Promising Drug Delivery Strategy Research Articles

Topical Emulgel: Basic Considerations in Development and Advanced Research

Emulgel is a promising drug delivery strategy that has gained popularity in recent years for topical delivery of hydrophobic drugs. Emulgel is an emulsion that is gelled by mixing it with gelling agents. It is an interesting topical drug delivery system as it has a dual release control system, i.e., gel and emulsion. Emulgel has several favorable properties for dermatological use such as being thixotropic, greaseless, easily spreadable, easily removable, emollient, nonstaining, long shelf life, transparent and pleasing appearance. Despite, many advantages of the emulgel, the disadvantages include low permeability, poor pharmacokinetics and pharmacodynamics performance; therefore an advanced concept nanoemulgel came into the existence. Regardless of having few limitations, nanoemulgel formulation can be considered as impending and promising candidates for topical delivery of lipophilic drugs in the future. To know the potential of emulgel as a delivery vehicle, the present review offers a comprehensive overview on the rationale behind the use of emulgel, formulation considerations and characterization of emulgel and advanced research in the emulgel. Furthermore, we have summarized and discussed the outcome of different in vitro and in vivo studies of emulgel or nanoemulgel. Finally, the major challenges of nanoemulgel drug delivery system, patented and marketed emulgel or nanoemulgel formulations have been discussed. Based on the studies covered in this manuscript, it was understood that emulgel or nanoemulgel has emerged as an optimistic approach in the topical delivery of hydrophobic drugs to improve solubility, permeability and bioavailability, and reduce toxicities.

Blood-Brain Barrier Opening by Individualized Closed-Loop Feedback Control of Focused Ultrasound.

Objective and Impact Statement. To develop an approach for individualized closed-loop feedback control of microbubble cavitation to achieve safe and effective focused ultrasound in combination with microbubble-induced blood-brain barrier opening (FUS-BBBO). Introduction. FUS-BBBO is a promising strategy for noninvasive and localized brain drug delivery with a growing number of clinical studies currently ongoing. Real-time cavitation monitoring and feedback control are critical to achieving safe and effective FUS-BBBO. However, feedback control algorithms used in the past were either open-loop or without consideration of baseline cavitation level difference among subjects. Methods. This study performed feedback-controlled FUS-BBBO by defining the target cavitation level based on the baseline stable cavitation level of an individual subject with "dummy" FUS sonication. The dummy FUS sonication applied FUS with a low acoustic pressure for a short duration in the presence of microbubbles to define the baseline stable cavitation level that took into consideration of individual differences in the detected cavitation emissions. FUS-BBBO was then achieved through two sonication phases: ramping-up phase to reach the target cavitation level and maintaining phase to control the stable cavitation level at the target cavitation level. Results. Evaluations performed in wild-type mice demonstrated that this approach achieved effective and safe trans-BBB delivery of a model drug. The drug delivery efficiency increased as the target cavitation level increased from 0.5 dB to 2 dB without causing vascular damage. Increasing the target cavitation level to 3 dB and 4 dB increased the probability of tissue damage. Conclusions. Safe and effective brain drug delivery was achieved using the individualized closed-loop feedback-controlled FUS-BBBO.

Engineered Exosomes: A Promising Drug Delivery Strategy for Brain Diseases

Engineered Exosomes: A Promising Drug Delivery Strategy for Brain Diseases

Prostate-Specific Membrane Antigen and Esterase Dual Responsive Camptothecin-Oligopeptide Self-Assembled Nanoparticles for Efficient Anticancer Drug Delivery.

BackgroundThe clinical utility of camptothecin (CPT) is restricted by poor aqueous solubility, high lipophilicity, active lactone ring instability, and off-targeted toxicities. We report here a prostate-specific membrane antigen (PSMA) and esterase dual responsive self-assembled nanoparticles (CPT-WT-H NPs) for highly efficient CPT delivery and effective cancer therapy.Methods and ResultsIn this study, smart self-assembled nanoparticles CPT-WT-H NPs were elaborately designed and synthesized by combing hydrophobic CPT with hydrophilic PSMA-responsive penta-peptide via a cleavable ester bond. This dual responsive nanoparticle with negatively charged surface first respond to the extracellular PSMA and then to the intracellular esterase, achieving a programmable release of CPT at the tumor site and producing the byproducts of biocompatible glutamic acid and aspartic acid. Our data demonstrated that CPT-WT-H NPs exhibited greatly improved water solubility and stability. Results from MTT and flow cytometry showed CPT-WT-H NPs exhibited significantly higher cytotoxicity as well as apoptosis-inducing activity against PSMA-expressing LNCaP-FGC cells than the non-PSMA-expressing cancer cells, showing excellent cytotoxic selectivity. Moreover, the unique nanostructure provided the efficient transportation of CPT to tumor site, which resulted in the effective inhibition of tumor growth and low systemic toxicity in vivo.ConclusionCPT-WT-H NPs exhibited excellent in vitro PSMA-response ability and in vivo antitumor activity and safety, holding the promise to become a new and potent anticancer drug. The current research presents a promising strategy for efficient drug delivery.

Transferrin receptors/magnetic resonance dual-targeted nanoplatform for precise chemo-photodynamic synergistic cancer therapy

Various drug delivery strategies to improve cancer therapeutic efficacy have been actively investigated. One major challenge is to improve the targeting ability. Here elaborately designed nanocarriers (NCs) named as Tf-5-ALA-PTX-NCs are demonstrated to address this problem. In this nanostructure, paclitaxel (PTX) and 5-aminolevulinic acid (5-ALA) were co-encapsulated within magnetic nanocarriers to achieve synergistic chemotherapy and photodynamic therapy, while transferrin (Tf) was conjugated with modified copolymer Pluronic P123 and embedded in the surface of the nanocarriers, which endows nanocarriers with Tf targeting and magnetic targeting to enhance the anti-tumor outcome. Results demonstrated that Tf-5-ALA-PTX-NCs significantly enhanced the targeting drug delivery to MCF-7 cells and synergistically induced apoptosis and death of MCF-7 cells in vitro and highly efficient tumor ablation in vivo. Intriguingly, Tf-5-ALA-PTX-NCs have a controllable “on/off” switch to enhance the drug release. The dual-targeted nanocarriers would be a promising versatile anti-tumor drug delivery and imaging-guided cancer chemo-photodynamic synchronization therapy strategy.

Construction and evaluation of novel αvβ3 integrin ligand-conjugated ultrasmall star polymer micelles targeted glomerular podocytes through GFB permeation

As glomerular cells, podocytes are the last line of defense for glomerular filtration barriers (GFB) and play a critical role in chronic kidney disease (CKD). Podocyte-targeted drug delivery is a promising direction in the treatment of CKD. In this study, we constructed four-arm star polymers conjugated with a novel linear RWrNM peptide. And poly ε-caprolactone (PCL) hydrophobic core and brush poly (2-hydroxyethyl methacrylate) (PHEMA) hydrophilic shell were synthesized by ROP and SET LRP polymerization. The PHEMA modified by succinic anhydride was coupled with the novel linear RWrNM peptide, and then the PCL hydrophobic core was loaded with dexamethasone acetate (Dexac) to form micelles with stable dimensions. Our findings showed that the novel micelles had an ultrasmall particle size of 16–30 nm. We, for the first time, showed that the specific affinity of the novel linear RWrNM peptide to primary podocytes (24.9 ± 1.7 times of the free RhB uptake) through the αvβ3 integrin receptor mediation was comparable to that of B16F10 cells (24.4 ± 1.2 times of the free RhB uptake). In vivo studies showed that the novel ultrasmall micelles possessed a significant kidney-targeted effect, excellent podocyte colocalization effect, and GFB permeability at 49%–60 % in normal SD rats. Besides, the novel ultrasmall micelles decreased the plasma elimination half-life of Dexac to 1.62–2.09 h and showed good safety in vitro and in vivo. Both in vitro and in vivo results demonstrated the novel ultrasmall micelles could be used as a promising drug delivery strategy for actively targeted therapy of CKD.

Mitochondria-targeted vitamin E succinate delivery for reversal of multidrug resistance

Inducing mitochondrial malfunction is an appealing strategy to overcome tumor multidrug resistance (MDR). Reported here a versatile mitochondrial-damaging molecule, vitamin E succinate (VES), is creatively utilized to assist MDR reversal of doxorubicin hydrochloride (DOX·HCl) via a nanovesicle platform self-assembled from amphiphilic polyphosphazenes containing pH-sensitive 1H-benzo-[d]imidazol-2-yl) methanamine (BIMA) groups. Driven by multiple non-covalent interactions, VES is fully introduced into the hydrophobic membrane of DOX·HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust anti-leakage property toward DOX·HCl under normal physiological conditions. More importantly, upon release within acidic tumor cells, VES can target mitochondria and result in various dysfunctions including excessive generation of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) loss, and inhibited adenosine triphosphate (ATP) synthesis, which contribute to cell apoptosis and insufficient energy supply for drug efflux pumps. Consequently, the killing-effect of DOX·HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX·HCl to VES. Further in vivo antitumor investigation on nude mice bearing xenograft drug-resistant human chronic myelogenous leukemia K562/ADR tumors verifies the extremely enhanced anti-tumor efficacy of the dual drug-loaded nanovesicle with the tumor inhibition rate (TIR) of 82.38%. Collectively, this study provides a s safe, facile and promising strategy for both precise drug delivery and MDR eradication to improve cancer therapy.

Versatile Ice Microneedles for Transdermal Delivery of Diverse Actives.

Microneedles are regarded as an emerging and promising transdermal drug delivery strategy. Great efforts are devoted to getting rid of their material restrictions and imparting them with abilities to carry various drugs. Here, inspired by ice formation in nature and based on characteristics of different frozen materials, the authors present novel ice microneedles made from versatile soft materials using a simple freezing template‐based fabrication stratagem for effective transdermal delivery of diverse actives. Their strategy can convert microneedles with almost all water‐containing components from softness into hardness for guaranteeing satisfactory penetration, thus removing their material component limitations. As all fabrication procedures are mild and actives can maintain activity during these processes, the ice microneedles can carry and deliver various actives from small molecules and macromolecules to even living organisms. They have demonstrated that these ice microneedles can easily penetrate mouse and swine skins using a microneedle injector, with their active‐carried tips left inside after their ice base melts. Thus, by loading heparin, erythropoietin, or biosafe Bacillus subtilis (B. subtilis) inside the ice microneedles to treat mouse models, the practical values of these microneedles are well displayed, indicating their bright prospects in universal drug delivery systems.

Platelet Membrane-Coated and VAR2CSA Malaria Protein-Functionalized Nanoparticles for Targeted Treatment of Primary and Metastatic Cancer.

Metastasis is the main cause of death in cancer patients. The efficacy of pharmacological therapy for cancer is limited by the heterogeneous nature of cancer cells and the lack of knowledge of microenvironments in metastasis. Evidence has shown that activated platelets possess both tumor-homing and metastasis-targeting properties via intrinsic cell adhesion molecules on platelets, and malaria protein VAR2CSA is able to specifically bind to oncofetal chondroitin sulfate, which is overexpressed on cancer cells with both epithelial and mesenchymal phenotypes. Inspired by these mechanisms, we developed a recombinant VAR2CSA peptide (rVAR2)-modified activated platelet-mimicking nanoparticles (rVAR2-PM/PLGA-ss-HA) by coating the surface of disulfide-containing biodegradable PLGA conjugate nanoparticles (PLGA-ss-HA) with an activated platelet membrane. The results demonstrated that the engineered 122 nm rVAR2-PM/PLGA-ss-HA inherited the innate properties of the activated platelet membrane and achieved enhanced homing to both primary and metastatic foci. The nanoparticles were endocytosed and responded to a high intracellular concentration of reduced glutathione, resulting in nanoparticle disintegration and the release of chemotherapeutic drugs to kill tumor cells. Thus, rVAR2-decorated activated platelet-targeting nanoparticles with controlled drug release provide a promising drug delivery strategy for efficient treatment of primary and metastatic cancer.

Multifeatured guar gum armed drug delivery system for the delivery of ofloxacin drug to treat ophthalmic dieases

Nanotargeting delivery system is recently much more attention for delivering drugs and bioactive compounds to treating ocular diseases. Here, the Guar gum (GG) armed drug delivery system with functionalization of poly-caprolactone (PCL), Retinol (RA), Biotinylated-Glutathione (B-GHS), carried out by the condensation reactions. The functional changes and crystallinity of the prepared micelle system were characterized by the FTIR and XRD techniques. The SEM observation represents the morphology of micelle GG-g-PCL-RA-B-GHS; it shows sphere-like morphology, and it was correlated with TEM results. The unloaded and drug-loaded micelle’s average spherical diameter was found as ~4.5 and ~6.8 nm, respectively, by the ImageJ software analysis. The carrier systems’ surface charge was found as a negative value from zeta potential analysis. From in-vitro drug release studies, the drug release in a tear fluid environment (PBS, pH 7.4) was observed 88.0% of OFL in 8 h, and the drug release rate renewed in a controlled manner leads to the requirement for prolonged drug delivery. The antibacterial activity, the incubation of OFL loaded GG-g-PCL-RA-B-GHS micelle groups, found an excellent antibacterial activity against both gram-negative Salmonella Typhi and gram-positive Bacillus cereus. Since the novel OFL loaded GG-g-PCL-RA-B-GHS maintaining a prominent role in the delivery of OFL and good antibacterial activity, it could be offered as a promising strategy for ocular drug delivery.

Particle Forming Amorphous Solid Dispersions: A Mechanistic Randomized Pharmacokinetic Study in Humans.

Amorphous solid dispersions (ASDs) are a promising drug-delivery strategy to overcome poor solubility through formulation. Currently, the understanding of drug absorption mechanisms from ASDs in humans is incomplete. Aiming to gain insights in this matter, we conducted a randomized cross-over design open-label clinical study (NCT03886766) with 16 healthy male volunteers in an ambulatory setting, using micro-dosed efavirenz as a model drug. In three phases, subjects were administered (1) solid ASD of efavirenz 50 mg or (2) dissolved ASD of efavirenz 50 mg or (3) a molecular solution of efavirenz 3 mg (non-ASD) as a control in block-randomized order. Endpoints were the pharmacokinetic profiles (efavirenz plasma concentration vs. time curves) and derived pharmacokinetic parameters thereof (AUC0–t, Cmax, tmax, and ka). Results showed that the dissolved ASD (intervention 2) exhibited properties of a supersaturated solution (compared to aqueous solubility) with rapid and complete absorption of the drug from the drug-rich particles. All interventions showed similar AUC0–t and were well tolerated by subjects. The findings highlight the potential of particle forming ASDs as an advanced drug-delivery system for poorly soluble drugs and provide essential insights into underlying mechanisms of ASD functioning in humans, partially validating current conceptual models.

Loading and Releasing Behavior of Selenium and Doxorubicin Hydrochloride in Hydroxyapatite with Different Morphologies.

Doxorubicin (Dox)-loaded or selenium-substituted hydroxyapatite (HA) has been developed to achieve anti-osteosarcoma or bone regeneration in a number of studies. However, currently, there is a lack of studies on the combination of Dox and selenium loading in/on HA and comparative research studies on which form and size of HA are more suitable for drug loading and release in the treatment osteogenesis after osteosarcoma resection. Herein, selenium-doped rod-shaped nano-HA (n-HA) and spherical mesoporous HA (m-HA) were successfully prepared. The doping efficiency of selenium and the Dox loading capacity of selenium-doped HA with different morphologies were studied. The release kinetics of Dox and the selenium element in phosphate-buffered saline with different pH values was also comparatively investigated. The drug loading results showed that n-HA exhibited 3 times higher selenium doping amount than m-HA, and the Dox entrapment efficiency of selenium-doped n-HA (0.1Se-n-HA) presented 20% higher than that of selenium-doped m-HA (0.1Se-m-HA). The Dox release behaviors of HA in two different morphologies showed similar release kinetics, with almost the same Dox releasing ratio but slightly more Dox releasing amount in selenium-doped HA than in HA without selenium. The selenium release from selenium-doped n-HA-D (0.1Se-n-HA-D) particles was 2 times as much as that of selenium-doped m-HA-D (0.1Se-m-HA) particles. Our study indicated that n-HA loaded with Dox and selenium may be a promising drug delivery strategy for inhibition of osteosarcoma recurrence and promoting osteogenesis simultaneously.

Efficient drug delivery and anticancer effect of micelles based on vitamin E succinate and chitosan derivatives

Nanocarriers have emerged as a promising cancer drug delivery strategy. Multi-drug resistance caused by overexpression of multiple-drug excretion transporters in tumor cells is the major obstacle to successful chemotherapy. Vitamin E derivatives have many essential functions for drug delivery applications, such as biological components that are hydrophobic, stable, water-soluble enhancing compounds, and anticancer activity. In addition, vitamin E derivatives are also effective mitocan which can overcome multi-drug resistance by binding to P glycoproteins. Here, we developed a carboxymethyl chitosan/vitamin E succinate nano-micellar system (O-CMCTS-VES). The synthesized polymers were characterized by Fourier Transform IR, and 1H NMR spectra. The mean sizes of O-CMCTS-VES and DOX-loaded nanoparticles were around 177 nm and 208 nm. The drug loading contents were 6.1%, 13.0% and 10.6% with the weight ratio of DOX to O-CMCTS-VES corresponding 1:10, 2:10 and 3:10, and the corresponding EEs were 64.3%, 74.5% and 39.7%. Cytotoxicity test, hemolysis test and histocompatibility test showed that it had good biocompatibility in vitro and in vivo. Drug release experiments implied good pH sensitivity and sustained-release effect. The DOX/O-CMCTS-VES nanoparticles can be efficiently taken up by HepG2 cancer cells and the tumor inhibition rate is up to 62.57%. In the in vivo study by using H22 cells implanted Balb/C mice, DOX/O-CMCTS-VES reduced the tumor volume and weight efficiently with a TIR of 35.58%. The newly developed polymeric micelles could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of solid tumors.

Comparison of Si Nanoparticle types for use as a Potencial Drug Delivery System for Central Nervous System Diseases

Diseases affecting the central nervous system (CNS) are considered to be some of the most debilitating conditions worldwide. The range of standard therapies for disorders affecting CNS is largely limited for many patients. Nonetheless, nanoparticle-based drug delivery offers itself to be a promising strategy for effective drug delivery into the brain, addressing the frequently arising complications with blood-brain barrier crossing. This study compared the drug adsorption ability and the surface chemistry of two types of silicon nanoparticles (Si-NPs). Si- NPs were prepared using two methods: electrochemical etching of Si wafers (Si-E) and low-pressure plasma synthesis (Si-P). Silicon nanoparticles were characterized by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and nitrogen physisorption (method of Barrett, Joyner, and Halenda (BJH) and method of Brunauer, Emmett and Teller (BET)). The size and morphology were characterized by high-resolution transmission electron microscopy (HRTEM) linked with energy-dispersive X-ray spectroscopy (EDAX) and dynamic light scattering (DLS), respectively. The concentration of the drug substance that was captured by the silicon-based drug delivery system was determined by ultra high-performance liquid-chromatography-diode-array (UHPLC-DAD) method. Results of XPS showed that the Si-E are more oxidized than Si-P. The BET analysis showed us that the Si-E have more surface area, pore volume and grain size then the Si-P, and Si-P have a bigger pore size than Si-E. We also demonstrated by XRD that silicon nanoparticles prepared by both methods have a crystalline structure. The Si-P adsorption analysis of the model compound (ferulic acid) showed better adsorption ability than Si-E. The size of the Si-P (40- 120 nm) was also measured by HRTEM.

Surface functionalized mesoporous silica nanoparticles for intravitreal application of tacrolimus.

Tacrolimus (TAC), a potent immunosuppressive macrolide, has been investigated for ocular diseases due to promising results in the treatment of anterior and posterior segments eye diseases. Mesoporous and functionalized silica nanoparticles show potential as TAC delivery platforms owing to their interesting characteristic as large surface area, uniform pore size distribution, high pore volume, and excellent biocompatibility. The purpose of this study was to incorporate TAC in functionalized silica nanoparticles with 3-aminopropyltriethoxysilane (MSNAPTES) and investigate the safety and biocompatibility of the systems. The MSNAPTES and MSNAPTES TAC nanoparticles were characterized. The in vitro cytotoxicity of MSNAPTES and MSNAPTES load with TAC (MSNAPTES-TAC) in retinal pigment epithelial cells (ARPE-19) was determined, chorioallantoic membrane (CAM) assay model was used to investigate the in vivo biocompatibility, and safety of intravitreal injection was evaluated using clinical examination (assessment of intraocular pressure and indirect fundus ophthalmoscopy), electroretinographic (ERG) and histologic studies in rats' eyes. The elemental analysis (CHN), thermogravimetric (TGA), photon correlation spectroscopy and Fourier transform infrared (FTIR) analysis confirmed the presence of functionalized agent and TAC in the MSNAPTES nanoparticles. TAC loading was estimated at 7% for the MSNAPTES TAC nanoparticles. MSNAPTES and MSNAPTES TAC did not present in vitro cytotoxicity. The drug delivery systems showed good biocompatibility on CAM. No retinal abnormalities, vitreous hemorrhage, neovascularization, retinal detachment, and optic nerve atrophy were observed during the in vivo study. Follow-up ERGs showed no changes in the function of the retina cells after 15 days of intravitreal injection, and histopathologic observations support these findings. In conclusion, MSNAPTES TAC was successfully synthesized, and physicochemical analyses confirmed the presence of TAC in the nanoparticles. In vitro and in vivo studies indicated that MSNAPTES TAC was safe to intravitreal administration. Taking into account the enormous potential of MSNAPTES to carry TAC, this platform could be a promising strategy for TAC ocular drug delivery in the treatment of eye diseases.

Biocompatible Ionic Liquid Enhances Transdermal Antigen Peptide Delivery and Preventive Vaccination Effect.

Ionic liquids (ILs) attract significant attention as novel solvents for drug delivery systems because of their ability to solubilize poorly soluble drugs and tune the physiological properties of active pharmaceutical ingredients. For the next generation of IL-based drug delivery systems, biocompatibility is a high priority. In the current study, choline-fatty acids ([Cho][FA]) were used as a biocompatible IL to mediate the dissolution of a water-soluble antigen peptide in an oil-based skin penetration enhancer. Among the candidate fatty acids (C8, C10, C12, C14, C16, C18:0, and C18:1), C18:1 was selected because of its low cytotoxicity and mediation of skin permeability for an antigen peptide. Using IL[Cho][C18:1] and an oil-based penetration enhancer, the flux of transdermal delivery of the peptide increased 28-fold compared with delivery using an aqueous vehicle. Furthermore, the IL-mediated transcutaneous vaccination succeeded in suppressing tumor growth in vivo compared to injection. The skin irritation produced by this formulation was tested using an in vitro 3D constructed skin tissue model and an in vivo histological study, which concluded that the formulation did not cause skin irritation. The results suggest that biocompatible IL-mediated dissolution in an oil-based skin penetration enhancer is a promising strategy for transdermal drug delivery.

Binary Prodrug of Dichloroacetic Acid and Doxorubicin with Enhanced Anticancer Activity.

The inevitable challenge in conventional chemotherapy is to deliver the anticancer drugs to the dense population of tumors cells while minimizing the drug-associated side effects on the normal cells. Cancer cells' preference for glycolysis for energy production is well recognized. Intuitively, taking advantage of such cancer-associated metabolism would be a promising strategy for anticancer drug delivery with minimal side effects. In this investigation, we have designed a binary prodrug PDOX as a sequential drug delivery regimens to realize the combination therapy for cancer. As cancer cells exhibit abrupt metabolism with elevated pyruvate dehydrogenase kinase (PDK) activity, dichloroacetic acid (DCA, a well-known PDK inhibitor) was used in combination with anticancer drug doxorubicin (DOX). The designed molecular prodrug was activated selectively by cancer-associated esterase to deliver DCA and DOX, respectively, and induced synergetic effects. Hence, sequential targeted delivery of molecular prodrug PDOX offers a promising approach to overcome the offside drug toxicity, pharmacokinetics, and biodistribution of individuals and provide an alternative option for cancer treatment.

Albumin coated trimethyl chitosan-based targeting delivery platform for photothermal/chemo-synergistic cancer therapy

Current metastatic breast cancer therapies are not only affected by limited drug delivery options, but also restricted to the monotherapies. Here, we synthesized trimethyl chitosan (TMC), loaded it with photosensitizer IR780 or bufalin by ionic gelation, and coated it with human serum albumin (HSA) by electrostatic absorption (designated TIH or TBH, respectively). The near-spherical nanoparticles had a size of approximately 30 nm, exerted strong photothermal effects, and enhanced cellular mitochondrion colocation and phototoxicity. Tumor microenvironments were disrupted by TIH-mediated photothermal effects, which enhanced the accumulation of a second TBH dose in the tumor that promoted deep penetration in the whole tumor mass. After laser irradiation our nanoplatform enhanced cancer tissue accessibility and substantially suppressed tumor growth, and causing a 98.46 % inhibition of lung metastasis. Thus HSA-masked TMC represents a promising tumor-targeted drug delivery strategy with synergistic modality that may improve the therapeutic outcome of metastatic breast cancer.

Protein assembled nano-vehicle entrapping photosensitizer molecules for efficient lung carcinoma therapy.

The efficiency of drug depends not only on its potency but also on its ability to reach the target sites in preference to non-target sites. In this regard, protein assembled nanocarrier is the most promising strategy for intracellular anti-cancer drug delivery. The key motive of this study is to fabricate biocompatible protein assembled nanocarrier conjugated photosensitizer system for stimuli-responsive treatment of lung carcinoma. Here, we have synthesized a unique nanohybrid of protein assembled gold nanoparticles (AuNPs), attaching a model photosensitizer, Protoporphyrin IX (PpIX) to the protein shell of the nanoparticles (NPs) imparting an ideal drug-carrier nature. Photo-induced alteration in hydrodynamic diameter suggests structural perturbation of the nanohybrid which in terms signifies on-demand drug delivery. The drug release profile has been further confirmed by using steady-state fluorescence experiments. AuNP-PpIX showed excellent anti-cancer efficiency upon green light irradiation on lung adenocarcinoma cell line (A549) through intracellular reactive oxygen species (ROS) generation. The cellular morphological changes upon PDT and internalization of nanohybrid were monitored using confocal laser scanning microscope. This anti-cancer effect of nanohybrid was associated with apoptotic pathway which was confirmed in the flow cytometric platform. The developed nanomedicine is expected to find relevance in clinical anti-cancer PDT models in the near future.

Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy

Pancreatic ductal adenocarcinoma (PDAC) is rich in cancer-associated fibroblasts (CAFs), which participate in the formation of tumor stroma. However, the dense tumor stroma of PDAC presents major barriers to drug delivery, resulting in an obstacle for PDAC therapy. Considering the special tumor microenvironment of PDAC, we constructed a novel nanoparticle which is responsive to the membrane biomarker FAP-α on CAFs and near-infrared (NIR) laser irradiation. Small sized albumin nanoparticle of paclitaxel (HSA-PTX) with strong tumor-penetration ability was encapsulated into the CAP-(a FAP-α responsive cleavable amphiphilic peptide) modified thermosensitive liposomes (CAP-TSL). Moreover, IR-780, a photothermal agent, was incorporated into CAP-TSL to afford CAP-ITSL. The designed HSA-PTX@CAP-ITSL increased the drug retention of HSA-PTX in solid tumor and HSA-PTX was released via FAP-α (specifically expresses on CAFs) triggered. Under sequential stimulation of NIR laser irradiation, IR-780 produced hyperthermia to kill tumor cells and expand the tumor interstitial space at the same time, which further promoted the release of small sized HSA-PTX in deep tumor regions. Consequently, the excellent antitumor efficacy of HSA-PTX@CAP-ITSL was demonstrated in Pan 02 subcutaneous and orthotopic tumor mouse models. Therefore, HSA-PTX@CAP-ITSL well combined chemotherapy with photothermal therapy, providing a promising drug delivery strategy for PDAC treatment.