Expert opinion on drug delivery最新文献

Introduction: Polymer-lipid hybrid nanoparticle (PLN) is an emerging nanoplatform with distinct properties and functionalities from other nanocarrier systems. PLN can be optimized to overcome various levels of drug delivery barriers to achieve desired therapeutic outcomes via rational selection of polymer and lipid combinations based on a thorough understanding of their properties and interactions with therapeutic agents and biological systems.

Areas covered: This review provides an overview of PLN including the motive and history of PLN development, types of PLN, preparation methods, attestations of their versatility, and design strategies to circumvent various barriers for increasing drug delivery accuracy and efficiency. It also highlights recent advances in PLN design including: rationale selection of polymer and lipid components to achieve spatiotemporal drug targeting and multi-targeted cascade drug delivery; utilizing the intracellular lipid transport mechanism for active targeting to desired organelles; and harnessing bioreactive lipids and polymers to magnify therapeutic effects.

Expert opinion: A thorough understanding of properties of PLN components and their biofate is important for enhancing disease site targeting, deep tumor tissue penetration, cellular uptake, and intracellular trafficking of PLN. For futuristic PLN development, active lipid transport and dual functions of lipids and polymers as both nanocarrier material and pharmacological agents can be further explored.

Introduction: Triple-negative breast cancer (TNBC) presents unique challenges in diagnosis and treatment. Resveratrol exhibits potential as a therapeutic intervention against TNBC by regulating various pathways such as the PI3K/AKT, RAS/RAF/ERK, PKCδ, and AMPK, leading to apoptosis through ROS-mediated CHOP activationand the expression of DR4 and DR5. However, the clinical efficacy of resveratrol is limited due to its poor biopharmaceutical characteristics and low bioavailability at the tumor site. Nanotechnology offers a promising approach to improving the biopharmaceutical characteristics of resveratrol to achieve clinical efficacy in different cancers. The small dimension (<200 nm) of nanotechnology-mediated drug delivery system is helpful to improve the bioavailability, internalization into the TNBC cell, ligand-specific targeted delivery of loaded resveratrol to tumor site including reversal of MDR (multi-drug resistance) condition.

Areas covered: This manuscript provides a comprehensive discussion on the structure-activity relationship (SAR), underlying anticancer mechanism, evidence of anticancer activity in in-vitro/in-vivo investigations, and the significance of nanotechnology-mediated delivery of resveratrol in TNBC.

Expert opinion: Advanced nano-formulations of resveratrol such as oxidized mesoporous carbon nanoparticles, macrophage-derived vesicular system, functionalized gold nanoparticles, etc. have increased the accumulation of loaded therapeutics at the tumor-site, and avoid off-target drug release. In conclusion, nano-resveratrol as a strategy may provide improved tumor-specific image-guided treatment options for TNBC utilizing theranostic approach.

Background: Myeloid-derived suppressor cells (MDSCs) are evolving as a prominent determinant in cancer occurrence and development and are functionally found to suppress T cells in cancer. Not much research is done regarding its involvement in viral infections. This research was designed to investigate the role of MDSCs in hepatitis B virus (HBV) infection and how targeting these cells with our novel all-trans retinoic acid encapsulated liposomal formulation could improve immunotherapy in C57BL/6 mice.

Methods: Ten micrograms (10 μg) of plasmid adeno-associated virus (pAAV/HBV 1.2, genotype A) was injected hydrodynamically via the tail vein of C57BL/6 mice. An all-trans retinoic acid encapsulated liposomal formulation (L-ATRA) with sustained release properties was used in combination with tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor (nRTI) to treat the HBV infection. The L-ATRA formulation was given at a dose of 5 mg/kg intravenously (IV) twice a week. The TDF was given orally at 30 mg/kg daily.

Results: Our results revealed that L-ATRA suppresses MDSCs in HBV infected mice and enhanced T-cell proliferation in vitro. In vivo studies showed higher and improved immunotherapeutic effect in mice that received L-ATRA and TDF concurrently in comparison with the groups that received monotherapy. Lower HBV DNA copies, lower concentrations of HBsAg and HBeAg, lower levels of ALT and AST and less liver damage were seen in the mice that received the combination therapy of L-ATRA + TDF.

Conclusions: In effect, targeting MDSCs with the combination of L-ATRA and TDF effectively reduced mMDSC and improved immunotherapy in the HBV infected mice. Targeting MDSCs could provide a breakthrough in the fight against hepatitis B virus infection.

Background: This study aimed to confirm that the incremental dose/clicks system dispenses accurate doses for the Merck family of fertility pen injectors.

Research design and methods: Set doses (V_set) for three dose dial settings (minimum dose [V_min], midpoint dose [V_mid] and maximum dose [V_max] for the follitropin alfa, choriogonadotropin alfa [D2 classification: single use/variable dose], and follitropin alfa:lutropin-alfa 2:1 combination pen injectors) or a single V_set for the choriogonadotropin alfa (D1 classification: single use/single dose) were assessed. Last dose administered by the multi-dose device was assessed for the 900 IU, 450 IU, 300 IU and 150 IU follitropin alfa, and the 900:450 IU, 450:225 IU and 300:150 IU follitropin alfa:lutropin-alfa 2:1 combination pen presentations.

Results: Dose accuracy tests for V_min, V_mid and V_max for the follitropin alfa and the follitropin alfa:lutropin-alfa 2:1 combination pen injectors, and last dose administered, were within acceptable limits according to ISO 11,608-1:2012/2014. Dose accuracy tests for the single use/single dose device classification and the single use/variable dose device classification of the choriogonadotropin alfa pen injector were also within the acceptable limits, according to ISO 11608-1:2000/2014.

Conclusions: The Merck family of fertility pen injectors functions reliably and the incremental dose/clicks system dispenses accurate doses.

Introduction: Tuberculosis (TB) is a global health problem that poses a challenge to global treatment programs. Rifampicin is a potent and highly effective drug for TB treatment; however, higher oral doses than the standard dose (10 mg/kg/day) rifampicin may offer better efficacy in TB treatment.

Areas covered: High oral dose rifampicin is not implemented in anti-TB regimens yet and requires about a 3-fold increase in dose for increased efficacy. We discuss inhaled delivery of rifampicin as an alternative or adjunct to oral high-dose rifampicin. Clinical results of safety, tolerability, and patient compliance with antibiotic dry powder inhalers are reviewed.

Expert opinion: Clinical trials suggest that an approximately 3-fold increase in the standard oral dose of rifampicin may be required for better clinical outcomes. On the other hand, animal studies suggest that inhaled rifampicin can deliver a high concentration of the drug to the lungs and achieve approximately double the plasma concentration than that from oral rifampicin. Clinical trials on inhaled antibiotics suggest that dry powder inhalation is a patient-friendly and well-tolerated approach in treating respiratory infections compared to conventional treatments. Rifampicin, a well-known anti-TB drug given orally, is a good candidate for clinical development as a dry powder inhaler.

Introduction: Using engineered exosomes produced from stem cells is an experimental therapeutic approach for treating brain diseases. According to reports, preclinical research has demonstrated notable neurogenesis and angiogenesis effects using modified stem cell-derived exosomes. These biological nanoparticles have a variety of anti-apoptotic, anti-inflammatory, and antioxidant properties that make them very promising for treating nervous system disorders.

Areas covered: This review examines different ways to enhance the delivery of modified stem cell-derived exosomes, how they infiltrate the blood-brain barrier (BBB), and how they facilitate their access to the brain. We would also like to determine whether these nanoparticles have the most significant transmission rates through BBB when targeting brain lesions.

Expert opinion: Using engineered stem cell-derived exosomes for treating brain disorders has generated considerable attention toward clinical research and application. However, stem cell-derived exosomes lack consistency, and their mechanisms of action are uncertain. Therefore, upcoming research needs to prioritize examining the underlying mechanisms and strategies via which these nanoparticles combat neurological disorders.

Background: Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection.

Methods: Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo.

Results: Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration.

Conclusions: The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Objectives: Nanomedicines are being actively developed as inhalable drug delivery systems. However, there is a distinct utility in developing smaller polymeric systems that can bind albumin in the lungs. We therefore examined the pulmonary pharmacokinetic behavior of a series of lipidated brush-PEG (5 kDa) polymers conjugated to 1C₂, 1C₁₂ lipid or 2C₁₂ lipids.

Methods: The pulmonary pharmacokinetics, patterns of lung clearance and safety of polymers were examined in rats. Permeability through monolayers of primary human alveolar epithelia, small airway epithelia and lung microvascular endothelium were also investigated, along with lung mucus penetration and cell uptake.

Results: Polymers showed similar pulmonary pharmacokinetic behavior and patterns of lung clearance, irrespective of lipid molecular weight and albumin binding capacity, with up to 30% of the dose absorbed from the lungs over 24 h. 1C₁₂-PEG showed the greatest safety in the lungs. Based on its larger size, 2C₁₂-PEG also showed the lowest mucus and cell membrane permeability of the three polymers. While albumin had no significant effect on membrane transport, the cell uptake of C₁₂-conjugated PEGs were increased in alveolar epithelial cells.

Conclusion: Lipidated brush-PEG polymers composed of 1C₁₂ lipid may provide a useful and novel alternative to large nanomaterials as inhalable drug delivery systems.

Introduction: Tackling low water solubility of drug candidates is a major challenge in today's pharmaceutics/biopharmaceutics, especially by means of modern solubility-enabling formulations. However, drug absorption from these formulations oftentimes remains unchanged or even decreases, despite substantial solubility enhancement.

Areas covered: In this article, we overview the simultaneous effects of the formulation on the solubility and the apparent permeability of the drug, and analyze the contribution of this solubility-permeability interplay to the success/failure of the formulation to increase the overall absorption and bioavailability. Three different patterns of interplay were identified: (1) solubility-permeability tradeoff in which every solubility gain comes with a price of concomitant permeability loss; (2) an advantageous interplay pattern in which the permeability remains unchanged alongside the solubility gain; and (3) an optimal interplay pattern in which the formulation increases both the solubility and the permeability. Passive vs. active intestinal permeability considerations in the context of the solubility-permeability interplay are also thoroughly discussed.

Expert opinion: The solubility-permeability interplay pattern of a given formulation has a critical effect on its overall success/failure, and hence, taking into account both parameters in solubility-enabling formulation development is prudent and highly recommended.

Introduction: Intravesical drug delivery (IDD) has gained recognition as a viable approach for treating bladder-related diseases over the years. However, it comes with its set of challenges, including voiding difficulties and limitations in mucosal and epithelial penetration. These challenges lead to drug dilution and clearance, resulting in poor efficacy. Various strategies for drug delivery have been devised to overcome these issues, all aimed at optimizing drug delivery. Nevertheless, there has been minimal translation to clinical settings.

Areas covered: This review provides a detailed description of IDD, including its history, advantages, and challenges. It also explores the physical barriers encountered in IDD, such as voiding, mucosal penetration, and epithelial penetration, and discusses current strategies for overcoming these challenges. Additionally, it offers a comprehensive roadmap for advancing IDD into clinical trials.

Expert opinion: Physical bladder barriers and limitations of conventional treatments result in unsatisfactory efficacy against bladder diseases. Nevertheless, substantial recent efforts in this field have led to significant progress in overcoming these challenges and have raised important attributes for an optimal IDD system. However, there is still a lack of well-defined steps in the workflow to optimize the IDD system for clinical settings, and further research is required to establish more comprehensive in vitro and in vivo models to expedite clinical translation.