42%). Also it displayed a higher CQ release rate (92.03%) under simulated acidic microenvironment of the digestive vacuole (DV) and tumor tissue whereas 40.01% CQ was released under a neutral physiological environment. More importantly, this unique pH-responsive nanogel lowered the IC50 of CQ by approximately 2.8-fold and 1.9-fold in MCF-7 cells at 24 and 48 h, respectively. Interestingly, blank PMAA-BSA nanogels displayed anti-plasmodial activity and no one to the best of our knowledge has developed a drug vehicle with inherent antimalarial features. PMAA-BSA-CQ through its synergistic effects exhibited great anti-plasmodial activity under both in vitro and in vivo conditions. Furthermore, PMAA-BSA-CQ fully eradicate the parasites in Plasmodium berghei infected mice and prolonged their survival rate. In conclusion, such pH-responsive nanogel with targeting ability and non-toxicity could be used as a very promising nanoplatform for intracellular and tumor trigger release of antimalarial/anti-cancer drugs.

A responsive hydrogel-based microneedle system for minimally invasive glucose monitoring

Blood glucose (BG) monitoring in patients with diabetes is critical for diabetes management. Minimally invasive BG monitoring is urgently required to increase the patient compliance. Herein, based on a responsive hydrogel system, we developed a smart microneedle patch system for minimally invasive glucose monitoring. The patch consisted of a transparent substrate of photocurable resin and microneedles made of a pH-responsive and glucose-responsive hydrogel. The responsive hydrogel was composed of a photocrosslinkable hydrogel of gelatin methacrylate (GelMA) together with a pH-responsive nanogel (nano(CMC-pHEA)) and glucose oxidase (GOx). The composite hydrogel showed fast response and high sensitivity to glucose levels in physiological range, mainly due to the ionization of CMC-pHEA component and proton balance. The microneedles showed sufficient mechanical strength to penetrate the skin of mice with minimal invasion, and achieved in situ extraction of glucose in interstitial fluid (ISF) and in situ glucose-responsive reaction. We demonstrated the rapid glucose monitoring by microneedle patch system in skin-mimicking gels in vitro and in diabetic mice in vivo. The microneedles quickly and sensitively responded to glucose concentrations, allowed quantitative readouts of glucose levels through the changes of microneedle heights and swelling ratios. Moreover, the readouts in mice in vivo were consistent with BG levels measured by glucometer. This smart microneedle system has potentials to replace blood sampling, and minimize patient discomfort during BG testing, therefore has potentials in minimally invasive, rapid and reliable BG monitoring.

5-Fluorouracil uptake and release from pH-responsive nanogels: An experimental and computational study

Chemotherapy is the treatment of choice in cancer therapy even though anti-tumor agents cause frequent and harmful effects on organs and tissues. Nanogels can efficiently improve cancer therapy by increasing the antineoplastic concentration in tumor sites and acting on cancer cells for prolonged periods without significantly affecting normal tissues. In this research, a pH-responsive Polyvinylpyrrolidone (PVP)-based nanogel for the controlled release of 5-Fluorouracil (5-FU) was developed. Nanogels were synthesized using γ-radiation, and 5-FU was loaded into nanogels by physical entrapment. These formulations were characterized by spectroscopy techniques, electronic microscopy, and light scattering measurements. Drug loading and release from nanogels are strongly influenced by %PVP and irradiation dose. Simulations showed a higher drug-polymer affinity at low pH according to experimental loading values (encapsulation efficiency = 17% and drug loading = 83%). The sustained release profile responds to pH change from 1.2 to 7.4, increasing the release rate in acid conditions. Furthermore, nanogels have a negative surface charge, spherical morphology, and diameter of 41.0 ± 0.9 nm. These properties show its potential as a nanocarrier of 5-FU for cancer treatment.

Herceptin-Conjugated DOX-Fe3O4/P(NIPAM-AA-MAPEG) Nanogel System for HER2-Targeted Breast Cancer Treatment and Magnetic Resonance Imaging

It is essential to synthesize a "diagnosis and therapy" integration nanocarrier for magnetic resonance imaging-guided breast cancer-targeted chemotherapy. Here, we report Fe3O4/P(NIPAM-AA-MAPEG) nanogels (MNLs) based on in situ loading of doxorubicin (DOX) by miniemulsion polymerization. Especially, propyl acrylic acid (AA) moieties were introduced to absorb DOX by electrostatic interactions and conjugated with the antibody herceptin (HER) through the amino-carboxyl coupling reaction. The size and morphology of MNLs could be adjusted by varying the polymerization parameters, such as the monomer feeding ratio, ferrofluid content, and cross-linker content. The MNLs showed superior stability in a physiological environment, but their structures were destroyed in an acidic environment to accelerate DOX release. The dissociation of the HER-DOX-MNLs accelerated the delivery of DOX and enhanced the therapeutic effects. The studies exhibited that the HER-DOX-MNLs could inhibit the tumor growth. In addition, the MNLs with a high magnetic content had the potential advantages in magnetic resonance imaging (MRI) of breast cancer diagnosis. The dual-targeted pH-responsive nanogels were successfully designed as a multifunctional nanocarrier for realizing HER2-positive breast cancer chemotherapy and diagnostics.

Systemically Administered TLR7/8 Agonist and Antigen-Conjugated Nanogels Govern Immune Responses against Tumors.

The generation of specific humoral and cellular immune responses plays a pivotal role in the development of effective vaccines against tumors. Especially the presence of antigen-specific, cytotoxic T cells influences the outcome of therapeutic cancer vaccinations. Different strategies, ranging from delivering antigen-encoding mRNAs to peptides or full antigens, are accessible but often suffer from insufficient immunogenicity and require immune-boosting adjuvants as well as carrier platforms to ensure stability and adequate retention. Here, we introduce a pH-responsive nanogel platform as a two-component antitumor vaccine that is safe for intravenous application and elicits robust immune responses in vitro and in vivo. The underlying chemical design allows for straightforward covalent attachment of a model antigen (ovalbumin) and an immune adjuvant (imidazoquinoline-type TLR7/8 agonist) onto the same nanocarrier system. In addition to eliciting antigen-specific T and B cell responses that outperform mixtures of individual components, our two-component nanovaccine leads in prophylactic and therapeutic studies to an antigen-specific growth reduction of different tumors expressing ovalbumin intracellularly or on their surface. Regarding the versatile opportunities for functionalization, our nanogels are promising for the development of highly customized and potent nanovaccines.

Temperature and pH-responsive nanogels as intelligent drug delivery systems: A comprehensive review

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Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance.

Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy.

Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).