Co-delivery Of Drugs Research Articles

Intranasally Co-administered Berberine and Curcumin Loaded in Transfersomal Vesicles Improved Inhibition of Amyloid Formation and BACE-1

Selective permeability of the blood-brain barrier restricts the treatment efficacy of neurologic diseases. Berberine (BBR) and curcumin (CUR)-loaded transferosomes (TRANS) were prepared for the effective management of Alzheimer's disease (AD). The study involved the syntheses of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS by the film hydration method. Vesicles were characterized to ensure the formation of drug-loaded vesicles and their in vivo performance. The particle sizes of BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS were 139.2 ± 7, 143.4 ± 8, and 165.3 ± 6.5 nm, respectively. The presence of diffused rings in the SED image indicates the crystalline nature of the payload. Low surface roughness in an AFM image could be associated with the presence of a surface lipid. BBR-CUR-TRANS showed 41.03 ± 1.22 and 47.79 ± 3.67% release of BBR and 19.22 ± 1.47 and 24.67 ± 1.94% release of CUR, respectively, in phosphate buffer saline (pH 7.4) and acetate buffer (pH 4.0). Formulations showed sustained release of both loaded drugs. BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS exhibited a lower percentage of hemolysis than pure BBR and CUR, indicating the safety of the payload from delivery vesicles. Lower percentages of binding were recorded from BBR-CUR-TRANS than BBR-TRANS and CUR-TRANS. Acetylcholinesterase inhibition activity of the prepared transferosomes was greater than that of pure drugs, which are thought to have good cellular penetration. The spatial memory was improved in treated mice models. The level of malondialdehyde decreased in AD animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS, respectively, as compared to the scopolamine-induced AD animals. BBR-CUR-TRANS-treated animals showed the highest decrease in the NO level. The catalase level was significantly restored in scopolamine-intoxicated animals treated with BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS. The immunohistochemistry result suggested that the BBR-TRANS, CUR-TRANS, and BBR-CUR-TRANS have significantly decreased the regulation of expression of BACE-1 through antioxidant activity. In conclusion, the study highlights the utility of formulated transferosomes as promising carriers for the co-delivery of drugs to the brain.

2D Hetero-Nanoconstructs of Black Phosphorus for Breast Cancer Theragnosis: Technological Advancements.

As per global cancer statistics of 2020, female breast cancer is the most commonly diagnosed cancer and also the foremost cause of cancer death in women. Traditional treatments include a number of negative effects, making it necessary to investigate novel smart drug delivery methods and identify new therapeutic approaches. Efforts for developing novel strategies for breast cancer therapy are being devised worldwide by various research groups. Currently, two-dimensional black phosphorus nanosheets (BPNSs) have attracted considerable attention and are best suited for theranostic nanomedicine. Particularly, their characteristics, including drug loading efficacy, biocompatibility, optical, thermal, electrical, and phototherapeutic characteristics, support their growing demand as a potential substitute for graphene-based nanomaterials in biomedical applications. In this review, we have explained different platforms of BP nanomaterials for breast cancer management, their structures, functionalization approaches, and general methods of synthesis. Various characteristics of BP nanomaterials that make them suitable for cancer therapy and diagnosis, such as large surface area, nontoxicity, solubility, biodegradability, and excellent near-infrared (NIR) absorption capability, are discussed in the later sections. Next, we summarize targeting approaches using various strategies for effective therapy with BP nanoplatforms. Then, we describe applications of BP nanomaterials for breast cancer treatment, which include drug delivery, codelivery of drugs, photodynamic therapy, photothermal therapy, combined therapy, gene therapy, immunotherapy, and multidrug resistance reversal strategy. Finally, the present challenges and future aspects of BP nanomaterials are discussed.

Thermo-sensitive hydrogel-mediated locally sequential release of doxorubicin and palbociclib for chemo-immunotherapy of osteosarcoma

Traditional cytotoxic drugs induce immunogenic cell death (ICD) of tumor cells to trigger anti-tumor immunity. Unfortunately, the presence of immunosuppressive cells such as regulatory T cells (Tregs) in tumor microenvironment offsets part of anti-tumor immunity. In this work, we engineered a methoxy poly(ethylene glycol)-block-poly(l-alanine) (mPEG − PLAla)-based thermo-sensitive hydrogel by ring-opening polymerization as a vehicle for locally sequential delivery of doxorubicin (DOX) and palbociclib (PAL) to induce the antitumor immunity in osteosarcoma. The copolymer exhibited an appropriate sol–gel transition behavior triggered by physiological temperature. Meanwhile, the superior rheological properties, the uniform morphology and the suitable biodegradability were also investigated in the hydrogel. Interestingly, codelivery of gel and DOX + PAL displayed sequential drug release behavior and exhibited improved antitumor effect toward the K7 orthotopic osteosarcoma mouse model. The DOX-induced immunogenic cell death (ICD) and PAL-mediated suppression of regulatory T cells jointly facilitate antitumor immunity in osteosarcoma. Furthermore, the dual drug codelivery hydrogel showed reduced lung metastasis and enhanced biosafety than free drugs in mouse models of osteosarcoma. Therefore, the locally sequential drug delivery system to induce antitumor immunity will have great potential in future tumor therapy.

Stimuli-responsive liposomal nanoformulations in cancer therapy: Pre-clinical & clinical approaches.

The site-specific delivery of antitumor agents is of importance for providing effective cancer suppression. Poor bioavailability of anticancer compounds and the presence of biological barriers prevent their accumulation in tumor sites. These obstacles can be overcome using liposomal nanostructures. The challenges in cancer chemotherapy and stimuli-responsive nanocarriers are first described in the current review. Then, stimuli-responsive liposomes including pH-, redox-, enzyme-, light-, thermo- and magneto-sensitive nanoparticles are discussed and their potential for delivery of anticancer drugs is emphasized. The pH- or redox-sensitive liposomes are based on internal stimulus and release drug in response to a mildly acidic pH and GSH, respectively. The pH-sensitive liposomes can mediate endosomal escape via proton sponge. The multifunctional liposomes responsive to both redox and pH have more capacity in drug release at tumor site compared to pH- or redox-sensitive alone. The magnetic field and NIR irradiation can be exploited for external stimulation of liposomes. The light-responsive liposomes release drugs when they are exposed to irradiation; thermosensitive-liposomes release drugs at a temperature of >40°C when there is hyperthermia; magneto-responsive liposomes release drugs in presence of magnetic field. These smart nanoliposomes also mediate co-delivery of drugs and genes in synergistic cancer therapy. Due to lack of long-term toxicity of liposomes, they can be utilized in near future for treatment of cancer patients.

Colistin Crosslinked Gemcitabine Micelles to Eliminate Tumor Drug Resistance Caused by Intratumoral Microorganisms.

In the tumor microenvironment, there exist microorganisms that metabolize anticancer drugs, leading to chemotherapy failure. To solve this problem, herein, we develop antibiotic and anticancer drug co-delivery micelles, termed colistin crosslinked gemcitabine micelle (CCGM). A self-immolative linker enables colistin and gemcitabine to be released on demand without affecting their antibacterial and anticancer effects. Once CCGM is delivered to the tumor microenvironment, intracellular glutathione triggers the release of colistin and gemcitabine, inhibiting the growth of microbes in the tumor, thus eliminating the microbe-induced drug resistance of tumor.

Progress in the Surface Functionalization of Selenium Nanoparticles and Their Potential Application in Cancer Therapy.

As an essential micronutrient, selenium participates in numerous life processes and plays a key role in human health. In the past decade, selenium nanoparticles (SeNPs) have attracted great attention due to their excellent functionality for potential applications in pharmaceuticals. However, the utilization of SeNPs has been restricted by their instability and low targeting ability. Since the existing reviews mainly focused on the applications of SeNPs, this review highlights the synthesis of SeNPs and the strategies to improve their stability and targeting ability through surface functionalization. In addition, the utilization of functionalized SeNPs for the single and co-delivery of drugs or genes to achieve the combination of therapy are also presented, with the emphasis on the potential mechanism. The current challenges and prospects of functionalized SeNPs are also summarized. This review may provide valuable information for the design of novel functionalized SeNPs and promote their future application in cancer therapy.

Development of highly efficient niosomal systems for co-delivery of drugs and genes to treat breast cancer in vitro and in vivo

In this paper, we step forward in optimizing the efficiency of niosomal systems for carrying curcumin and miR-34a as single-/co-delivery to treat breast cancer. Curcumin, via regulation of p53 protein, affects the molecular signaling pathways and leads to cell death. Likewise, miRNAs, via alternation of the expression of genes, can suppress the development of tumor activities. To conquer and optimize the delivery limitation of curcumin and miRNA, niosomal systems with certain compositions (seven formulations) of Tween-80:Tween-60:cholesterol:DOTAP:PEG are introduced, which enhances the carrier size, surface charge, entrapment efficiency, transfection, and drug release. The results showed that Tween-60 has a significant influence on the entrapment efficiency of the composition. By including the PEG and DOTAP, high enhancements in the overall characteristics of the delivery system were observed. To assess the biological activity of samples, with/without the niosomal delivery system, cytotoxicity, apoptosis, in-vitro, and in-vivo cellular uptake were studied. The recorded data revealed better results from niosomal carriers than their free forms. The best result in single delivery was achieved by miRNA in F6, which had the highest apoptosis, uptake, and smallest tumor volumes under a controlled release. In conclusion, we successfully designed a nanoscale niosomal system to carry drugs and genes to the tumor site to treat cancer cells and provided remarkable data for the scientific society.

Isoginkgetin synergizes with doxorubicin for robust co-delivery to induce autophagic cell death in hepatocellular carcinoma

Doxorubicin (DOX) widely used in hepatocellular carcinoma (HCC) can induce serious side effects and drug resistance. Herein, we aimed to seek a strategy to improve the efficacy and reduce the side effects of DOX in HCC based on an autophagy inducer drug called isoginkgetin (ISO). The design of multifunctional nanocarriers based on hyaluronic acid-conjugated and manganese-doped mesoporous silica nanoparticles (HM) for the co-delivery of antitumor drugs against HCC provided an effective and promising antitumor strategy. Our results showed that HM@ISO@DOX could efficiently inhibit HCC cell proliferation through activating autophagy through AMPKa-ULK1 pathway. Moreover, intravenous injection of HM@ISO@DOX significantly suppressed HCC tumor progression in nude mouse HCC model. Collectively, our findings revealed an anti-HCC mechanism of HM@ISO@DOX through autophagy and provide an effective therapeutic strategy for HCC. Statement of significanceIn our study, we constructed a co-delivery system by loading ISO and DOX in the mesoporous channels of manganese-doped mesoporous silica nanoparticles, which could be further conjugated with hyaluronic acid to obtain HM@ISO@DOX. The nanocarriers had been demonstrated to be biodegradable under the acidic and reducing tumor microenvironment, as well as to possess the tumor targeting capability via the conjugated hyaluronic acid. In addition, HM@ISO@DOX enhanced the therapeutic efficacy against human HCC tumor through the combinatorial therapies of chemotherapeutics, Mn2+-mediated chemodynamic therapeutics and autophagic cell death, which might be achieved through AMPK-ULK1 signaling. This work revealed that such a nanomedicine exhibited superior tumor accumulation and antitumor efficiency against HCC with extremely low systemic toxicity in an autophagy-boosted manner.

Nanocarriers for intracellular co-delivery of proteins and small-molecule drugs for cancer therapy.

In the past few decades, the combination of proteins and small-molecule drugs has made tremendous progress in cancer treatment, but it is still not satisfactory. Because there are great differences in molecular weight, water solubility, stability, pharmacokinetics, biodistribution, and the ways of release and action between macromolecular proteins and small-molecule drugs. To improve the efficacy and safety of tumor treatment, people are committed to developing protein and drug co-delivery systems. Currently, intracellular co-delivery systems have been developed that integrate proteins and small-molecule drugs into one nanocarrier via various loading strategies. These systems significantly improve the blood stability, half-life, and biodistribution of proteins and small-molecule drugs, thus increasing their concentration in tumors. Furthermore, proteins and small-molecule drugs within these systems can be specifically targeted to tumor cells, and are released to perform functions after entering tumor cells simultaneously, resulting in improved effectiveness and safety of tumor treatment. This review summarizes the latest progress in protein and small-molecule drug intracellular co-delivery systems, with emphasis on the composition of nanocarriers, as well as on the loading methods of proteins and small-molecule drugs that play a role in cells into the systems, which have not been summarized by others so far.

Integrated and dual-responsive lipopeptide nanovector with parallel effect to tumor and micro-environment regulation by efficient gene and drug co-delivery

The integrated lipopeptide (RVA)/gene complexes are fabricated with bi-directional regulation on tumor cells and micro-environment. After self-assembling and target coating modification, the poly(γ-glutamic acid) (γ-PGA)/RVA nano-vectors can sequentially respond to pH & redox stimuli, and guarantee efficient therapeutic gene delivery and control release of all-trans retinoic acid. The design provides a facile but promising strategy to treat refractory cancers.

Co-transplantation of Islets-Laden Microgels and Biodegradable O2-Generating Microspheres for Diabetes Treatment.

Pancreatic islets transplantation is an optimal alternative to exogenous insulin injection for long-term effective type 1 diabetes treatment. However, direct islets transplantation without any protection can induce cell necrosis due to severe host immune rejection. Insufficient O2 supply induced by the lack of capillary network at the early stage of islets transplantation is another critical constraint limiting islets survival and insulin-secretion function. In this paper, we design a novel co-transplantation system composed of islets-laden nanocomposite microgels and O2-generating microspheres. In particular, nanocomposite microgels confer the encapsulated islets with simultaneous physical protection and chemical anti-inflammation/immunosuppression by covalently anchoring rapamycin-loaded cyclodextrin nanoparticles to microgel network. Meanwhile, O2-generating microspheres prepared by blending inorganic peroxides in biodegradable polycaprolactone and polylactic acid can generate in situ O2 gas and thus avoid hypoxia environment around transplanted islets. In vivo therapeutic effect of diabetic mice proves the reversion of the high blood glucose level back to normoglycemia and superior glucose tolerance for at least 90 days post co-transplantation. In brief, the localized drug and oxygen codelivery, as well as physical protection provided by our co-transplantation system, has the potential to overcome to a large extent the inflammatory, hypoxia, and host immune rejection after islets transplantation. This new strategy may have wider application in other cell replacement therapies.

Co-delivery of curcumin and Bcl-2 siRNA to enhance therapeutic effect against breast cancer cells using PEI-functionalized PLGA nanoparticles

Purpose Breast cancer is the second major cause of death worldwide among women. Co-delivery of anticancer drugs and nucleic acids targeting the apoptosis pathway could be a promising new approach. Methods In the present study, we synthesized a novel nanostructure for the co-delivery of curcumin and siRNA to breast cancer cells. Curcumin-loaded polylactic-co-glycolic acid (PLGA) was synthesized using an O/W emulsion-solvent diffusion method. It was coated with polyethylenimine (PEI) and subsequently complexed with Bcl-2 siRNA. Also, nanoparticles were characterized such as zeta potential, size distribution and drug encapsulation. Finally, the cytotoxicity of NP and Bcl-2 expression was evaluated. Results The curcumin-loaded PLGA nanoparticles were 70 nm in size, and increased to 84 nm after incorporation of PEI plus Bcl-2 siRNA. The encapsulation ratio of the drug in our nanoparticle was 78%. Cellular internalization of PLGA-CUR-PEI/Bcl-2 siRNA NPs was confirmed by fluorescence microscopy with the broadcasting of the fluorescence in the cytoplasm and into the nucleus. The results of the cell viability assay revealed that curcumin-loaded PLGA coated with PEI and Bcl-2 siRNA exhibited the highest cytotoxicity against the T47D cell line, while the siRNA decreased the Bcl-2 expression by 90.7%. Conclusion The co-delivery of curcumin plus Bcl-2 siRNA with the PLGA-PEI nanosystem could be a synergistic drug carrier against breast cancer cells.

Aptamer-conjugated nano-liposome for immunogenic chemotherapy with reversal of immunosuppression.

Cancer cells have various immune evasion mechanisms that resist the immune cells by reprogramming the tumor microenvironment (TME), such as programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase-1 (IDO1) overexpression. One of the approaches to restore antitumor immune response by T-cells is through induction of immunogenic cell death (ICD). Thus, drug carrier containing IDO1 siRNA and ICD inducer would be effective anticancer regimen to modulate the immunosuppressive TME by reversing the IDO1-mediated immunosuppression in a synergistic combination with ICD induction. However, numerous nanocarrier platforms for co-delivery of multiple drugs mostly depend on the enhanced permeation and retention (EPR), which is insufficient to achieve selectivity in tumor sites harboring various types of cells. We designed a targeted drug delivery system using nano-sized liposomes functionalized with anti-CD44 and anti-PD-L1 DNA aptamers, which target breast cancer cells and inhibit PD-1/PD-L1 interaction between cancer cells and T-cells. To reverse immunosuppressive TME and reactivate immune response, cancer-targeting nano-liposomes were prepared to contain immunogenic cell death inducer (Doxorubicin, DOX) and IDO1 siRNA, namely Aptm[DOX/IDO1]. The Aptm[DOX/IDO1] specifically delivered the loaded DOX and IDO1 siRNA into target breast cancer cells through aptamer-mediated endocytosis. Cancer-targeted DOX/IDO1 siRNA delivery enhanced ICD and suppressed IDO1 expression with significantly high toxicity in cancer cells. We demonstrated that Aptm[DOX/IDO1] could achieve synergistic antitumor effects by facilitating ICD response and simultaneous reversal of the immunosuppressive TME with IDO1 knockdown in the subcutaneous breast cancer model mice, thus reducing tumor size. These antitumor effects were exerted with intratumoral infiltration of CD8+ cytotoxic T lymphocyte as well as attenuation of regulatory T-cell recruitment in the tumor sites. We further proved that our Aptm[DOX/IDO1] strategy significantly reduced tumor metastasis in tumor-xenograft mice through a synergistic combination of cancer cell-targeted ICD induction and reversal of the IDO1-mediated immunosuppressive TME. Our nanocarrier platform based on cationic liposomes containing DOX and IDO1 siRNA, which are conjugated with two DNA aptamers targeting the cancer cell surface, accomplished synergistic chemoimmunotherapy through tumor-specific immune modulation into immune-favorable TME in vivo.

Co-Delivery of siRNA and Chemotherapeutic Drug Using 2C5 Antibody-Targeted Dendrimer-Based Mixed Micelles for Multidrug Resistant Cancers.

Multidrug resistance (MDR) observed in tumors significantly hinders the efficacy of chemotherapy. Downregulation of efflux proteins, such as P-glycoprotein (P-gp), using small interfering RNA (siRNA) can be an effective way to minimize the resistance in tumors. In this study, monoclonal antibody 2C5 (mAb 2C5)-PEG7k-DOPE conjugates were post-inserted into the mixed dendrimer micelles containing generation 4 (G4) polyamidoamine (PAMAM)-PEG2k-DOPE and PEG5k-DOPE. The inherent amphiphilic nature of DOPE conjugates causes the copolymers to self-assemble to form a micelle, which can encapsulate hydrophobic chemotherapeutic drugs in its core. The siRNA electrostatically binds to the cationic charges on the G4 PAMAM dendrimer. The tumor-specific mAb 2C5 on the surface of these nano-preparations resulted in improved tumor targeting. This active targeting to tumors can cause increase in the drug and siRNA accumulation at the tumor site, and thereby minimizing the off-target effects. The micelles were shown to have higher cellular association and effectiveness in vitro. The immunomicelle preparation was also tested for cytotoxicity in breast (MDA-MB-231) and ovarian (SKOV-3TR) MDR cancer cell lines.

Gold nanoparticles conjugated DNA-tile nanomaterials for simultaneous delivery of morpholino antisense oligonucleotides and doxorubicin

Current therapies have limited treatment effect on cancer. Combinational delivery of multiple therapeutics has been commonly investigated to enhance the therapeutic outcome of the disease. The carrier systems have the great importance for effective co-delivery of the multiple drugs. In this report, we demonstrated a DNA nanomaterial for simultaneous delivery of morpholino antisense oligonucleotides (AONs) and doxorubicin to breast cancer cells. DNA-tile nanostructures were prepared by embedding morpholino oligos against ERα and HER2 genes and the morpholino embedded DNA-tiles were modified with gold nanoparticles by sticky-ended association to obtain increased internalization. Then the DNA-carrier was loaded with doxorubicin. Morpholino and doxorubicin therapeutics were successfully delivered to breast cancer cells. It was observed that the co-delivery system showed 50% enhanced intracellular uptake of the chemotherapy drug, better cytotoxic effect and significantly higher level of cell cycle arrest than free doxorubicin at targeted receptor-positive breast cancer cells. The obtained results indicated that the proposed nanosystem is an effective delivery vehicle for combinational cancer therapies and increased anti-cancer activity of chemotherapy.

Biomimetic nanoparticles for effective mild temperature photothermal therapy and multimodal imaging.

Downregulation of adenosine triphosphate (ATP)-dependent heat shock proteins (HSPs) can significantly reduce the tumorigenicity of cancer cells and overcome heat endurance to achieve high-performance mild temperature (≤45°C) photothermal therapy (PTT). Herein, we designed and constructed 4T1 cancer cell membrane-coated, lonidamine (LN)-loaded and DL-menthol (DLM)-loaded hollow mesoporous Prussian blue nanoparticles (PBLM@CCM NPs). DLM with mild phase change characteristics served as a plugging agent to avoid early leakage and allow thermally controllable release of LN, which enabled selective intracellular delivery of LN to reduce the HSPs and overcome the heat endurance in PTT by inhibiting the generation of intracellular ATP. The biocompatible PBLM@CCM NPs with good tumor targeting efficiency achieved high-efficiency mild temperature PTT. Meanwhile, PBLM@CCM NPs could allow photoacoustic (PA) imaging and generate heat to promote the phase change of DLM for ultrasound (US) imaging, which is of great value for future clinical translational studies.

PH-Responsive Chitosan-Adorned Niosome Nanocarriers for Co-Delivery of Drugs for Breast Cancer Therapy

pH-Responsive Chitosan-Adorned Niosome Nanocarriers for Co-Delivery of Drugs for Breast Cancer Therapy

PH-Responsive Copolymeric Network Gel Using Methacrylated β-Cyclodextrin for Controlled Codelivery of Hydrophilic and Hydrophobic Drugs

In medical science, sometimes two drugs with different solubilities are simultaneously required in combination to treat various diseases. Herein, a pH-responsive, copolymeric, antioxidant, biocompatible, and chemically crosslinked network gel is prepared to explore its capability as a matrix for controlled release of both hydrophobic [ibuprofen (IB)] and hydrophilic [tetracycline hydrochloride (TCH)] drugs, simultaneously. This three-dimensional β-CD-Meth-cl-(PHPMA-co-PAAc) network hydrogel is synthesized via two steps: (I) methacrylation of β-cyclodextrin and (II) grafting of poly(hydroxypropyl methacrylate) and poly(acrylic acid), followed by crosslinking of poly(ethylene glycol) diacrylate onto the backbone of methacrylated β-cyclodextrin (β-CD-Meth). The successful synthesis of the hydrogel is confirmed using several physiochemical characterizations. The β-CD-Meth-cl-(PHPMA-co-PAAc) hydrogel has an excellent network-like surface morphology. The potential pH-responsive high swelling behavior and excellent shrinking features suggest the reversible nature of the synthesized gel. Besides, rheological analyses affirm its excellent viscoelastic nature. This network gel is biodegradable and its non-cytotoxic nature toward human dermal fibroblast cells is demonstrated. Moreover, the dual drug release pattern from the copolymer under both in vitro and in vivo conditions portrays that this hydrogel has superior ability to be used as a controlled release matrix for both hydrophobic and hydrophilic drugs (TCH and IB) with varying solubilities concurrently.

Photoactive polymers-decorated Cu-Al layered double hydroxide hexagonal architectures: A potential non-viral vector for photothermal therapy and co-delivery of DOX/pCRISPR

Gene and drug co-delivery is considered a promising strategy in combination cancer therapy. In this study, we fabricated Cu-Al layered double hydroxide (LDH) decorated with nanoscale ortho-, meta-, and para-poly(phenylenediamine), and afterward, doxorubicin (DOX) was loaded into nanoparticles. Finally, LDH was wrapped with plasmid CRISPR (pCRISPR). The modified nanohexagonals had particle sizes of approximately less than 100 nm with drug uptake up to 62.3%. pH-responsive nanocarriers exhibited higher cargo release in an acidic environment (pH 5.5) compared to a neutral buffer of pH 7.4. CLSM analysis demonstrated internalization in MEF-7 and HEK-293 cells with high transfection efficiency, further confirming them as promising nanostructures in cargo delivery. Besides, the potential usage of the cell-imprinted technique in order to increase the interactions to the cells, and enhance the cellular internalizations/transfections were assessed and showed a considerable increase (up to 72%) in the cellular internalizations. LDH nanostructures displayed high biocompatibility against HEK-293 and PC12 cells after 24 and 48 h. While they had no significant impact on the viability of MCF-7 cells with the assistance of the cell-imprinted method, these non-viral vectors significantly reduced the viability of HT-29 cells, showing their anti-cancer activity. Ortho, meta, and para forms of the poly(phenylenediamine)s decorated on the surface of the LDH showed transfection efficiencies up to 29.1, 28.2, and 40.1%, respectively. Therefore, this study could be considered the highest record of the pCRISPR delivery using a composite substrate in the literature.

A pH-stable, mucin based nanoparticle system for the co-delivery of hydrophobic and hydrophilic drugs

Biopolymer-based drug carriers are commonly used for the development of safe delivery systems. However, biopolymer-based systems are often highly sensitive to the acidic pH levels in the stomach and release most of their cargo before they have reached their point of destination. Such premature drug release combined with the resulting high dose requirements is not cost-efficient and comes with the risk of unwanted side effects on non-target tissues/organs. This problem can be mitigated by the mucin-based drug carriers developed here, which exhibit good stability at acidic pH levels as proven by dynamic light scattering and enzymatic degradation tests with pepsin. In addition, the mucin-based particles can deliver hydrophobic and hydrophilic drugs simultaneously, which is demonstrated both with experiments performed under in vitro sink conditions and with drug transport tests involving eukaryotic cells as targets. As photo-induced cross-links covalently stabilize those particles, they can release their payload over time in a sustained manner. The drug carrier system introduced here combines good stability with high drug encapsulation efficiency and very good biocompatibility and thus may be valuable for a broad spectrum of applications in biological settings.