Search

Tumour-associated macrophages (TAMs) support tumour development and have emerged as important regulators of therapeutic response to cytostatic agents. To target TAMs, we have developed a novel drug delivery approach which induces drug release as it inhibits cysteine cathepsin activity. This inhibitory prodrug (IPD) approach establishes a self-regulated system where drug release stops after all cysteine cathepsins are inhibited. This could improve the therapeutic window for drugs with severe side effects. We demonstrate and characterise this self-regulation concept with a fluorogenic IPD model. Next, we applied this IPD strategy to deliver cytotoxic drugs, as doxorubicin and monomethyl auristatin E, which are efficiently released and dose-dependently eliminate RAW264.7 macrophages. Lastly, by exploiting the increased cathepsin activity in TAM-like M2-polarised primary macrophages, we show that IPD-Dox selectively eliminates M2 over M1 macrophages. This demonstrates the potential of our IPD strategy for selective drug delivery and modulation of the tumour microenvironment.

Inflammation occurring within the transplanted organ from the time of harvest is an important stimulus of early alloimmune reactivity and promotes chronic allograft rejection. Chronic immune-mediated injury remains the primary obstacle to the long-term success of organ transplantation. However, organ transplantation represents a rare clinical setting in which the organ is accessible ex vivo, providing an opportunity to use nanotechnology to deliver therapeutics directly to the graft. This approach facilitates the directed delivery of immunosuppressive agents (ISA) to target local pathogenic immune responses prior to the transplantation. Here, we have developed a system of direct delivery and sustained release of mycophenolate mofetil (MMF) to treat the donor organ prior to transplantation. Perfusion of a donor mouse heart with MMF-loaded PEG-PLGA nanoparticles (MMF-NPs) prior to transplantation abrogated cardiac transplant vasculopathy by suppressing intragraft pro-inflammatory cytokines and chemokines. Our findings demonstrate that ex vivo delivery of an ISA to donor organs using a nanocarrier can serve as a clinically feasible approach to reduce transplant immunity.

Inflammation occurring within the transplanted organ from the time of harvest is an important stimulus of early alloimmune reactivity and promotes chronic allograft rejection. Chronic immune-mediated injury remains the primary obstacle to the long-term success of organ transplantation. However, organ transplantation represents a rare clinical setting in which the organ is accessible ex vivo, providing an opportunity to use nanotechnology to deliver therapeutics directly to the graft. This approach facilitates the directed delivery of immunosuppressive agents (ISA) to target local pathogenic immune responses prior to the transplantation. Here, we have developed a system of direct delivery and sustained release of mycophenolate mofetil (MMF) to treat the donor organ prior to transplantation. Perfusion of a donor mouse heart with MMF-loaded PEG-PLGA nanoparticles (MMF-NPs) prior to transplantation abrogated cardiac transplant vasculopathy by suppressing intragraft pro-inflammatory cytokines and chemokines. Our findings demonstrate that ex vivo delivery of an ISA to donor organs using a nanocarrier can serve as a clinically feasible approach to reduce transplant immunity.

Tumour-associated macrophages (TAMs) support tumour development and have emerged as important regulators of therapeutic response to cytostatic agents. To target TAMs, we have developed a novel drug delivery approach which induces drug release as it inhibits cysteine cathepsin activity. This inhibitory prodrug (IPD) approach establishes a self-regulated system where drug release stops after all cysteine cathepsins are inhibited. This could improve the therapeutic window for drugs with severe side effects. We demonstrate and characterise this self-regulation concept with a fluorogenic IPD model. Next, we applied this IPD strategy to deliver cytotoxic drugs, as doxorubicin and monomethyl auristatin E, which are efficiently released and dose-dependently eliminate RAW264.7 macrophages. Lastly, by exploiting the increased cathepsin activity in TAM-like M2-polarised primary macrophages, we show that IPD-Dox selectively eliminates M2 over M1 macrophages. This demonstrates the potential of our IPD strategy for selective drug delivery and modulation of the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Magnetic actuation offers a means to wirelessly control flow in ferrofluids for applications including microfluidic pumping and targeted drug delivery. Despite the promise of these concepts, practical use of synthetic ferrofluids as actuators of flow frequently requires high concentrations and is hindered by low ferrohydrodynamic coupling efficiency and inhomogeneous flow fields. Inspired by the magnetic properties and hydrodynamic forms displayed by magnetotactic bacteria (MTB), this work studies the use of these microbes as a living, self‐replicating ferrofluid for improved fluidic transport via magnetically coerced rotation. Using multicore iron oxide nanoparticles as a performance benchmark, MTB under rotating magnetic fields are shown to produce more homogeneous and efficient flow. Coupling is enhanced whether the comparison is made in terms of volume of magnetic material or total volume fraction. To clarify the mechanistic role of interactions with boundaries in transport, a computational model is developed and validated experimentally. Applying this model, two distinct and feasible magnetic control strategies are predicted: a rotating gradient field that generates directional flow despite boundaries that promote flow in opposing directions and a magnetostatic gating field that enables spatially selective actuation. The advantageous properties identified for MTB open a design space for these strategies to be realized. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is a complex and heterogeneous disease associated with high mortality and morbidity worldwide. Standard therapeutic management of advanced HNC, which is based on radiotherapy often combined with chemotherapy, has been hampered by severe long-term side effects. To overcome these side effects, tumor-selective nanoparticles have been exploited as a potential drug delivery system to improve HNC therapy. A combination of MEDLINE, EMBASE, Cochrane Oral Health Group’s Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception up to June 2020 was used for this systematic review. A total of 1747 published manuscripts were reviewed and nine relevant references were retrieved for analysis, while eight of them were eligible for meta-analysis. Based on these studies, the level of evidence about the efficacy of nanoformulation for HNC therapy on tumor response and adverse side effects (SAE) was low. Even though basic research studies have revealed a greater promise of nanomaterial to improve the outcome of cancer therapy, none of them were translated into clinical benefits for HNC patients. This systematic review summarized and discussed the recent progress in the development of targeted nanoparticle approaches for HNC management, and open-up new avenues for future perspectives.

An innovative process of integrating microneedle array with carbon nanotube (CNT) nanofilters is developed for a novel transdermal drug delivery device with nanometer-scale selectivity and control mechanism. The SU-8 microneedle array is fabricated by the double drawing lithography process. This microneedle array is capable of penetrating stratum corneum (SC) layer. Then, drug molecules can selectively pass through CNT nanofilters with the aid of pressure, or an electric field, and are effectively delivered into the tissues under the SC layer. The CNT bundles integrated within the microneedle array act as nanofilters to block particles and molecules larger than the inner diameter of the CNTs. Moreover, the CNT nanofilters can selectively control the delivered drugs when they are under various electric fields. Three kinds of biomolecules, e.g., glucose, insulin, and hemagglutininare are investigated. The results demonstrate that the proposed novel transdermal drug delivery device can effectively deliver drug molecules in a selectively control mechanism. [ABSTRACT FROM AUTHOR]

Increasing antibiotic concentrations within bacterial cells while reducing them in mammalian ones would ultimately result in an enhancement of antibacterial actions, overcoming multidrug resistance, all while minimizing toxicity. Nanoparticles (NPs) have been used in numerous occasions to overcome antibiotic resistance, poor drug solubility, and stability. However, the concomitant increase in antibiotic concentration in mammalian cells and the resultant toxicity are usually overlooked. Without compromising bacterial cell fusion, large liposomes (Lip) have been reported to show reduced uptake in mammalian cells. Therefore, in this work, small NP fraught liposomes (NP-Lip) were formulated with the aim of increasing NP uptake and antibiotic delivery in bacterial cells but not in mammalian ones. Small polylactic- co -glycolic acid NPs were therefore loaded with erythromycin (Er), an antibiotic with low membrane permeability that is susceptible to drug efflux, and 3c, a 5-cyanothiazolyl urea derivative with low solubility and stability. In vitro experiments demonstrated that the incorporation of small NPs into large Lip resulted in a reduction in NP uptake by HEK293 cells while increasing it in Gram-negative bacteria ( Escherichia coli DH5α, E. coli K12, and Pseudomonas aeruginosa ), consequently resulting in an enhancement of antibiotic selectivity by fourfold toward E. coli (both strains) and eightfold toward P. aeruginosa . Ocular administration of NP-Lip in a P. aeruginosa keratitis mouse model demonstrated the ability of Er/3c-loaded NP-Lip to result in a complete recovery. More importantly, in comparison to NPs, the ocular administration of NP-Lip showed a reduction in TNF-alpha and IL-6 levels, implying reduced interaction with mammalian cells in vivo. This work therefore clearly demonstrated how tailoring the nano-bio interaction could result in selective drug delivery and a reduction in toxicity.

Head and neck cancer (HNC) is a complex and heterogeneous disease associated with high mortality and morbidity worldwide. Standard therapeutic management of advanced HNC, which is based on radiotherapy often combined with chemotherapy, has been hampered by severe long-term side effects. To overcome these side effects, tumor-selective nanoparticles have been exploited as a potential drug delivery system to improve HNC therapy. A combination of MEDLINE, EMBASE, Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception up to June 2020 was used for this systematic review. A total of 1747 published manuscripts were reviewed and nine relevant references were retrieved for analysis, while eight of them were eligible for meta-analysis. Based on these studies, the level of evidence about the efficacy of nanoformulation for HNC therapy on tumor response and adverse side effects (SAE) was low. Even though basic research studies have revealed a greater promise of nanomaterial to improve the outcome of cancer therapy, none of them were translated into clinical benefits for HNC patients. This systematic review summarized and discussed the recent progress in the development of targeted nanoparticle approaches for HNC management, and open-up new avenues for future perspectives. [ABSTRACT FROM AUTHOR]

Background: Application of magnetic nanoparticles as a drug delivery system has attracted great attention in the cancer therapy, interests in the pH and thermo-sensitive polymers have been increased exponentially in biomedicine., Objective: (N-isopropylacrylamide)-ethylene glycol dimethacrylate copolymer was coated on the surface of Fe3O4 magnetic nanoparticles and utilized as a pH and temperature responsive nanocarrier for encapsulation and delivery of doxorubicin, as an anti-cancer drug., Method: First, Fe3O4 nanoparticles were prepared through the chemical co-precipitation method and then coated by poly (N-isopropylacrylamide)-ethylene glycol dimethacrylate copolymer shell. The synthesized nanocarrier were later used as a drug carrier for the DOX drug delivery., Results: Nanocarriers were characterized by a number of techniques i.e. scanning electron microscopy (SEM), dynamic light scattering (DLS(X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Thermo gravimetric analysis (TGA) and vibrating sample magnetometer (VSM). The effects of pH and temperature on the drug release rate were evaluated. The obtained result revealed that doxorubicin release rate of the polymer is temperature and pH dependent, which are desirable properties for a selective delivery system. At the end of 72 h, only 15% of doxorubicin had been released in pH 7.4 conditions comparing to that of 58% in pH 5.8 acidic conditions at 40°C., Conclusion: This project improves the delivery of anti-cancer drug. The preparation of this nanocarrier was simple and fast and the prepared sorbent is biocompatible., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Among numerous drug-delivery approaches, reconstituted high-density lipoprotein (rHDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs. In this study, we have investigated the enhancement of the therapeutic impact of valrubicin (AD-32), an antineoplastic agent that has been limited to intravesicular application against bladder cancer, despite the encouraging original preclinical data. Earlier studies validated the superior therapeutic efficacy of AD-32 over doxorubicin. In the present study, rHDL/AD-32 nanoparticles were formulated and characterized with regard to encapsulation efficiency, physicochemical properties, selective toxicity, and receptor-mediated uptake. The half maximal inhibitory concentration values (IC(50)) for rHDL/AD-32 nanoparticles were 1.8 and 2.6 times lower than the free AD-32 for prostate (PC-3) and ovarian (SKOV-3) cancer cell lines, respectively, whereas nonmalignant cell lines demonstrated 5 and 1.48 times higher IC(50) doses with rHDL/AD-32 formulations. The data obtained demonstrated effective receptor- mediated uptake of AD-32 from the rHDL nanocarriers by PC-3 and SKOV-3 cancer cells via a targeted drug-delivery process. The rHDL/AD-32 formulation was stable for 6 months when stored at 4°C or at -20°C, as 92% of the AD-32 was retained in the nanoparticles. The findings from this study show that the rHDL/AD-32 formulation can overcome the solubility barriers of AD-32 and thus serve as an effective systemically administered chemotherapeutic agent.