Expert Opinion on Drug Delivery最新文献

Introduction: Biomacromolecules have proven to be an attractive choice for treating diseases due to their properties of strong specificity, high efficiency, and low toxicity. Besides greatly improving the patient's complaint, oral delivery of macromolecules also complies with hormone physiological secretion, which has become one of the most innovative fields of research in recent years.

Areas covered: Oral delivery biological barriers for biomacromolecule, transport mechanisms, and various administration strategies were discussed in this review, including absorption enhancers, targeting nanoparticles, mucoadhesion nanoparticles, mucus penetration nanoparticles, and intelligent bionic drug delivery systems.

Expert opinion: The oral delivery of biomacromolecules has important clinical implications; however, these are still facing the challenges of low bioavailability due to certain barriers. Various promising technologies have been developed to overcome the barriers and improve the therapeutic effect of oral biomacromolecules. By considering safety and efficacy comprehensively, the development of intelligent nanoparticles based on the GIT environment has demonstrated some promise in overcoming these barriers; however, a more comprehensive understanding of the oral fate of oral biomacromolecules is still required.

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa (LD) with carbidopa (CD). As PD progresses, despite higher doses of LD/CD, plasma levels of LD fluctuate, and may be associated with motor fluctuations and dyskinesia.

Areas covered: The development of two new subcutaneous preparations of LD/CD (ND0612 and ABBV-951) for the treatment of motor fluctuations in PD is described in detail. Both reduce motor fluctuations and dyskinesia with minor infusion site adverse events. A third subcutaneous preparation, DIZ102, is in early-stage development.

Expert opinion: The premise for using continuous release LD in advanced PD is that steady state levels of LD will prevent motor fluctuations/dyskinesia, but this is not the whole story, and will limit the benefits of subcutaneous continuous release LD. With its present pump system ND0612 cannot be used as monotherapy, whereas ABBV-951 can be. Having to combine with oral LD/CD will complicate the use of ND0612. Both ND0612 and ABBV-951 only cause modest reductions in OFF time. It is not clear whether these subcutaneous preparations will have more benefits than the intestinal gel, which also reduces OFF time and dyskinesia.

Introduction: The blood-brain barrier (BBB) restricts brain access of virtually all macromolecules. Receptor-mediated transcytosis (RMT) is one strategy toward their brain delivery. In this strategy, targeting ligands conjugated to therapeutic payload or decorating particles containing the payload interact with targets on brain capillary endothelial cells (BCEC), triggering internalization, trafficking, and release from BCEC.

Areas covered: RMT at the BBB has leveraged multiple formats of macromolecules and large particles. Interactions between those and BCEC have been studied primarily using antibodies, with findings applicable to the design of larger particles. BBB-penetrant constructs have also been identified in screening campaigns and directed evolution, and subsequently found to interact with RMT targets. In addition, BCEC targeted by constructs incorporating genomic payload can be made to produce therapeutic proteins.

Expert opinion: While targeting may not be strictly necessary to reach a therapeutic effect for all macromolecules, it can improve a molecule's BBB transport, exposing it to the entire brain parenchyma and enhancing its effect. Constructs with better BCEC transcytosis may be designed rationally, leveraging knowledge about BCEC trafficking, and found in screening campaigns, where this knowledge can reduce the search space and improve iterative refinement. Identification of new targets may also help generate BBB-crossing constructs.

Objectives: Oxaliplatin induces chemobrain in cancer patients/survivors. Nutraceutical naringin has antioxidant and anti-inflammatory properties with low oral bioavailability. Our aim was to formulate naringin in chitosan nanoparticles for nose to brain delivery and assess its neuroprotective effect against oxaliplatin-induced chemobrain in rats.

Methods: Naringin chitosan nanoparticles were prepared by ionic gelation. Rats were administered oral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loaded chitosan nanoparticles (0.3 mg/kg). Naringin's neuroprotective efficacy was assessed based on behavioral tests, histopathology, and measuring oxidative stress and inflammatory markers.

Results: Selected nanoparticles formulation showed drug loading of 5%, size of 150 nm and were cationic. Intranasal naringin administration enhanced memory function, inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-induced histological changes. Moreover, it reduced malondialdehyde and elevated reduced glutathione hippocampal levels. Furthermore, it decreased levels of inflammatory markers: NF-kB and TNF-α by 1.25-fold. Upstream to this inflammatory status, intranasal naringin downregulated the hippocampal protein levels of two pathways: cGAS/STING and HMGB1/RAGE/TLR2/MYD88.

Conclusion: Intranasal naringin-loaded chitosan nanoparticles showed superior amelioration of oxaliplatin-induced chemobrain in rats at a dose 267-fold lower to that administered orally. The potential involvement of cGAS/STING and HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of either oxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.

Introduction: Respiratory diseases represent a worldwide health issue. The recent Sars-CoV-2 pandemic, the burden of lung cancer, and inflammatory respiratory diseases urged the development of innovative therapeutic solutions. In this context, therapeutic antibodies (Abs) offer a tremendous opportunity to benefit patients with respiratory diseases. Delivering Ab through the airways has been demonstrated to be relevant to improve their therapeutic index. However, few inhaled Abs are on the market.

Areas covered: This review describes the different barriers that may alter the fate of inhaled therapeutic Abs in the lungs at steady state. It addresses both physical and biological barriers and discusses the importance of taking into consideration the pathological changes occurring during respiratory disease, which may reinforce these barriers.

Expert opinion: The pulmonary route remains rare for delivering therapeutic Abs, with few approved inhaled molecules, despite promising evidence. Efforts must focus on the intertwined barriers associated with lung diseases to develop appropriate Ab-formulation-device combo, ensuring optimal Ab deposition in the respiratory tract. Finally, randomized controlled clinical trials should be carried out to establish inhaled Ab therapy as prominent against respiratory diseases.

Introduction: Cerebral diseases have been threatening public physical and psychological health in the recent years. With the existence of the blood-brain barrier (BBB), it is particularly hard for therapeutic proteins like peptides, enzymes, antibodies, etc. to enter the central nervous system (CNS) and function in diagnosis and treatment in cerebral diseases. Fortunately, the past decade has witnessed some emerging strategies of delivering macromolecular therapeutic proteins across the BBB.

Areas covered: Based on the structure, functions, and substances transport mechanisms, various enhanced delivery strategies of therapeutic proteins were reviewed, categorized by molecule-mediated delivery strategies, carrier-mediated delivery strategies, and other delivery strategies.

Expert opinion: As for molecule-mediated delivery strategies, development of genetic engineering technology, optimization of protein expression and purification techniques, and mature of quality control systems all help to realize large-scale production of recombinant antibodies, making it possible to apply to the clinical practice. In terms of carrier-mediated delivery strategies and others, although nano-carriers/adeno-associated virus (AAV) are also promising candidates for delivering therapeutic proteins or genes across the BBB, some issues still remain to be further investigated, including safety concerns related to applied materials, large-scale production costs, quality control standards, combination therapies with auxiliary delivery strategies like focused ultrasound, etc.

Objective: Colitis-associated cancer (CAC) treatment lacks effective small-molecule drugs and efficient targeted delivery systems. Here, we loaded M13 (an anti-cancer drug candidate) to colon-targeting ginger-derived nanoliposomes (NL) and investigated if orally administered M13-NL could enhance the anticancer effects of M13 in CAC mouse models.

Methods: The biopharmaceutical properties of M13 were assessed by physicochemical characterizations. The in vitro immunotoxicity of M13 was assessed against PBMCs using FACS and the mutagenic potential of M13 was evaluated by the Ames assay. The in vitro efficacy of M13 was tested in 2D- and 3D-cultured cancerous intestinal cells. AOM/DSS-induced CAC mice were used to evaluate the therapeutic effects of free M13 or M13-NL on CAC in vivo.

Results: M13 has beneficial physiochemical properties, including high stability, and no apparent immunotoxicity or mutagenic potential in vitro. M13 is effective against the growth of 2D- and 3D-cultured cancerous intestinal cells in vitro. The in vivo safety and efficacy of M13 were significantly improved by using NL for drug delivery (p < 0.001). Oral administration of M13-NL exhibited excellent therapeutic effects in AOM/DSS-induced CAC mice.

Conclusion: M13-NL is a promising oral drug formulation for CAC treatment.

Introduction: Advances in understanding the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD) led to investigation of biologic drugs targeting specific inflammatory pathways. No biologics are licensed for COPD while all the approved monoclonal antibodies (mAbs) for severe asthma treatment are systemically administered. Systemic administration is associated with low target tissue exposure and risk of systemic adverse events. Thus, delivering mAbs via inhalation may be an attractive approach for asthma and COPD treatment due to direct targeting of the airways.

Areas covered: This systematic review of randomized control trials (RCTs) evaluated the potential role of delivering mAbs via inhalation in asthma and COPD treatment. Five RCTs were deemed eligible for a qualitative analysis.

Expert opinion: Compared to systemic administration, delivering mAbs via inhalation is associated with rapid onset of action, greater efficacy at lower doses, minimal systemic exposure, and lower risk of adverse events. Although some of the inhaled mAbs included in this study showed a certain level of efficacy and safety in asthmatic patients, delivering mAbs via inhalation is still challenging and controversial. Further adequately powered and well-designed RCTs are needed to assess the potential role of inhaled mAbs in the treatment of asthma and COPD.

Introduction: Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins have multiple advantages, including high bioactivity and specificity with low toxicity. Developing oral dosage forms with active proteins is a route to improve patient compliance and significantly reduce production costs. However, the gastrointestinal environment remains a challenge to this delivery path due to enzymatic degradation, low permeability, and weak absorption, leading to reduced delivery efficiency and poor clinical outcomes.

Areas covered: This review describes the barriers to oral delivery of peptides and complex proteins, current oral delivery strategies utilized and the opportunities and challenges ahead to try and circumvent these barriers. Oral protein drugs on the market and clinical trials provide insights and approaches for advancing delivery strategies.

Expert opinion: Although most current studies on oral protein delivery rely on in vitro and in vivo animal data, the safety and limitations of the approach in humans remain uncertain. The shortage of clinical data limits the development of new or alternative strategies. Therefore, designing appropriate oral delivery strategies remains a significant challenge and requires new ideas, innovative design strategies and novel model systems.

Objectives: Metastasis is still one of the main obstacles in the treatment of breast cancer. This study aimed to develop disulfiram (DSF) and doxorubicin (DOX) co-loaded nanoparticles (DSF-DOX NPs) with enzyme/pH dual stimuli-responsive characteristics to inhibit breast cancer metastasis.

Methods: DSF-DOX NPs were prepared using the amphiphilic poly(ε-caprolactone)-b-poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer by a classical dialysis method. In vitro release tests, in vitro cytotoxicity assay, and anti-metastasis studies were conducted to evaluate pH/enzyme sensitivity and therapeutic effect of DSF-DOX NPs.

Results: The specific pH and enzyme stimuli-responsiveness of DSF-DO NPs can be attributed to the transformation of secondary structure and the degradation of amide bonds in the PGlu segment, respectively. This accelerated drug release significantly increased the cytotoxicity to 4T1 cells. Compared with the control group, the DSF-DOX NPs showed a strong inhibition of in vitro metastasis with a wound healing rate of 36.50% and a migration rate of 18.39%. Impressively, in vivo anti-metastasis results indicated that the metastasis of 4T1 cells was almost completely suppressed by DSF-DOX NPs.

Conclusion: DSF-DOX NPs with controllable tumor site delivery of DOX and DSF were a prospectively potential strategy for metastatic breast cancer treatment.