Multiple Drug Delivery Research Articles

Multivariate Modulation of the Zr MOF UiO-66 for Defect-Controlled Combination Anticancer Drug Delivery.

Metal–organic frameworks (MOFs) are emerging as leading candidates for nanoscale drug delivery, as a consequence of their high drug capacities, ease of functionality, and the ability to carefully engineer key physical properties. Despite many anticancer treatment regimens consisting of a cocktail of different drugs, examples of delivery of multiple drugs from one MOF are rare, potentially hampered by difficulties in postsynthetic loading of more than one cargo molecule. Herein, we report a new strategy, multivariate modulation, which allows incorporation of up to three drugs in the Zr MOF UiO‐66 by defect‐loading. The drugs are added to one‐pot solvothermal synthesis and are distributed throughout the MOF at defect sites by coordination to the metal clusters. This tight binding comes with retention of crystallinity and porosity, allowing a fourth drug to be postsynthetically loaded into the MOFs to yield nanoparticles loaded with cocktails of drugs that show enhancements in selective anticancer cytotoxicity against MCF‐7 breast cancer cells in vitro. We believe that multivariate modulation is a significant advance in the application of MOFs in biomedicine, and anticipate the protocol will also be adopted in other areas of MOF chemistry, to easily produce defective MOFs with arrays of highly functionalised pores for potential application in gas separations and catalysis.

Multivariate Modulation of the Zr MOF UiO‐66 for Defect‐Controlled Combination Anticancer Drug Delivery

AbstractMetal–organic frameworks (MOFs) are emerging as leading candidates for nanoscale drug delivery, as a consequence of their high drug capacities, ease of functionality, and the ability to carefully engineer key physical properties. Despite many anticancer treatment regimens consisting of a cocktail of different drugs, examples of delivery of multiple drugs from one MOF are rare, potentially hampered by difficulties in postsynthetic loading of more than one cargo molecule. Herein, we report a new strategy, multivariate modulation, which allows incorporation of up to three drugs in the Zr MOF UiO‐66 by defect‐loading. The drugs are added to one‐pot solvothermal synthesis and are distributed throughout the MOF at defect sites by coordination to the metal clusters. This tight binding comes with retention of crystallinity and porosity, allowing a fourth drug to be postsynthetically loaded into the MOFs to yield nanoparticles loaded with cocktails of drugs that show enhancements in selective anticancer cytotoxicity against MCF‐7 breast cancer cells in vitro. We believe that multivariate modulation is a significant advance in the application of MOFs in biomedicine, and anticipate the protocol will also be adopted in other areas of MOF chemistry, to easily produce defective MOFs with arrays of highly functionalised pores for potential application in gas separations and catalysis.

In situ tumor-triggered subcellular precise delivery of multi-drugs for enhanced chemo-photothermal-starvation combination antitumor therapy.

Rationale: Drug combination therapy for cancer treatment exerts a more potent antitumor effect. The targeted delivery and release of multiple drugs in a patient's body thus presents a more effective treatment approach, warranting further research. Methods: Two antitumor drugs (ICG: indocyanine green and THP: pirarubicin) were successfully screened to sequentially trigger self-assembling peptides (P60) to produce bacteria-sized particles (500-1000 nm, P60-ICG-THP). First, after mixing equal amount of P60 and ICG, trace amount of water (the mass ratio between P60 and water: 100:1) was used to trigger their assembly into P60-ICG. Subsequently, the assembly of P60-ICG and THP was further triggered by ultrasound treatment to produce P60-ICG-THP. Results: P60-ICG-THP constituted a cluster of several nanoparticles (50-100 nm) and possessed a negative charge. Owing to its size and charge characteristics, P60-ICG-THP could remain outside the cell membrane, avoiding the phagocytic clearance of blood and normal tissue cells in vivo. However, after localizing in the tumor, the size and charge switches of P60-ICG-THP, rapidly triggered by the low pH of the tumor microenvironment, caused P60-ICG-THP to segregate into two parts: (i) positively charged nanoparticles with a size of approximately 50 nm, and (ii) negatively charged particles of an uneven size. The former, mainly carrying THP (chemotherapeutic agent), could immediately cross the cell membrane and deliver pirarubicin into the nucleus of tumor cells. The latter, carrying ICG (used for photothermal therapy), could also enter the cell via the endocytosis pathway or accumulate in tumor blood vessels to selectively block the supply of nutrients and oxygen (cancer starvation). Both these particles could avoid the rapid excretion of ICG in the liver and were conducive to accumulation in the tumor tissue for photothermal therapy. Conclusion: Our drug delivery system not only achieves the precise subcellular delivery of two anticancer drugs due to their size and charge switches in the tumor site, but also provides a new strategy to combine chemotherapy, photothermal therapy, and cancer starvation therapy for the development of a highly efficient antitumor therapeutic regimen.

Sequential delivery of synergistic drugs by silica nanocarriers for enhanced tumour treatment.

Herein hybrid silica nanoparticles have been engineered to direct the sequential delivery of multiple chemotherapeutic drugs in response to external stimuli such as variations in pH. The nanocarriers consist of conventional MCM-41-type nanoparticles, which have been functionalised with an organic ligand (or stalk) grafted onto the external surface. The stalk is designed to "recognise" a complementary molecule, which serves as a "cap" to block the pores of the nanoparticles. First, camptothecin is introduced into the pores by diffusion prior to capping the pore apertures via molecular recognition. The cap, which is a derivative of 5-fluorouracil, serves as a second cytotoxic drug for synergistic chemotherapy. In vitro tests revealed that negligible release of the drugs occurred at pH 7.4, thus avoiding toxic side effects in the blood stream. In contrast, the stalk/cap complex is destabilised within the endolysosomal compartment (pH 5.5) of cancer cells, where release of the drugs was demonstrated. Furthermore, this environmentally responsive system exhibited a synergistic effect of the two drugs, where the pH-triggered release of the cytotoxic cap followed by diffusion-controlled release of the drug cargo within the pores led to essentially complete elimination of breast cancer cells.

Synthesis, physicochemical characterization, toxicity and efficacy of a PEG conjugate and a hybrid PEG conjugate nanoparticle formulation of the antibiotic moxifloxacin.

Antibiotic resistance is increasing at such an alarming rate that it is now one of the greatest global health challenges. Undesirable toxic side-effects of the drugs lead to high rates of non-completion of treatment regimens which in turn leads to the development of drug resistance. We report on the development of delivery systems that enable antibiotics to be toxic against bacterial cells while sparing human cells. The broad-spectrum fluoroquinolone antibiotic moxifloxacin (Mox) was successfully conjugated to poly(ethylene glycol) (PEG) which was further encapsulated into the hydrophobic poly(ε-caprolactone) (PCL) nanoparticles (NPs) with high efficiency, average particle size of 241.8 ± 4 nm and negative zeta potential. Toxicity against erythrocytes and MDBK cell lines and drug release in human plasma were evaluated. Hemocompatibility and reduced cytotoxicity of the PEG–Mox and PCL(PEG–Mox) NPs were demonstrated in comparison to free Mox. Antimicrobial activity was assessed against drug sensitive and resistant: Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. The antibacterial activity of Mox was largely maintained after conjugation. Our data shows that the toxicity of Mox can be effectively attenuated while, in the case of PEG–Mox, retaining significant antibacterial activity. At the conditions employed in this study for antimicrobial activity the encapsulated conjugate (PCL(PEG–Mox) NPs) did not demonstrate, conclusively, significant antibacterial activity. These systems do, however, hold promise if further developed for improved treatment of bacterial infections.

Design and in vitro/in vivo evaluations of a multiple-drug-containing gingiva disc for periodontotherapy.

In the current work, we set out to develop and evaluate a gingiva disc of cellulose acetate phthalate and poloxamer F-127 for the simultaneous delivery of multiple drugs, namely minocycline, celecoxib, doxycycline hyclate, and simvastatin, to abolish infection, impede inflammation, avert collagen destruction, and promote alveolar bone regeneration, respectively. In vitro release studies revealed the sustained release profiles of the drugs for 12 h and that they were active against Staphylococcus aureus, Escherichia coli and Streptococcus mutans. The in vivo bioactivity levels of these drugs were assessed by comparing the number of colony forming units during different phases of a study on Wistar rats, and the results showed a reduction in the number of bacterial colonies with the applied formulation. A mucosal irritation study conducted on Wistar rat gingiva confirmed the non-irritancy of the optimal gingiva disc. Hence, this customized, non-invasive polymeric gingiva disc displaying a sustained release of drugs can be a useful tool to treat acute to moderate stages of periodontitis.

PLGA nanoparticle-reinforced supramolecular peptide hydrogels for local delivery of multiple drugs with enhanced synergism

Localized drug delivery offers great therapeutic efficacy at local tissues while avoiding the systemic toxicity of drugs. Yet it demands the development of structurally-stable drug carrier systems with excellent injectability, as well as the capability to facilitate controlled release of multiple drugs. Herein, we describe the design and synthesis of a supramolecular hydrogel (Cis/Peptide@NP/Irino) for the combined delivery of cisplatin (Cis) and irinotecan (Irino). The self-assembled hydrogel consisted of an inner phase of irinotecan-loaded PLGA nanoparticles (NP/Irino) and an outer phase of cisplatin-loaded peptide nanofibers (Cis/Peptide). Through the structural reinforcement of PLGA nanoparticles, the Cis/Peptide@NP/Irino hydrogel exhibited better mechanical properties than Cis/Peptide or Peptide hydrogels. With excellent shear-thinning properties, it facilitated the development of a localized drug delivery system with an improved retention time in vivo. The hydrogel incorporated two anticancer drugs, Cis and Irino, at the Peptide and PLGA domains, respectively, and exhibited a faster release of Cis prior to the continuous release of Irino in vitro. Furthermore, the Cis/Peptide@NP/Irino formulation showed a better inhibition efficacy against the proliferation of cancerous A549 cells, with the synergism of Cis and Irino exceeding that of the simple solution mixtures, which was plausibly due to the enhanced cellular uptake of drugs through endocytosis. We believe that structurally-stable supramolecular hydrogels show great promise in the local delivery of various drug combinations for cancer therapy.

Multicompartmental Mesoporous Silica/Polymer Nanostructured Hybrids: Design Capabilities by Integrating Linear and Star-Shaped Block Copolymers.

Poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) linear diblock copolymer and polystyrene–poly(ethylene oxide) (PS10PEO10) heteroarm star copolymer were used as building elements to prepare organic–inorganic hybrids. By using the layer-by-layer (LbL) methodology, these elements were integrated on mesoporous silica through non-covalent interactions, namely, ionic and H-bonding. For the latter, tannic acid (TA) was used as an intermediate layer. The deposition of the various layers was monitored by thermogravimetric analysis (TGA), electrophoretic measurements, and confocal microscopy. The final silica hybrid, bearing alternating P2VP-b-PEO and PS10PEO10 star layers was capable of carrying one hydrophilic and two hydrophobic chemical species in distinct compartments. These multicompartmental organic–inorganic hybrids could be used as nanostructured carriers for pH-responsive multiple drug delivery and potential theranostic applications.

Verteporfin-Loaded Anisotropic Poly(Beta-Amino Ester)-Based Micelles Demonstrate Brain Cancer-Selective Cytotoxicity and Enhanced Pharmacokinetics.

BackgroundNanomedicine can improve traditional therapies by enhancing the controlled release of drugs at targeted tissues in the body. However, there still exists disease- and therapy-specific barriers that limit the efficacy of such treatments. A major challenge in developing effective therapies for one of the most aggressive brain tumors, glioblastoma (GBM), is affecting brain cancer cells while avoiding damage to the surrounding healthy brain parenchyma. Here, we developed poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE) (PEG-PBAE)-based micelles encapsulating verteporfin (VP) to increase tumor-specific targeting.MethodsBiodegradable, pH-sensitive micelles of different shapes were synthesized via nanoprecipitation using two different triblock PEG-PBAE-PEG copolymers varying in their relative hydrophobicity. The anti-tumor efficacy of verteporfin loaded in these anisotropic and spherical micelles was evaluated in vitro using patient-derived primary GBM cells.ResultsFor anisotropic micelles, uptake efficiency was ~100% in GBM cells (GBM1A and JHGBM612) while only 46% in normal human astrocytes (NHA) at 15.6 nM VP (p ≤ 0.0001). Cell killing of GBM1A and JHGBM612 vs NHA was 52% and 77% vs 29%, respectively, at 24 hrs post-treatment of 125 nM VP-encapsulated in anisotropic micelles (p ≤ 0.0001), demonstrating the tumor cell-specific selectivity of VP. Moreover, anisotropic micelles showed an approximately fivefold longer half-life in blood circulation than the analogous spherical micelles in a GBM xenograft model in mice. In this model, micelle accumulation to tumors was significantly greater for anisotropic micelle-treated mice compared to spherical micelle-treated mice at both 8 hrs (~1.8-fold greater, p ≤ 0.001) and 24 hrs (~2.1-fold greater, p ≤ 0.0001).ConclusionOverall, this work highlights the promise of a biodegradable anisotropic micelle system to overcome multiple drug delivery challenges and enhance efficacy and safety for the treatment of brain cancer.

Low density lipoprotein receptor (LDLR)-targeted lipid nanoparticles for the delivery of sorafenib and Dihydroartemisinin in liver cancers

AimsLiver cancer is one of the leading causes of cancer mortality worldwide. Inspired by the biological structure and function of low-density lipoprotein (LDL), in this study, an ApopB-100 based targeted lipid nanoparticles was synthesized to improve the therapeutic efficacy in liver cancer treatment. Main methodsThe biological composition of ApopB is similar to LDL which can effectively increase the targeting efficiency of nanoparticles in LDL receptor (LDLR)-overexpressed liver tumors. KeyfindingsWe have demonstrated that the co-administration of sorafenib (SRF) and Dihydroartemisinin (DHA) could exhibit synergistic anticancer effect in HepG2 liver cancer cells. DHA produced excessive cellular reactive oxygen species (ROS) and induced greater apoptosis of cancer cells. LDL-based SRF/DHA-loaded lipid nanoparticles (LD-SDN) showed remarkable decrease in the cell viability compared to that of either of single drug treated cancer cells. Combination of SRF+DHA resulted in predominant SubG1 proportion of cells. LD-SDN exhibited the highest SubG1 (%) of cells compared to that of any of the individual drugs. Most importantly, robust antitumor response and delayed tumor growth was observed for LD-SDN treated xenograft tumor model. Ki67 proliferation index of LD-SDN (22.1 ± 5.6%) is significantly lesser compared to that of either control (86.2 ± 6.9%) or SRF (75.4 ± 4.89%) or DHA (69.4 ± 6.9%). SignificancesThese data provide strong evidence that LDL-mimetic lipid nanoformulations could be utilized as a biocompatible and tumor targeted platform for the delivery of multiple anticancer drugs in cancer treatment.

Bi-faceted delivery of phytochemicals through chitosan nanoparticles impregnated nanofibers for cancer therapeutics

Drug delivery through nanotechnological approaches has predominantly gained significance owing to the enhanced bioavailability, stability and targeted sequel. Multiple drug delivery is also on its stride to achieve holistic therapeutic regime. In our quest for such a treatment for cancer we selected two phytochemicals namely resveratrol (RS) and ferulic acid (FA) that have gained wide attention in the field of medicine due to their array of properties. Albeit their multifaceted application their therapeutic potential is mired due to its physicochemical instability and low bioavailability. Therefore, in the present study combinatorial effect of these compounds in cancer therapeutics have been scrutinized by fabricating chitosan nanoparticle loaded polycaprolactone nanofibers for delivering RS and FA. The materials were physico-chemical characterized. The nanoparticle incorporation within the nanofibers was corroborated through FITC tagging. The anti-cancer effect of drug loaded nanofibers were studied using A431 cells which displayed 30% and 50% reduction in the cell viability when treated with nanoparticles and nanofibrous scaffold. In congruence, the anti-angiogenic potential of the scaffold was elucidated using Chick chorioallantoic membrane assay and aortic ring assay. Thus, the nanofibrous delivery system opens up new venue in the field of cancer therapeutics with reduced side effects and efficient cancer targeting.

Sequential drug delivery for liver diseases.

The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.

Polydopamine-coated mesoporous silica nanoparticles for multi-responsive drug delivery and combined chemo-photothermal therapy.

Synergistic therapy of chemotherapy and photothermal therapy exhibits great potential to improve the therapeutic efficiency for cancer therapy. In this study, a new biocompatible multiple sensitive drug delivery system (DDS) was synthesized by covering a polydopamine (PDA) layer on doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) via disulfide bonds (MSN-SS-PDA/DOX). PDA worked as a photothermal therapy (PTT) agent and also a gate keeper to control drug release, which was highly sensitive to pH and could prolong the residence time, simultaneously increase water solubility and biocompatibility of the nanoparticles. The DDS exhibited excellent monodispersity, redox/pH/NIR-multi-dependent release characteristics, remarkable photothermal conversion property (photothermal conversion efficiency η = 40.21%) and outstanding tumor cell synergistic killing efficiency of chemotherapy and photothermal therapy (combination index CI = 0.175). The biodistribution and pharmacodynamics experiments of MSN-SS-PDA/DOX in 4T1 tumor models indicated that MSN-SS-PDA made more DOX accumulate in tumor tissue than free DOX, extend circulation time of DOX in the body, and exhibit a significant synergistic antitumor efficacy. Meanwhile, the tumor growth was remarkably inhibited, which was much more obvious than any monotherapy effect. Thus, the novel nanoplatform presents a promising future as a drug delivery system for combination therapy.

Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation.

Both in vivo neuropharmacology and optogenetic stimulation can be used to decode neural circuitry, and can provide therapeutic strategies for brain disorders. However, current neuronal interfaces hinder long-term studies in awake and freely behaving animals, as they are limited in their ability to provide simultaneous and prolonged delivery of multiple drugs, are often bulky and lack multifunctionality, and employ custom control systems with insufficiently versatile selectivity for output mode, animal selection and target brain circuits. Here, we describe smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits. We demonstrate the use of the probes for the control of the locomotor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation. Owing to their ability to deliver both drugs and photopharmacology into the brain repeatedly over long time periods, the probes may contribute to uncovering the basis of neuropsychiatric diseases.

Synthesis and Biological Studies of New Multifunctional Curcumin Platforms for Anticancer Drug Delivery.

Scientists have extensively investigated curcumin, yielding many publications on treatments of cancer. Numerous derivatives of curcumin were synthesized, evaluated for their anti-oxidant and free-radical scavenging, SAR, ADME properties and tested in anticancer applications. We decided to exploit curcumin as a bioactive core platform for carrying anticancer drugs, which likely possesses a carboxyl moiety for potential linkage to the carrier for drug delivery. The goal of this work is to develop biolabile multifunctional curcumin platforms towards anticancer drug delivery, including determination of drug release profiling in hydrolytic media, in vitro cytotoxicity, antioxidant properties and blockage of relevant cell survival pathways. We report on a facile synthesis of the bioactive multifunctional curcumin-based platforms linked to a variety of anticancer drugs like amonafide and chlorambucil, and release of the drugs in a hydrolytic environment. The leading curcumin-based platform has presented antioxidant activity similar to curcumin, but with much more potent cytotoxicity in vitro in agreement with the augmented blockage of the NF-kB cell survival pathway. The approach presented here may prove beneficial for bioactive curcumin-based delivery applications where multiple drug delivery is required in a consecutive and controlled mode.

Photodynamic PEG-coated ROS-sensitive prodrug nanoassemblies for core-shell synergistic chemo-photodynamic therapy

The combination of chemotherapy with photodynamic therapy (PDT) holds promising applications in cancer therapy. However, co-encapsulation of chemotherapeutic agents and photosensitizers (PS) into the conventional nanocarriers suffers from inefficient co-loading and aggregation-caused quenching (ACQ) effect of PS trapped in dense carrier materials. Herein, we report a light-activatable photodynamic PEG-coated prodrug nanoplatform for core–shell synergistic chemo-photodynamic therapy. A novel photodynamic polymer is rationally designed and synthesized by conjugating pyropheophorbide a (PPa) to polyethylene glycol 2000 (PEG2k). PPa is used as the hydrophobic and photodynamic moiety of the amphipathic PPa-PEG2k polymer. Then, a core–shell nanoassembly is prepared, with an inner core of a reactive oxygen species (ROS)-responsive oleate prodrug of paclitaxel (PTX) and an outer layer of PPa-PEG2k. PPa-PEG2k serves for both PEGylation and PDT. Instead of being trapped in the inner core, PPa in the outer PPa-PEG2k layer significantly alleviates the ACQ effect. Under laser irradiation, ROS generated by PPa-PEG2k not only is used for PDT but also synergistically promotes PTX release in combination with the endogenous ROS overproduced in tumor cells. The photodynamic PEG-coated nanoassemblies demonstrated synergistic antitumor activity in vivo. Such a unique nanoplatform, with an inner chemotherapeutic core and an outer photodynamic PEG shell, provides a new strategy for synergistic chemo-photodynamic therapy. Statement of SignificationThe combination of chemotherapy with photodynamic therapy (PDT) holds promising prospects in cancer therapy. However, it remains a tremendous challenge to effectively co-deliver chemotherapeutic drugs and photosensitizers into tumors. Herein, we construct a photodynamic PEGylation-coated prodrug-nanoplatform for high-efficiency synergistic cancer therapy, which is composed of a light-activatable PPa-PEG2k shell and a ROS-responsive paclitaxel (PTX) prodrug core. The PPa-PEG2k-generated ROS not only was used for synergistic PTX release but also synergistically facilitated tumor cell apoptosis in combination with PTX-initiated chemo-cytotoxicity. The light-activatable nanoassemblies exhibited multiple drug delivery advantages including high co-loading efficiency, self-enhanced PTX release, extended circulation time, favorable biodistribution, and potent synergistic anticancer activity. Our findings provide a new strategy for the rational design of advanced nano-DDS for high-efficiency combinational chemo-photodynamic therapy.

Hydroxyapatite-poly(vinyl alcohol) core-shell nanoparticles for dual delivery of methotrexate and gemcitabine for bone cancer treatment

The delivery of multiple drugs with bone substitutes is the current strategy for the treatment of bone diseases. In this study, hydroxyapatite nanoparticles (HA NPs) as a core and poly(vinyl alcohol) (PVA) as the corona were developed for the dual delivery of anti-cancer drugs methotrexate (MTX) and gemcitabine (GEM). MTX was conjugated to PVA through ester linkages with a high payload of around 20%. GEM was then physically loaded onto the MTX conjugated-PVA-HA NPs with a loading efficiency of 83%. In vitro drug release studies of GEM-loaded-MTX conjugated-PVA-HA NPs in phosphate buffered saline (pH 7.4) showed a combined release of both MTX (25%) and GEM (60%) at the end of 10 days. Physically loaded MTX showed a burst release of around 50% compared to 16% by conjugated MTX within 24 h which supports the significance of conjugating drug molecules. Cell viability studies using osteosarcoma MG-63 cells confirmed that polymer grafted NPs were non-cytotoxic, while the drug-loaded NPs showed dose-dependent cytotoxicity. The synthesized NPs will be a promising bone-substitute material for the co-delivery of many therapeutic molecules for the treatment of bone diseases.

New Approach of Transdermal Drug Delivery: Sonophoresis

The stratum corneum serves as a barrier that limits the penetration of substances to the skin. Application of ultrasound to the skin increases its permeability (sonophoresis) and enables the delivery of various substances through and into the skin. Various studies have been conducted on ultrasonic penetration in transdermal drug delivery, focusing on parameter optimization, delivery mechanism, transport pathways and delivery of multiple drugs. Cavitation effect is the main mechanism responsible for drug delivery. The studies on sonophoresis was discussed, including the latest trends, the delivery of drugs, the pathways and mechanisms of sonophoresis, and the outlook for future research.

Nanoparticle-Peptide-Drug Bioconjugates for Unassisted Defeat of Multidrug Resistance in a Model Cancer Cell Line.

Multidrug resistance (MDR) is a significant challenge in the treatment of many types of cancers as membrane-associated transporters actively pump drugs out of the cell, limiting therapeutic efficacy. While nanoparticle (NP)-based therapeutics have emerged as a mechanism for overcoming MDR, they often rely on the delivery of multiple anticancer drugs, nucleic acid hybrids, or MDR pump inhibitors. The effectiveness of these strategies, however, can be limited by their off-target toxicity or the need for genetic transfection. In this paper, we describe a NP-peptide-drug bioconjugate that achieves significant cell killing in MDR-positive cancer cells without the need for additional drugs. We use a quantum dot (QD) as a central scaffold to append two species of peptide, a cell-uptake peptide to facilitate endocytic internalization and a peptide-drug conjugate that is susceptible to cleavage by esterases found within the endocytic pathway. This approach relies on spatiotemporal control over drug release, where endosomes traffic drug away from membrane-resident pumps and release it closer to the nucleus. Cellular internalization studies showed high uptake of the NP-drug complex and nuclear localization of the drug after 48 h in MDR-positive cells. Additionally, cellular proliferation assays demonstrated a 40% decrease in cell viability for the NP-drug bioconjugate compared to free drug, confirming the utility of this system in overcoming MDR in cancer cells.

Multiple Drug Delivery from Mesoporous Coating Realizing Combination Therapy for Bare Metal Stents

The simultaneous loading of multifunctional drugs has been regarded as one of the major challenges in the drug delivery system. Herein, a mesoporous silica coating was constructed on a bare metal stent surface by an evaporation-induced self-assembly method, in which both hydrophilic and hydrophobic drugs (heparin and rapamycin) were encapsulated by a one-pot method for the first time, and the release behaviors of these drugs were studied. The releasing mechanisms of these drugs were investigated in detail. Rapid release of heparin can achieve anticoagulation and endothelialization, whereas slow release of rapamycin can realize antiproliferative therapy for long term. In vitro hemocompatibility and promotion for proliferation of vein endothelial cells and the inhibition of smooth muscle cells were conducted. In vivo stent implantation results verify that the mesoporous silica coating with both heparin and rapamycin can successfully accelerate the endothelialization process and realize the antiproliferative therapy for as long as 3 months. These results indicate that this multifunctional mesoporous coating containing both hydrophilic and hydrophobic drugs might be a promising stent coating in the future.