Polymeric Delivery Systems Research Articles

Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface.

Interest in nanomedicines has grown rapidly over the past two decades, owing to the promising therapeutic applications they may provide, particularly for the treatment of cancer. Personalised medicine and ‘smart’ actively targeted nanoparticles represent an opportunity to deliver therapies directly to cancer cells and provide sustained drug release, in turn providing overall lower off-target toxicity and increased therapeutic efficacy. However, the successful translation of nanomedicines from encouraging pre-clinical findings to the clinic has, to date, proven arduous. In this review, we will discuss the use of nanomedicines for the treatment of cancer, with a specific focus on the use of polymeric and lipid nanoparticle delivery systems. In particular, we examine approaches exploring the surface functionalisation of nanomedicines to elicit active targeting and therapeutic effects as well as challenges and future directions for nanoparticles in cancer treatment.

Trial working groups for paediatric brain tumours

Abstract Aims Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. Method The authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. Called the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’, this aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for the treatment of paediatric brain tumours. On March 1st, 2021, CBTDDC with guest chair, Mr Kristian Aquilina (Consultant Paediatric Neurosurgeon at Great Ormond Street Hospital), hosted the first virtual meeting of this group. Results We have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting on March 1st, 2021, 38 leading brain tumour research scientists and clinicians from the UK, EU and US tackled the challenges head-on, with commitment and a driving passion to identify and move forwards with the most effective ways of translating drug delivery modalities into clinical trials. Attendees were split into three break-out sessions based on distinct drug delivery systems, and lots of insightful comments were collated. Conclusion The ideas generated during the 1st March meeting will help form the basis of a CBTDDC ‘Clinical Trials’ workshop in the autumn of 2021. In particular, there was an agreed consensus that a key objective will be the creation of a ‘Roadmap’ document for pre-clinical to clinical translation which would be shared with the paediatric neuro-oncology research community. CBTDDC look forward to working with steering group as we act on their recommendations to address the current challenges faced by translational drug delivery research. We present this abstract to the BNOS Annual 2021 Meeting to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

Preparation and evaluation of polymeric beads composed of Chitosan\u2013Gellan Gum\u2013Gum Ghatti/-Gum Karaya polyelectrolyte complexes as polymeric carrier for enteric sustained delivery of Diclofenac sodium

BackgroundAn enteric coating is a multistep technique that involves deposition of a polymeric barrier over uncoated orally administered tablets to prevent them from dissolving or disintegrating in the stomach. However, as soon as the coating dissolves in the alkaline environment of intestine, the whole of the drug come in direct contact with gastric mucosa leading to irritation to distal parts of the gastrointestinal tract (GIT). Considering the above facts, there is clear need to develop a simple and effective enteric release formulation for gastric irritant drugs like Diclofenac sodium (DS). The goal of this study was to create enteric release polymeric polyelectrolyte complex (PEC) beads made up of cationic Chitosan (CH) and anionic Gellan Gum (GG) for sustained DS delivery to the intestine. The beads were prepared by extruding a solution of GG and Gum Ghatti (GT) or GG and Gum Karaya (GK) bearing DS into CH solution in 1% w/v acetic acid, with the help of a syringe fitted with a 18 gauge hypodermic needle.ResultsInstantly created spherical beads were dried in a hot air oven 60 °C overnight. In 0.1 M HCl and 6.8 pH phosphate buffer, the dried beads were tested for drug entrapment in the beads, in vitro swelling of beads and in vitro drug release studies from the beads. The % drug entrapment efficiencies (% DEE) of these PEC beads ranged from 59.54 ± 2.09 to 81.03 ± 4.22%. In 0.1 M HCl, the PEC beads swelled the least in vitro, but expanded significantly in phosphate buffer (pH 6.8). The in vitro release of Diclofenac sodium from different PEC beads in 0.1 M HCl was found to be less than 7.5 percent, whereas the release was sustained for 6 h in phosphate buffer (pH 6.8).ConclusionsFrom the experimental data, it may be concluded that these PEC beads can be useful as potential multiple-unit enteric release polymeric carrier systems for sustained delivery of gastric irritant drugs like Diclofenac sodium.

Development and Characterization of an Active Pharmaceutical Ingredient Using Polymeric Carriers Delivery System

Development and Characterization of an Active Pharmaceutical Ingredient Using Polymeric Carriers Delivery System

CLRM-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS

INTRODUCTIONBrain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the outlook for these children, including intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate these. In addition, custom-built hardware, novel surgical procedures and the testing and licensing of implantable devices add difficulty at the regulatory level.METHODSThe authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium), the CBTDDC and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group launched the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’. This aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for the treatment of paediatric brain tumours.RESULTSOn 1 March, 2021, CBTDDC and Mr Kristian Aquilina (Consultant Paediatric Neurosurgeon at Great Ormond Street Hospital) hosted the first steering group meeting, comprising 38 leading brain tumour research scientists and clinicians from the UK, EU and US.CONCLUSIONThe ideas generated during the March meeting are driving the agenda for a Clinical Trials Workshop that will be held in the autumn of 2021. In particular, there was agreed consensus that a ‘Roadmap’ document for pre-clinical to clinical translation needs to be created and shared with the paediatric neuro-oncology research community. We present this abstract to the CNS Clinical Trials Meeting to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

Co-Delivery of Curcumin and Bioperine via PLGA Nanoparticles to Prevent Atherosclerotic Foam Cell Formation.

Cholesterol-rich arterial plaques characterize atherosclerosis, a significant cause of heart disease. Nutraceuticals have received attention over the years, demonstrating potential benefits towards treating and preventing cardiovascular diseases (CVD), including atherosclerosis. Curcumin, a potent polyphenol present in Curcuma longa, has shown remarkable anti-atherosclerotic activity via anti-inflammatory and anti-oxidative properties. The bioavailability and low water solubility of curcumin limit its clinical translational purposes. These issues can be circumvented effectively by nano-drug delivery systems that can target atherosclerotic plaque sites. In this work, we chose to use curcumin and a natural bioenhancer called Bioperine (derived from Piper nigrum) inside a polymeric nano-drug delivery system for targeting atherosclerotic plaque sites. We selected two different ratios of curcumin:Bioperine to study its comparative effect on the inhibition of oxidized low-density lipoprotein (Ox-LDL)-induced foam cell formation. Our studies demonstrated that Cur-Bio PLGA NPs (both ratios) maintained the cell viability in THP-1 monocyte-derived macrophages above 80% at all periods. The 1:0.2:10 ratio of Cur-Bio PLGA NPs at a concentration of 250 μg/mL illustrated an enhanced reduction in the relative cholesterol content in the THP-1-derived foam cells compared to the 1:1:10 ratio. Confocal microscopy analysis also revealed a reduction in macrophage-mediated foam cell formation when administered with both the ratios of Cur-Bio PLGA NPs. Relative fold change in the mRNA expression of the genes involved in the inflammatory pathways in the atherosclerotic process downregulated NF-κB, CCL2/MCP-1, CD-36, and STAT-3 activity while upregulating the SCAR-B1 expression when treated with the Cur-Bio PLGA NPs. This study thus highlights the importance of natural-based compounds towards the therapeutic intervention against atherosclerotic activity when administered as preventive medicine.

An Integrated Tumor Microenvironment Responsive Polymeric Micelle for Smart Drug Delivery and Effective Drug Release.

Tumor microenvironment (TME) responsive polymeric micelles are promising carriers for drug delivery. In order to meet the needs of various applications, multifarious TME-responsive switches are used to construct smart polymeric micelles, which causes the complexity and corpulence of the polymeric micelle system and increases the difficulty of preparation. In this study, we designed and synthesized an ingenious TME-responsive switch through grafting disulfide bond-modified piperidinepropionic acid (CPA) on copolymer poly(ethylene glycol)-b-poly(aspartate)(PEG-b-PAsp) and built a novel pH/reduction-responsive PEG-b-PAsp-g-CPA polymeric micelle delivery system. The CPA-pendants can reverse the surface charge of the polymeric micelle from negative to positive at pH 6.5 because of the protonation of piperidine groups, thereby enhancing the internalization of cell. Subsequently, more piperidine groups are protonated at pH 5.0 which will increase the hydrophilicity of polymeric micelles and cause the hydrophobic core to swell, thus making the disulfide bonds packed in the core to be more easily broken by GSH. With the synergistic effect of the pH-triggered protonation of piperidine groups and reduction triggered break of disulfide bonds, the polymeric micelles will disintegrate and achieve efficient intracellular drug release. The TME-responsive polymeric micelles exhibited good biological safety, enhanced internalization, and rapid intracellular doxorubicin (DOX) release in vitro. Moreover, the PEG-b-PAsp-g-CPA/DOX polymeric micelles showed excellent antitumor efficacy and low systemic toxicity in lung tumor-bearing BALB/C mice. These results indicated that the novel integrated TME-responsive switch CPA helps the PEG-b-PAsp-g-CPA polymeric micelles to obtain excellent TME-responsiveness and antitumor drug delivery capabilities, while it also makes the preparation of TME-responsive polymeric micelles simpler and more convenient. This work provides a new idea for the architecture of TME-responsive polymeric micelles.

The Influence of Modified Experimental Dental Resin Composites on the Initial In Situ Biofilm-A Triple-Blinded, Randomized, Controlled Split-Mouth Trial.

The purpose of the study was to investigate the bacterial viability of the initial biofilm on the surface of experimental modified dental resin composites. Twenty-five healthy individuals with good oral hygiene were included in this study. In a split-mouth design, they received acrylic splints with five experimental composite resin specimens. Four of them were modified with either a novel polymeric hollow-bead delivery system or methacrylated polymerizable Irgasan (Antibacterial B), while one specimen served as an unmodified control (ST). A delivery system based on Poly-Pore® was loaded with one of the active agents: Tego® Protect 5000 (Antiadhesive A), Dimethicone (Antiadhesive B), or Irgasan (Antibacterial A). All study subjects refrained from toothbrushing during the study period. Specimens were detached from the splints after 8 h and given a live/dead staining before fluorescence microscopy. A Friedman test and a post hoc Nemenyi test were applied with a significance level at p < 0.05. In summary, all materials but Antibacterial B showed a significant antibacterial effect compared to ST. The results suggested the role of the materials’ chemistry in the dominance of cell adhesion. In conclusion, dental resin composites with Poly-Pore-loaded active agents showed antibacterial effectiveness in situ.

Using rheology to quantify the effects of localized collagenase treatments on uterine fibroid digestion

Uterine fibroids are stiff, benign tumors containing excessive, disordered collagens that occur in 70-80% of women before age 50 and cause bleeding and pain. Collagenase Clostridium histolyticum (CCH) is a bacterial enzyme capable of digesting the collagens present in fibroids. By combining CCH with injectable drug delivery systems to enhance effectiveness, a new class of treatments could be developed to reduce the stiffness of fibroids, preventing the need for surgical removal and preserving fertility. In this work, we achieved localization of CCH via physical entrapment by co-injecting a thermoresponsive pNIPAM-based polymeric delivery system called LiquoGel (LQG), which undergoes a sol-gel transition upon heating. Toxicity study results for LQG injected subcutaneously into mice demonstrate that LQG does not induce lesions or other adverse effects. We then used rheology to quantify the effects of localized CCH injections on the modulus and viscoelasticity of uterine fibroids, which exhibit gel-like behavior, through ex vivo and in vivo digestion studies. Ex vivo CCH injections reduce the tissue modulus by over two orders of magnitude and co-injection of LQG enhances this effect. Rheological results from an in vivo digestion study in mice show a significant reduction in tissue modulus and increase in tissue viscoelasticity 7 days after a single injection of LQG+CCH. Parallel histological staining validates that the observed rheological changes correspond to an increase in collagen lysis after treatment by LQG+CCH. These results show promise for development of injectable and localized enzymatic therapies for uterine fibroids and other dense tumors. Statement of significanceUterine fibroids are stiff, benign tumors containing high collagen levels that cause bleeding and pain in women. Fertility-preserving and minimally-invasive treatments to soften fibroids are needed as an alternative to surgical removal via hysterectomy. We demonstrate through ex vivo and in vivo studies that co-injecting a thermoresponsive polymer delivery system (LQG) alongside a bacterial collagenase (CCH) enzyme significantly increases treatment effectiveness at softening fibroids through CCH localization. We use rheology to measure the modulus and viscoelasticity of fibroids and histology to show that fibroid softening corresponds to a decrease in collagen after treatment with LQG+CCH. These results highlight the utility of rheology at quantifying tissue properties and present a promising injectable therapy for fibroids and other dense tumors.

Non-viral delivery of CRISPR\u2013Cas9 complexes for targeted gene editing via a polymer delivery system

Recent advances in molecular biology have led to the CRISPR revolution, but the lack of an efficient and safe delivery system into cells and tissues continues to hinder clinical translation of CRISPR approaches. Polymeric vectors offer an attractive alternative to viruses as delivery vectors due to their large packaging capacity and safety profile. In this paper, we have demonstrated the potential use of a highly branched poly(β-amino ester) polymer, HPAE-EB, to enable genomic editing via CRISPRCas9-targeted genomic excision of exon 80 in the COL7A1 gene, through a dual-guide RNA sequence system. The biophysical properties of HPAE-EB were screened in a human embryonic 293 cell line (HEK293), to elucidate optimal conditions for efficient and cytocompatible delivery of a DNA construct encoding Cas9 along with two RNA guides, obtaining 15–20% target genomic excision. When translated to human recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes, transfection efficiency and targeted genomic excision dropped. However, upon delivery of CRISPR–Cas9 as a ribonucleoprotein complex, targeted genomic deletion of exon 80 was increased to over 40%. Our study provides renewed perspective for the further development of polymer delivery systems for application in the gene editing field in general, and specifically for the treatment of RDEB.

Formoterol PLGA-PEG Nanoparticles Induce Mitochondrial Biogenesis in Renal Proximal Tubules.

Formoterol is a long-acting β2 agonist (LABA). Agonism of the β2-adrenergic receptor by formoterol is known to stimulate mitochondrial biogenesis (MB) in renal proximal tubules and recover kidney function. However, formoterol has a number of cardiovascular side effects that limits its usage. The goal of this study was to design and develop an intravenous biodegradable and biocompatible polymeric nanoparticle delivery system that targets formoterol to the kidney. Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) nanoparticles containing encapsulated formoterol were synthesized by a modified single-emulsion solvent evaporation technique resulting in nanoparticles with a median hydrodynamic diameter of 442 + 17 nm. Using primary cell cultures of rabbit renal proximal tubular cells (RPTCs), free formoterol, encapsulated formoterol polymeric nanoparticles, and drug-free polymeric nanoparticles were biocompatible and not cytotoxic over a wide concentration range. In healthy male mice, polymeric nanoparticles were shown to localize in tubules of the renal cortex and improved the renal localization of encapsulated formoterol compared to the free formoterol. At a lower total formoterol dose, the nanoparticle localization resulted in increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the master regulator of MB, and increased electron transport chain proteins, markers of MB. This was confirmed by direct visual quantification of mitochondria and occurred with both free formoterol and the encapsulated formoterol polymeric nanoparticles. At the same time, localization of nanoparticles to the kidneys resulted in reduced induction of MB markers in the heart. These new nanoparticles effectively target formoterol to the kidney and successfully produce MB in the kidney.

Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL).

Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36–92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

Design and In Vitro Study of a Dual Drug-Loaded Delivery System Produced by Electrospinning for the Treatment of Acute Injuries of the Central Nervous System.

Vascular and traumatic injuries of the central nervous system are recognized as global health priorities. A polypharmacology approach that is able to simultaneously target several injury factors by the combination of agents having synergistic effects appears to be promising. Herein, we designed a polymeric delivery system loaded with two drugs, ibuprofen (Ibu) and thyroid hormone triiodothyronine (T3) to in vitro release the suitable amount of the anti-inflammation and the remyelination drug. As a production method, electrospinning technology was used. First, Ibu-loaded micro (diameter circa 0.95–1.20 µm) and nano (diameter circa 0.70 µm) fibers were produced using poly(l-lactide) PLLA and PLGA with different lactide/glycolide ratios (50:50, 75:25, and 85:15) to select the most suitable polymer and fiber diameter. Based on the in vitro release results and in-house knowledge, PLLA nanofibers (mean diameter = 580 ± 120 nm) loaded with both Ibu and T3 were then successfully produced by a co-axial electrospinning technique. The in vitro release studies demonstrated that the final Ibu/T3 PLLA system extended the release of both drugs for 14 days, providing the target sustained release. Finally, studies in cell cultures (RAW macrophages and neural stem cell-derived oligodendrocyte precursor cells—OPCs) demonstrated the anti-inflammatory and promyelinating efficacy of the dual drug-loaded delivery platform.

EPCT-08. TRIAL WORKING GROUPS FOR PAEDIATRIC BRAIN TUMOURS

IntroductionBrain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children. These include ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial, intra-CSF and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate any of these. The science and technology underlying these developments is not traditionally embedded within the standard paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures and, in some cases, the testing and licensing of implantable devices, add difficulty at the regulatory level. MethodsThe authors participated in an international workshop funded by the charity Children with Cancer UK in 2016, where different experimental techniques aimed at optimising CNS drug delivery were discussed. Following this workshop and two subsequent workshops run by the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) in 2018 and 2020, the CBTDDC and the recently developed ITCC (Innovative Therapies for Children with Cancer) brain tumour group started working together to set up a new initiative. This aims to develop CNS-delivery-focused trial working groups for paediatric brain tumours. ResultsWe have assembled a prestigious steering group, comprising international researchers and clinicians with expertise in diverse aspects of translational and clinical research in CNS drug delivery. At our first group meeting in March, participants will discuss the most effective ways of translating the emerging drug delivery modalities into clinical trials. Prioritised actions will be taken forward and the group will reconvene to discuss developments and next steps at a workshop in the Autumn. ConclusionWe present this abstract to the SNO Paediatric conference to raise awareness of this initiative with the large number of relevant stakeholders who will be attending the event.

Efficacy of DAN-222, a novel investigational polymeric nanoparticle with topoisomerase I inhibitor, as monotherapy in breast cancer models and when combined with PARP inhibitor.

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

Design and fabrication of drug‐delivery systems toward adjustable release profiles for personalized treatment

AbstractAdvanced polymeric controlled delivery systems are designed to effectively treat chronic diseases by adjusting the temporal profile of drug release. Most conventional controlled‐release carriers provide a constant and sustained‐release profile of therapeutics for an extended time. Although these systems have improved the patients’ compliance and adherence and have reduced the administration frequency, they cannot be used for optimal treatment of diseases that require variable patterns of drug release in the treatment regimen. These patterns and the specific rhythms of medical conditions determined by both the body's internal biological clock cycles (i.e., circadian rhythm) and each patient's characteristics call for patient‐specific controlled drug‐delivery systems that can provide adjustable drug release profiles. The importance of individualized therapy and the variety of biodegradable polymers with tunable physicochemical properties promote the design and manufacturing of polymeric delivery systems that release therapeutics at controllable rates. In the past two decades, novel biomaterials and fabrication methods have been utilized to improve the traditional drug‐delivery design and manufacturing technologies. This review article provides a critical discussion of emerging polymeric controlled‐release systems and the mechanisms through which they release their therapeutic agents. Advances and challenges in the design and the fabrication processes of polymeric drug‐delivery systems, particularly solid oral dosage forms and implantable microchips, with controllable release profiles of drugs, are reviewed, focusing on the application of microtechnology and 3D printing techniques in their manufacturing.

Design of Polymers for Intracellular Protein and Peptide Delivery

AbstractCytosolic protein delivery techniques are of great importance for cell biology, biotechnology and protein drug development. The design of carriers with robust efficiency in cytosolic protein delivery is challenging. This account provides a progress report of polymeric carriers for this purpose in our group. During the past years, we have developed several types of functionalized polymers for cytosolic protein and peptide delivery by engineering polymers with ligands such as guanidinium, boronate, coordination ligands and fluoroalkyls. The designed polymers showed improved protein/peptide binding affinities, and successfully delivered various cargo proteins into the cytosol of living cells, while maintaining their bioactivity. In addition, the polymers showed potent efficiencies in the delivery of tumor antigens, therapeutic peptides, toxins and antioxidant proteins in vivo. We hope these polymers could be translated for protein delivery in the treatment of various diseases in the future. What is the most favorite and original chemistry developed in your research group?Fluorinated polymers for cytosolic biomolecule delivery.How do you get into this specific field? Could you please share some experiences with our readers?I get into this field by unexpected discoveries when designing polymeric gene delivery systems. Usually, modification of polymers with hydrophobic ligands yields more efficient gene carriers. Fluoroalkyl ligands wereproposed as one type of hydrophobic candidates in our experiments. Interestingly, the fluorous ligand modified polymers showed unprecedented efficiency in gene delivery. More importantly, the polymers exhibited excellent serum resistance and could achieve high efficiency at extremely low polymer dose. These unexpected discoveries motivated us to investigate the fluorine effect of fluorinated materials in gene, protein and peptide delivery.

Protecting Plant Stands: Peanut Industry Moves Quickly to Address Emerging Disease Threat

AbstractUniform stands of 4 plants/ft are recommended for runner peanuts to obtain maximum yield and manage stand‐sensitive diseases such as tomato spotted wilt virus that can cause serious crop loss. Numerous seed‐ and soil‐borne diseases can threaten stands if not controlled. With increasing heat and drought stress, such as experienced in 2019, Aspergillus is of particular concern. Seed treatment fungicides are the first line of defense, but the unexpected development of resistance to a key fungicide class (QoIs) just prior to planting in 2020 caused the industry to rapidly alter its standard programs. Another major industry change is a shift from dust formulations to a liquid polymer delivery system. Earn 0.5 CEUs in Integrated Pest Management by reading the article and taking the quiz at www.certifiedcropadviser.org/education/classroom/classes/980.

Polymeric nano- and microparticulate drug delivery systems for treatment of biofilms.

Now-a-days healthcare systems face great challenges with antibiotic resistance and low efficacy of antibiotics when combating pathogenic bacteria and bacterial biofilms. Administration of an antibiotic in its free form is often ineffective due to lack of selectivity to the infectious site and breakdown of the antibiotic before it exerts its effect. Therefore, polymeric delivery systems, where the antibiotic is encapsulated into a formulation, have shown great promise, facilitating a high local drug concentration at the site of infection, a controlled drug release and less drug degradation. All this leads to improved therapeutic effects and fewer systemic side effects together with a lower risk of developing antibiotic resistance. Here, we review and provide a comprehensive overview of polymer-based nano- and microparticles as carriers for antimicrobial agents and their effect on eradicating bacterial biofilms. We have a main focus on polymeric particulates containing poly(lactic-co-glycolic acid), chitosan and polycaprolactone, but also strategies involving combinations of these polymers are included. Different production techniques are reviewed and important parameters for biofilm treatment are discussed such as drug loading capacity, control of drug release, influence of particle size and mobility in biofilms. Additionally, we reflect on other promising future strategies for combating biofilms such as lipid-polymer hybrid particles, enzymatic biofilm degradation, targeted/triggered antibiotic delivery and future alternatives to the conventional particles.

Development of Polymeric Nanoparticles for Blood-Brain Barrier Transfer-Strategies and Challenges.

Neurological disorders such as Alzheimer's disease, stroke, and brain cancers are difficult to treat with current drugs as their delivery efficacy to the brain is severely hampered by the presence of the blood–brain barrier (BBB). Drug delivery systems have been extensively explored in recent decades aiming to circumvent this barrier. In particular, polymeric nanoparticles have shown enormous potentials owing to their unique properties, such as high tunability, ease of synthesis, and control over drug release profile. However, careful analysis of their performance in effective drug transport across the BBB should be performed using clinically relevant testing models. In this review, polymeric nanoparticle systems for drug delivery to the central nervous system are discussed with an emphasis on the effects of particle size, shape, and surface modifications on BBB penetration. Moreover, the authors critically analyze the current in vitro and in vivo models used to evaluate BBB penetration efficacy, including the latest developments in the BBB‐on‐a‐chip models. Finally, the challenges and future perspectives for the development of polymeric nanoparticles to combat neurological disorders are discussed.