Current Drug Delivery - Volume 20, Issue 9, 2023

The mitochondria are a dynamic powerhouse organelle that contributes greatly to cancer therapy. Solving the current problems that occur mostly in chemotherapy and diagnosis of various cancers targeting the Mitochondria is an implying approach. In this review, it is discussed how the tethering of mitochondrial-targeting moieties to chemotherapeutics, fluorescent dyes and photothermal molecules can enhance the anticancer effect. The most extensively used mitochondrial targeting conjugate is Triphenyl phosphonium (TPP), which is a delocalized lipophilic cation that gets easily accumulated via the endocytosis mechanism due to the decreased mitochondrial membrane potential of the cancer cell. Credited for this characteristic, TPP has been extensively investigated in targeting mitochondria and delivery of cancer theranostics. This mitochondrial targeting strategy attracted great attention in cancer targeting nanotechnology. The TPP based nanoformulation have exhibited amplified therapeutic outcomes in the treatment of various cancer. Thus, TPP is an ultimate carrier with magnificent potential as a mitochondrial targeting agent.

The nanoproducts prepared by electrospinning have a large specific surface area, adjustable porosity, and controllable structure. Therefore, electrospinning has attracted an increasing attention in the current drug delivery systems (CDDs). In general cognition, the morphology of electrospinning nanoproducts should be homogeneous and stable to provide reproducible functions. Thus, numerous studies have been conducted to overcome the generation of beads-on-the-string by optimizing experimental conditions. This review introduces a specific electrospun nanoproduct, which is beads-on-thestring nanofibers. The presence of beads in the beads-on-the-string nanofibers can effectively encapsulate the model drug, which reduce the initial burst release of the drug and provide sustained release. At the same time, the beads-on-the-string nanofibers with composite structures can modulate the release properties of model drugs in CDDs. This review mainly summarizes the current research on the preparation of beads-on-the-string nanofibers by electrospinning and the application of beads-on-the-string nanofibers in the field of drug delivery. The future challenges and opportunities of beads-on-the-string nanofibers are also anticipated.

Nanotechnology has attracted researchers around the globe owing to the small size and targeting properties of the drug delivery vectors. The interest in self-nanoemulsifying drug delivery systems (SNEDDS) has shown an exponential increase from the formulator's point of view. SNEDDS have shown wide applicability in terms of controlled and targeted delivery of various types of drugs. They chemically consist of oil, surfactants and co-surfactants that decrease the emulsion particle size to the range of <100 nm. However, stability issues such as drug precipitation during storage, incompatibility of ingredients in shell, decrease their application for the long run and these issues have been highlighted in this paper. The current review throws limelight on the biological aspects and process parameters. In addition, the process of absorption from GI is also discussed in detail. SNEDDS have been utilized as a treatment option for various diseases like cancer, diabetes, and ocular and pulmonary diseases. Along with this, the authors highlight the advances involving in vivo and in vitro lipolysis studies on SNEDDS, also highlighting recent innovations in this field, such as novel combinations of drug-free solid SNEDDS + solid dispersions, lipid-modified chitosan containing mucoadhesive SNEDDS, pHsensitive SNEDDS and several others.

Molecular pharmaceutics play a critical role in the drug delivery system, representing the direct interconnection of drug bioavailability with its molecular form. There is a diversity in the molecular structures by which it affects its properties, such as amorphous form, crystalline form, partialamorphous molecular dispersion, and disordered state. The active pharmaceutical ingredient (API) and the excipients utilized in the formulation process contain various divergent modes used in the formulation process. They include better formulations of any type to obtain good quality pharmaceutical products. This review reveals how the molecular states affect the API and are important in maintaining the quality of dosage forms. Furthermore, the physio-chemical properties of the components and various pharmaceutical approaches employed in the formulation of dosage forms are studied from the point of view of molecular pharmaceutics.

Mosquito-borne diseases such as dengue, malaria, yellow fever, chikungunya and Zika virus affect millions of people worldwide each year. Vector control and personal protection are very important to minimize the spread of diseases, and the use of repellent is an economic practice to prevent them. The application of repellent, which acts on the skin to form a vapor layer with a repellent odor to mosquitos, is recommended as an economic prevention and practice. The natural botanical product Citronella is an effective mosquito repellent due to the high concentrations of active chemical constituents present, notably terpenic alcohols. However, citronella tends to evaporate quickly from the skin surface, resulting in a rapid loss of activity. Strategies to increase repellency time, while at the same time minimizing toxicity, are major focuses of research and development in natural repellent products. Here we highlight the role of extended-release systems (ERS) of citronella oil in this approach.

Background: Currently, there is ongoing research in the pharmaceutical technology field to develop innovative drug delivery systems with improved therapeutic efficacy. Objectives: Although there is a high need for new drug molecules, most scientists focus on the advancement of novel pharmaceutical formulations since the present excipients lack important properties such as low release rate leading to repeated dosing. Aside from this, pharmaceutical technologists aim to develop drug formulations that can target specific organs and tissues, lowering the possibility of adverse effects. Methods: This review aims to cover the different polymer-based gel types, the development and characterization methods, as well as applications thereof. Finally, the recent advancements and future perspectives focusing on radiolabeled gels will be addressed. Results: In the last decades, polymer based pharmaceutical gels have shown attractive properties and therefore have raised the attention of pharmaceutical scientists. Gels are either chemically or physically cross-linked networks that can absorb fluids such as water (hydrogels), oil (organogels) and even air(aerogels). A variety of polymers, either synthetic or natural, have been employed as components for the gels. Stimuli-responsive gels based on stimuli-sensitive polymers are among the most studied gel class of last years. Conclusion: The use of polymer-based gels as drug delivery systems would be beneficial for targeting numerous diseases.

Retinoids represent a class of chemical compounds derived from or structurally and functionally related to vitamin A. Retinoids play crucial roles in regulating a range of crucial biological processes spanning embryonic development to adult life. These include regulation of cell proliferation, differentiation, and cell death. Due to their promising characteristics, retinoids emerged as potent anti-cancer agents, and their effects were validated in vitro and in vivo preclinical models of several solid and hematological malignancies. However, their clinical translation remained limited due to poor water solubility, photosensitivity, short half-life, and toxicity. The development of retinoid delivery formulations was extensively studied to overcome these limitations. This review will summarize some preclinical and commercial synthetic retinoids in cancer and discuss their different delivery systems.

Background: The development of nanogels has become an attractive strategy to enhance the antibacterial activity performance of bacteria. Methods: The ciprofloxacin composite nanogels were successfully prepared by electrostatic interaction between gelatin (positive charge) and CMC (negative charge) with the help of sodium tripolyphosphate (TPP) as ionic crosslinkers, to increase the antibacterial activity of ciprofloxacin against Staphylococcus aureus (S. aureus) mastitis infection. The formulation screening, characterization, in vitro release, antibacterial activity, and biosafety were studied. Results: The optimized formulation was fabricated of 20 mg/mL (CMC) and 50mg/mL (gelatin). The optimized ciprofloxacin composite nanogels were homogenous canary yellow suspension with a sedimentation rate of 1 and were incorporated in nano-sized cross-linked polymeric networks. The particle sizes were distributed as, 402.7±1.3 nm, PDI of 0.12±0.01, ZP of -24.5±0.2mv, EE of 74.28%±0.03%, LC of 20.5%±0.05%. Scanning electron microscope images revealed that ciprofloxacin might be incorporated in nano-sized cross-linked polymeric networks. Fourier transform infrared showed that the spontaneous electrostatic interactions between CMC and gelatin produce the network structure and form the composite nanogels. Meanwhile, in vitro release study showed that ciprofloxacin composite nanogels had sustained-release performances. The ciprofloxacin composite nanogels had shown better antibacterial activity against SCV 102 isolate than S. aureus ATCC 29213 and S. aureus 101isolates. The biosafety studies suggested the great promise of the injectable ciprofloxacin composite nanogels as a biocompatible breast injection. Conclusion: This study will afford a potential approach for developing injectable ciprofloxacin-loaded gelatin-CMC composite nanogels for cow S. aureus mastitis therapy.

Background: Mesoporous silica nanoparticles (MSNs) are one of the most promising carriers for drug delivery. MSNs have been widely used in pharmaceutical research as drug carriers because of their large pore volume, high surface area, excellent biocompatibility, nontoxicity, ease to functionalize, and sustained release effects. MSNs have attracted much attention during drug delivery because of their special structure. Objective: The present study aimed to synthesize mesoporous silica nanoparticles (MSNs), dendritic mesoporous silica nanoparticles (DMSN), and hollow mesoporous silica nanoparticles (HMSN) through facile methods, and to compare the drug release properties of nano-porous silica with different pore structures as a stroma for PUE drug. Methods: MSN, DMSN, and HMSN were characterized by SEM, TEM, FT-IR, nitrogen adsorptiondesorption isotherms, XRD, and zeta potential methods. Subsequently, puerarin (PUE) was used as the active ingredient and loaded into the three mesoporous materials, respectively. And, the drug delivery behavior was measured in PBS solution with different pH values. The sustained-release properties of MSN, DMSN, and HMSN loaded with PUE were investigated. Finally, the biocompatibility and stability of MSN, DMSN, and HMSN were studied by MTT assay and hemolysis assay. Results: Our results showed that MSN, DMSN, and HMSN were successfully synthesized and the three types of mesoporous silica nanoparticles had higher drug loading and encapsulation efficiency. According to the first-order release equation curve and Higuchi equation parameters, the results showed that the PUE-loaded MSN, DMSN, and HMSN exhibited sustained-release properties. Finally, MTT and hemolysis methods displayed that MSN, DMSN, and HMSN had good biocompatibility and stability. Conclusion: In this study, MSN, DMSN, and HMSN were successfully synthesized, and to compare the drug release properties of nano-porous silica with different pore structures as a stroma for PUE drug, we provided a theoretical and practical basis for the application of PUE.

Background: Diacerein, an osteoarthiritis drug, experiences slow topical permeation due to limited solubility. Additionally, it shows a laxative effect due to acid/base hydrolysis of the drug in the colon. Objective: Diacerein solubility was improved to increase percutaneous drug delivery. Methods: To improve saturation solubility of the drug, Diacerein was pre-treated with Polysorbate 80 aqueous solution (1% v/v) to obtain lyophilized powder after wet milling or formulated as solid dispersion using PEG 4000 by fusion method. The lyophilized Diacerein in hydroxypropyl methylcellulose (HPMC 8% w/w) and polyvinyl pyrrolidone (PVP 30% w/w) matrix, with PEG 400 as co-solvent, provided an optimized array. The solid dispersion was loaded in the CMC based gel for subsequent administration on dissolving microneedle-treated skin. Results: The addition of PEG 400 increased Diacerein loading in microneedles to 390.35±4.28 μg per array. The lyophilized drug displayed amorphous characteristics in the dissolving microneedles as per XRD analysis. SEM photographs showed uniformity in the surface topology of microneedles. The needles showed rapid polymer dissolution within 5 minutes, whereas methylene-blue distribution confirmed the formation of microcavities in excised rat skin. The drug-loaded arrays showed better permeation (74.39%) and skin deposition (15.75%) after 24 hours, however, 129;“12% of Diacerein remained in the baseplate. This led to the tailoring of CMC-based gel (3% w/v) containing 0.4% solid dispersion of Diacerein. When compared to untreated skin, the gel improved permeation rate by 2.43 folds through aqueous microchannels generated by dissolving microneedle pre-treatment and allowed 98% drug permeation. The quasi-Fickian diffusion mechanism was found to drive ex vivo release kinetics, with a shorter lag time (0.88 h) and higher flux (26.65 μg/sq.cm.h). Microneedle-assisted Diacerein gel showed a positive anti-inflammatory effect in the paw edema model and reduced diarrheal episodes in comparison to the marketed oral formulation. The gel showed desired characteristics at 5°C±2°C when tested under accelerated stability conditions. Conclusion: The present study reports for the first time the verification of efficacy and safety to advocate the suitability of Diacerein for percutaneous delivery through dissolving microneedle-treated skin.

Background: Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease. There is no effective treatment for PF. Hepatocyte growth factor (HGF) has anti-inflammatory and antifibrotic effects but has limited potential owing to its short half-life. Methods: To increase the transfection efficiency of pVAX-HGF, we prepared polyethyleneiminepolyethylene glycol: polyethyleneimine/pVAX-HGF (PEG-PEI: PEI/pVAX-HGF) nanocomposite loaded with a plasmid encoding the HGF gene. The PEG-PEI:PEI/pVAX-HGF characteristics, including morphology, particle size, zeta-potential, and DNA entrapment efficiency, were investigated. The pVAX-HGF nanocomposites with low toxicity and high transfection efficiency were screened by cell viability assay and cell transfection. The antifibrotic effect of pVAX-HGF nanocomposite on PF rats induced by bleomycin (BLM) was evaluated by pulmonary function measurement, pathological examination and collagen content assay. Results: Different nanocomposites were prepared to deliver pVAX-HGF, in which mix1 (PEGPEI: PEI/pVAX-HGF) has lower potential and better entrapment ability. PEG-PEI:PEI/pVAX-HGF (N/P=25) nanocomposite with low toxicity and high transfection efficiency was administered to PF rats. After treatment with mix 1/pVAX-HGF, the index of lung function(including EF50, MV, TV, PEF and PIF) in mix 1/pVAX-HGF group was higher than that of the PF group. The number of cells in BALF of the mix 1/pVAX-HGF group was significantly lower than that of the PF groups, and the content of hydroxyproline(HYP) and collagen Type I (Col-I) in the lung of the mix 1/pVAX-HGF group was much lower than that of the PF groups in the early stage. The result of pathological examination showed that rats in the mix1/pVAX-HGF group showed obviously reduced alveolar septal thickening, fewer infiltrated inflammatory cells and less collagen deposition. Conclusion: The PEG-PEI:PEI/pVAX-HGF nanocomposite can ameliorate PF induced by BLM. The pVAX-HGF nanocomposite is a latent therapeutic strategy for PF.

Background: Platinum-based chemotherapeutics are the main treatment options for ovarium cancer. However, the development of drug resistance is one of the major issues in chemotherapy. Even targeting a specific pathway may not produce an efficient sensitization to the chemo agent due to various pathways related to developing resistance against cisplatin. Hence, more effective strategies against drug resistance are essential for cancer treatment. In the presence of the ultrasonic waves, increased membrane porosity enables more drug uptake into the cancer cell. Therefore, the promising method in cancer therapy is seen as the use of the combined effect of chemotherapy and low-Intensity Ultrasound (LIUS) to overcome chemoresistance. Objective: The present study aimed to examine the effects of Ultrasound (US)+Cisplatin (Cis)- based combination therapy to advance an effective treatment against drug resistance in cisplatinresistant ovarian cancer cells A2780 (A2780cis) under in vitro conditions. Methods: Treatment groups as Cis and LIUS with two different ultrasound parameters (10% duty cycle (DC), 1 MHz, 1.0 W/cm², 1 min and 50% DC, 1 MHz, 1.0 W/cm², 3 min) were investigated to cope with the chemoresistance in A2780cis. After Cis therapy with IC50 concentrations determined in A2780 and A2780cis, drug-sensitive/resistant ovarian cancer cells were treated by ultrasound. The effects of the US+Cis combination therapy were evaluated by cell viability assays, colony formation, and cell cycle analyses. Results: In both US parameters, the waveform was shown to be more effective in preventing drug resistance. While more than 80% of the cell population was suppressed with the US+Cis combination treatment, more than 90% of the colony formation was suppressed according to the colony formation test results. In addition, US+Cis combination therapy caused different cell cycle arrests in both A2780 and A2780cis cells. Conclusion: Ultrasound-based combination therapies show promising results in combating chemoresistance, and the disadvantages of conventional cancer treatments, such as cancer recurrence, drug resistance, and high cost, might reduce by the effectiveness of combination therapy of ultrasound therapy and chemotherapy.

Background: Coenzyme Q10 (Q10) is a powerful lipophilic antioxidant with poor solubility in aqueous media. Curcumin (Cur) is a natural polyphenolic phytochemical molecule with poor aqueous solubility. The liposome is an improved administration of drugs because it is biocompatible and permeable for nutraceutical delivery. Chitosan, a hydrophilic polymer, is often used as a polymer coating for its good biocompatible and biodegradable properties, and its relatively low toxicity level. Methods: Q10 and Cur co-loaded liposomes coated with chitosan (Q10-Cur-Lip-Chi) were constructed. The co-encapsulation of Q10 and Cur in liposomes coated with chitosan was verified by TEM, DLS, DSC, FT-IR, and XRPD. The release profile and antioxidant activity of Q10-Cur-Lip-Chi were accessed. Results: The particle size of Q10-Cur-Lip-Chi was about 1440 nm with narrow particle distribution. A satisfactory encapsulation efficiency (EE) of Q10 was about 98%, and 25% for that of Cur. Q10-Cur- Lip-Chi showed higher solubility and better pH resistance with 98.5% of Q10 and Cur retention at pH 7.0 - 9.0. Q10-Cur-Lip also showed great salt stability with a vesicle size change of less than 5%. PSof Q10-Cur-Lip-Chi changed less than 10% at 4°C of storage. Q10-Cur-Lip-Chi also exhibited a good controlled release profile with its accumulative release of less than 34% for Q10 and 30% for curcumin after 24 h. The Q10-Cur-Lip-Chi performed a synergistic effect on antioxidant activity reaching 41.86±1.84%, which was 5.9 times higher than that of Q10, 2.5 times higher than that of Cur, and 1.7 times higher than that of the mixture. Conclusion: The co-encapsulation Q10-Cur-Lip-Chi improves the solubility and stability of Q10 and Cur for good release performance and antioxidative activity.