Delivery Of Small Molecule Drugs Research Articles

Encapsulation of proteins with high/low pI in PLGA-particles for oral delivery

Polylactic co-glycolic acid (PLGA) is a biocompatible and biodegradable polymer used for controlled drug delivery of small molecules or macromolecules including protein. Proteins highly requires an advanced drug delivery system because of its sensitivity towards many factors such as temperature, hygroscopicity, and biological system. Particularly for oral dosage form, protein must be encapsulated in extremely low pH resistant particle. Protein’s intrinsic characterization determines effectivity of the encapsulation. The recent method of PLGA particle preparation was more suitable for proteins with low pI. PLGA showed higher effectivity to encapsulate protein with low pI such as BSA (pI = ˜ 4.8) than that of high pI for instance lysozyme (pI = ˜ 11). In the study, protein release and physico-chemical characterizations of BSA loaded PLGA-particle were performed.

An oligopeptide/aptamer-conjugated dendrimer-based nanocarrier for dual-targeting delivery to bone.

Bone targeting is one of the most potentially valuable therapeutic methods for medically treating bone diseases, such as osteoarthritis, osteoporosis, nonunion bone defects, bone cancer, and myeloma-related bone disease, but its efficacy remains a challenge due to unfavorable bone biodistribution, off-target effects, and the lack of cell specificity. To address these problems, we synthesized a new dual-targeting nanocarrier for delivery to bone by covalently modifying the G4.0 PAMAM dendrimer with the C11 peptide and the CH6 aptamer (CH6-PAMAM-C11). The molecular structure was confirmed using 1H-NMR and FT-IR spectroscopy. CLSM results showed that the novel nanocarrier could successfully accumulate in the targeted cells, mineralized areas and tissues. DLS and TEM demonstrated that CH6-PAMAM-C11 was approximately 40-50 nm in diameter. In vitro targeting experiments confirmed that the C11 ligand had a high affinity for HAP, while the CH6 aptamer had a high affinity for osteoblasts. The in vivo biodistribution analysis showed that CH6-PAMAM-C11 could rapidly accumulate in bone within 4 h and 12 h and then deliver drugs to sites of osteoblast activity. The components of CH6-PAMAM-C11 were well excreted via the kidneys. The accumulation of many more CH6-PAMAM-C11 dual-targeting nanocarriers than single-targeting nanocarriers was observed in the periosteal layer of the rat skull, along with aggregation at sites of osteoblast activity. All of these results indicate that CH6-PAMAM-C11 may be a promising nanocarrier for the delivery of drugs to bone, particularly for the treatment of osteoporosis, and our research strategy may serve as a reference for research in targeted drug, small molecule drug and nucleic acid delivery.

A multi-functionalized calcitriol sustainable delivery system for promoting osteoporotic bone regeneration both in vitro and in vivo

Among metabolic and systemic bone diseases, osteoporosis is known as one of the most progressive disease characterized by bone microstructural deterioration and bone mass reduction. Calcitriol (Cal) is widely accepted as a fat-soluble small molecule drug with reported anti-osteoporotic activity. However, delivery systems capable of local sustained release of small molecule drugs remain a significant challenge. Herein, based on poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PDLLA-PEG-PDLLA) hydrogels, we developed a thermosensitive and multifunctional sustainable delivery system by doubly integrating with polydopamine modified nano-hydroxyapatite (HA-D) and calcitriol-loaded amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PCL-PEG-NH2) micelles to realize the long-term delivery of small molecule drugs. The sustained release of Cal from the system was associate with triple controlled release effects including the protective screen of the hydrogels over micelles, the reservoir effect of the HA nanoparticles for Cal, and the encapsulation of Cal in micelles. In vitro, results from the present study demonstrated that sustainable delivery system effectively activated osteogenesis, proliferation and migration in these bone mesenchymal stromal cells of ovariectomized rats (OVX-rBMSCs). In vivo, the composite Cal-loaded system was verified to promote bone regeneration in the critical-size femoral epicondyle bone defect model. Meanwhile, little cytotoxicity and appropriate degradation rate of the composite Cal delivery system were revealed. Thus, incorporating Cal into a multifunctional delivery system to perform a long-acting drug delivery in an injectable hydrogel form is a promising therapeutic to improve anti-osteoporotic ability and promote bone regeneration of osteoporosis.

Cyclodextrins based delivery systems for macro biomolecules

Macro biomolecules are of vital importance in regulating the biofunctions in organisms, in which proteins (including peptides when mentioned below) and nucleic acids (NAs) are the most important. Therefore, these proteins and NAs can be applied as "drugs" to regulate the biofunctions from abnormal to normal. Either for proteins and NAs, the most challenging thing is to avoid the biodegradation or physicochemical degradation before they reach the targeted location, and then functions as complete functional structures. Hence, appropriate delivery systems are very important which can protect them from these degradations. Cyclodextrins (CDs) based delivery systems achieved mega successes due to their outstanding pharmaceutical properties and there have been several reviews on CDs based small molecule drug delivery systems recently. But for biomolecules, which are getting more and more important for modern therapies, however, there are very few reviews to systematically summarize and analyze the CDs-based macro biomolecules delivery systems, especially for proteins. In this review, there were some of the notable examples were summarized for the macro biomolecules (proteins and NAs) delivery based on CDs. For proteins, this review included insulin, lysozyme, bovine serum albumin (BSA), green fluorescent protein (GFP) and IgG's, etc. deliveries in slow release, stimulating responsive release or targeting release manners. For NAs, this review summarized cationic CD-polymers and CD-cluster monomers as NAs carriers, notably, including the multicomponents targeting CD-based carriers and the virus-like RNA assembly method siRNA carriers.

Has PEG-PLGA advantages for the delivery of hydrophobic drugs? Risperidone as an example

To overcome the disadvantages seen with current long-acting injectable formulations for risperidone (i.e., nonlinear release with initial lag time), an alternative delivery system was developed. The use of biodegradable PEG-PLGA polymers enabled us to formulate microparticles with a linear release over one month with no observable lag time.Diblock copolymers with PEG contents of 5 and 10% were transformed into risperidone-loaded highly porous microparticles with median particle sizes of 20–30 μm and narrow size distributions as confirmed by laser diffraction, electron and confocal microscopy. In parallel to characterizing the in vitro drug release behavior of the formulations, we studied their degradation/erosion profile by a couple of complementary techniques in detail. Compared to drug-free microparticles, the presence of risperidone led to a significantly faster polymer degradation accompanied by a more rapid mass loss and release of lactic acid. Proton nuclear magnetic resonance spectroscopy revealed a constant PEG content for the PEG-PLGA containing 5% of PEG over the course of incubation, while a decrease was observed for the diblock copolymer having an initial PEG content of 10%.In conclusion, PEG-PLGA polymers are also useful materials for the prolonged drug delivery of small lipophilic molecules, in addition to their application for the sustained release of sensitive drugs like peptides and proteins. Compared to “standard” polyesters such as PLGA, diblock copolymers avoid initial lag times and nonlinear “unpredictable” drug release profiles.

Bioengineered in Vitro Tissue Models to Study SARS-CoV-2 Pathogenesis and Therapeutic Validation.

Given the various viral outbreaks in the 21st century, specifically the present pandemic situation arising from SARS-CoV-2 or the coronavirus, of unknown magnitude, there is an unmet clinical need to develop effective therapeutic and diagnostic strategies to combat this infectious disease worldwide. To develop precise anticoronavirus drugs and prophylactics, tissue engineering and biomaterial research strategies can serve as a suitable alternative to the conventional treatment options. Therefore, in this Review, we have highlighted various tissue engineering-based diagnostic systems for SARS-CoV-2 and suggested how these strategies involving organ-on-a-chip, organoids, 3D bioprinting, and advanced bioreactor models can be employed to develop in vitro human tissue models, for more efficient diagnosis, drug/vaccine development, and focusing on the need for patient-specific therapy. We believe that combining the basics of virology with tissue engineering techniques can help the researchers to understand the molecular mechanism underlying viral infection, which is critical for effective drug design. In addition, it can also serve to be a suitable platform for drug testing and delivery of small molecules that can lead to therapeutic tools in this dreaded pandemic situation. Additionally, we have also discussed the essential biomaterial properties which polarize the immune system, including dendritic cells and macrophages, toward their inflammatory phenotype, which can thus serve as a reference for exhibiting the role of biomaterial in influencing the adaptive immune response involving B and T lymphocytes to foster a regenerative tissue microenvironment. The situation arising from SARS-CoV-2 poses a challenge to scientists from almost all disciplines, and we feel that tissue engineers can thus provide new translational opportunities in this dreadful pandemic situation.

Articular Cartilage- and Synoviocyte-Binding Poly(ethylene glycol) Nanocomposite Microgels as Intra-Articular Drug Delivery Vehicles for the Treatment of Osteoarthritis.

Intra-articular (IA) injection is an attractive route of administration for the treatment of osteoarthritis (OA). However, free drugs injected into the joint space are rapidly cleared and many of them can induce adverse off-target effects on different IA tissues. To overcome these limitations, we designed nanocomposite 4-arm-poly(ethylene glycol)-maleimide (PEG-4MAL) microgels, presenting cartilage- or synoviocyte-binding peptides, containing poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) as an IA small molecule drug delivery system. Microgels containing rhodamine B (model drug)-loaded PLGA NPs were synthesized using microfluidics technology and exhibited a sustained, near zero-order release of the fluorophore over 16 days in vitro. PEG-4MAL microgels presenting synoviocyte- or cartilage-targeting peptides specifically bound to rabbit and human synoviocytes or to bovine articular cartilage in vitro, respectively. Finally, using a rat model of post-traumatic knee OA, PEG-4MAL microgels were shown to be retained in the joint space for at least 3 weeks without inducing any joint degenerative changes as measured by EPIC-μCT and histology. Additionally, all microgel formulations were found trapped in the synovial membrane and significantly increased the IA retention time of a model small molecule near-infrared (NIR) dye compared to that of the free dye. These results suggest that peptide-functionalized nanocomposite PEG-4MAL microgels represent a promising intra-articular vehicle for tissue-localized drug delivery and prolonged IA drug retention for the treatment of OA.

Crosslinked polymer nanocapsules for therapeutic, diagnostic, and theranostic applications.

Crosslinked polymer nanocapsules (CPNCs) are hollowed nanoparticles with network-like polymeric shells stabilized by primary bonds. CPNCs have drawn broad and significant interests as nanocarriers for biomedical applications in recent years. As compared with conventional polymeric nanoparticles systems without cavity and/or crosslinking architectures, CPNCs possess significant biomedical relevant advantages, including (a) superior structural stability against environmental conditions, (b) high loading capacity and ability for region-specific loading of multiple cargos, (c) tuneable cargo release rate via crosslinking density, and (d) high specific surface area to facilitate surface adsorption, modification, and interactions. With appropriate base polymers and crosslinkages, CPNCs can be biocompatible and biodegradable. While CPNC-based biomedical nanoplatforms can possess relatively stable physicochemical properties owing to their crosslinked architectures, various biomedically relevant stimuli-responsivities can be incorporated with them through specific structural designs. CPNCs have been studied for the delivery of small molecule drugs, genes, proteins, and other therapeutic agents. They have also been investigated as diagnostic platforms for magnetic resonance imaging, ultrasound imaging, and optical imaging. Moreover, CPNCs have been utilized to carry both therapeutics and bioimaging agents for theranostic applications. This article reviews the therapeutic, diagnostic and theranostic applications of CPNCs, as well as the preparation of these CPNCs, reported in the past decade. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

Dextran methacrylate hydrogel microneedles loaded with doxorubicin and trametinib for continuous transdermal administration of melanoma

Microneedles (MNs) technology has many advantages and is an ideal local transdermal drug delivery method. Here we synthesized photocrosslinkable dextran methacrylate (DexMA), and its degree of substitution is 5 % higher than the previous method. We used DexMA hydrogel for the first time to develop a new type of MNs for continuous transdermal administration. The prepared hydrogel MNs can successfully penetrate the epidermal layer and achieve sustained drug release. Doxorubicin (DOX) and trametinib (Tra) are anticancer drugs approved by FDA. Besides, Tra can also reverse P-gp-mediated multidrug resistance (MDR) to effectively block the efflux of DOX by P-gp. We used MNs to simultaneously load Tra and DOX, and achieved synergy in a B16 cell xenograft nude mouse model. The DexMA hydrogel MNs developed in this study can be used to enhance the transdermal delivery of small molecule drugs and reduce systemic toxicity and side effects.

Combinatorial Library of Cyclic Benzylidene Acetal-Containing pH-Responsive Lipidoid Nanoparticles for Intracellular mRNA Delivery.

Lipidoid nanoparticles have been demonstrated to be effective for intracellular delivery of small molecule drugs, proteins, and nucleic acids. Stimuli-responsive lipidoid nanoparticles are able to further improve delivery efficacy and reduce carrier-induced toxicity. Our group previously developed reduction and photoresponsive combinatorial libraries of lipidoid nanoparticles for small molecule and biologics delivery. Herein, we describe the synthesis, characterization, and intracellular mRNA delivery application of a new library of pH-responsive lipidoid nanoparticles. The acid-degradable cyclic benzylidene acetal-containing cationic lipidoids (R-O16CBA) were synthesized through a multistep reaction and characterized by NMR and MS. The acid-triggered degradation of lipidoids was studied using NMR, MS, DLS, and TEM. The results revealed that the R-O16CBA lipidoid can be completely degraded at pH 5. The R-O16CBA lipidoid nanoparticles were then fabricated with different formulations of DOPE and cholesterol and tested in vitro for intracellular mRNA delivery.

Nanoparticles containing constrained phospholipids deliver mRNA to liver immune cells in vivo without targeting ligands.

Once inside the cytoplasm of a cell, mRNA can be used to treat disease by upregulating the expression of any gene. Lipid nanoparticles (LNPs) can deliver mRNA to hepatocytes in humans, yet systemic non‐hepatocyte delivery at clinical doses remains difficult. We noted that LNPs have historically been formulated with phospholipids containing unconstrained alkyl tails. Based on evidence that constrained adamantyl groups have unique properties that can improve small molecule drug delivery, we hypothesized that a phospholipid containing an adamantyl group would facilitate mRNA delivery in vivo. We quantified how 109 LNPs containing “constrained phospholipids” delivered mRNA to 16 cell types in mice, then using a DNA barcoding‐based analytical pipeline, related phospholipid structure to in vivo delivery. By analyzing delivery mediated by constrained phospholipids, we identified a novel LNP that delivers mRNA to immune cells at 0.5 mg/kg. Unlike many previous LNPs, these (a) did not preferentially target hepatocytes and (b) delivered mRNA to immune cells without targeting ligands. These data suggest constrained phospholipids may be useful LNP components.

Potential Application of Ionic Liquids in Pharmaceutical Dosage Forms for Small Molecule Drug and Vaccine Delivery System.

Ionic liquids are salts in which the ions are poorly coordinated, which causes them to exist in liquid form below 100°C, or at room temperature. Therefore, these are also defined as room temperature ionic liquids (RTILs). In ionic liquids, at least one ion has a delocalized charge and one component is organic, which prevents the formation of a stable solid form of crystal lattice. Physical properties of ionic liquids, such as melting point, viscosity, and solubility of starting materials and other solvents, are impacted by the substituents on the organic component and by the counterions. Many ionic liquids have even been developed to address specific synthetic problems and that is the reason these are also termed as "designer solvents". Ionic liquids are considered as "green solvents" that exhibit several unique characteristics such as high ionic conductivity, high solvation power, thermal stability, low volatility, and recyclability. Although very useful with several advantages, ionic liquids have some limitations that include high cost and ease of recycling. Moreover, the toxicity and biodegradability of ionic liquids are not yet well understood. Nonetheless, ionic liquids can potentially be used in the field of pharmacy in drug design and formulation development. In drug or vaccine dosage formulation development, ionic liquids can be used as a solubility enhancer, permeability enhancer, stabilizer, targeted delivery inducer, stealth property provider or bioavailability enhancer. In this article we reviewed the physical properties of ionic liquids and potential application of ionic liquids in developing formulations for vaccines and small molecule drugs (A table has been added).

Role of Tissue Engineering in COVID-19 and Future Viral Outbreaks.

In light of the current novel coronavirus (COVID-19) pandemic, as well as other viral outbreaks in the 21st century, there is a dire need for new diagnostic and therapeutic strategies to combat infectious diseases worldwide. As a convergence science, tissue engineering has traditionally focused on the application of engineering principles to biological systems, collaboration across disciplines, and rapid translation of technologies from the benchtop to the bedside. Given these strengths, tissue engineers are particularly well suited to apply their skill set to the current crisis and viral outbreaks in general. This work introduces the basics of virology and epidemiology for tissue engineers, and highlights important developments in the field of tissue engineering relevant to the current pandemic, including in vitro model systems, vaccine technology, and small-molecule drug delivery. COVID-19 serves as a call to arms for scientists across all disciplines, and tissue engineers are well trained to be leaders and contributors in this time of need.Impact statementGiven the steep mortality caused by the recent novel coronavirus (COVID-19) pandemic, there is clear need for advances in diagnostics and therapeutics for viral outbreaks. Tissue engineering has the potential for critical impact on clinical outcomes in viral outbreaks. Tissue engineers, if mobilized, could play key roles as leaders in the outbreak, given their ability to apply engineering principles to biological processes, experience in collaborative environments, and penchant for technological translation from benchtop to bedside. In this work, three areas pioneered by tissue engineers that could be applied to the current COVID-19 crisis and future viral outbreaks are highlighted.

Chimeric siRNA-DNA Surfactants for the Enhanced Delivery and Sustained Cytotoxicity of a Gold(III) Metallodrug.

Using a recently developed nucleic acid delivery platform, we demonstrate the effective delivery of metallodrug [AuIIIBr2(SSC-Inp-OEt)] (AP228; Inp = isonipecotic moiety), a hydrophobic, low solubility gold complex cytotoxic to cancer cells. It is shown that AP228 is delivered more effectively into HeLa cells using micellular surfactant assemblies compared to that of a more polar derivative [AuIIIBr2(SSC-Inp-GlcN1)] (AP209; GlcN1 = (α,β)-d-glucosamino moiety). When AP228 is codelivered with siRNA targeting Bcl-2, a key regulator of apoptosis, the overall cytotoxic therapeutic effects of the drug are maximized. The optimized delivery and distribution of the compound is monitored by both fluorescence microscopy and inductively coupled plasma mass spectrometry. We show that codelivery of the AP228 and Bcl-2 targeting siRNA results in a substantial increase in drug efficacy, wherein the cytotoxic therapeutic effects of the drug are maximized, reducing the IC50 from 760 nM to 11 nM. This hybrid small molecule drug and therapeutic nucleic acid delivery vehicle is shown to enable both the improved solubility and uptake of the gold(III) metallodrugs and the delivery of chemically unmodified siRNA, resulting in enhanced cytotoxic effects.

Transporter-Mediated Delivery of Small Molecule Drugs to the Brain: A Critical Mechanism That Can Advance Therapeutic Development for Ischemic Stroke.

Ischemic stroke is the 5th leading cause of death in the United States. Despite significant improvements in reperfusion therapies, stroke patients still suffer from debilitating neurocognitive deficits. This indicates an essential need to develop novel stroke treatment paradigms. Endogenous uptake transporters expressed at the blood-brain barrier (BBB) provide an excellent opportunity to advance stroke therapy via optimization of small molecule neuroprotective drug delivery to the brain. Examples of such uptake transporters include organic anion transporting polypeptides (OATPs in humans; Oatps in rodents) and organic cation transporters (OCTs in humans; Octs in rodents). Of particular note, small molecule drugs that have neuroprotective properties are known substrates for these transporters and include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) for OATPs/Oatps and 1-amino-3,5-dimethyladamantane (i.e., memantine) for OCTs/Octs. Here, we review current knowledge on specific BBB transporters that can be targeted for improvement of ischemic stroke treatment and provide state-of-the-art perspectives on the rationale for considering BBB transport properties during discovery/development of stroke therapeutics.

Hierarchical integration of degradable mesoporous silica nanoreservoirs and supramolecular dendrimer complex as a general-purpose tumor-targeted biomimetic nanoplatform for gene/small-molecule anticancer drug co-delivery.

Biomacromolecule therapeutic systems are intrinsically susceptible to degradation and denaturation. Nanoformulations are promising delivery vehicles for therapeutic biomacromolecules (antibodies, genes and so on). However, their applications in these areas still face many challenges including in vivo stability, premature leakage and accurate tumor recognition. In this study, a generally applicable new strategy for tumor-targeted delivery of biomacromolecules was developed through the hierarchical integration of degradable large-pore dendritic mesoporous silica nanoparticles (dMSNs) and cyclodextrin-modified polyamidoamine (PAMAM-CD) dendrimers. The orifice rim of the dMSNs was modified with ROS-responsive nitrophenyl-benzyl-carbonate (NBC) groups while disulfide-bonded azido ligands were subsequently grafted onto the inner channel walls via heterogeneous functionalization. The PAMAM-CD was then interred into the dendritic pores via click reactions and supramolecularly loaded with archetypal hydrophobic small-molecule anticancer model drug (SN-38) and therapeutic model gene (Bcl-2 siRNA), after which dMSNs were eventually coated with a 4T1 cancer cell membrane (CCM). Experimental evidence demonstrated that the synthesized nanocarriers could efficiently deliver therapeutic cargos to target cancer cells and release them in the tumor cytosol in a cascade-responsive manner. This biomimetic nanoplatform presents a novel strategy to efficiently deliver biomolecular therapeutics in a tumor-targeted manner.

Multi-arm Avidin nano-construct for intra-cartilage delivery of small molecule drugs

Targeted drug delivery to joint tissues like cartilage remains a challenge that has prevented clinical translation of promising osteoarthritis (OA) drugs. Local intra-articular (IA) injections of drugs suffer from rapid clearance from the joint space and slow diffusive transport through the dense, avascular cartilage matrix comprised of negatively charged glycosaminoglycans (GAGs). Here we apply drug carriers that leverage electrostatic interactions with the tissue's high negative fixed charge density (FCD) for delivering small molecule drugs to cartilage cell and matrix sites. We demonstrate that a multi-arm cationic nano-construct of Avidin (mAv) with 28 sites for covalent drug conjugation can rapidly penetrate through the full thickness of cartilage in high concentration and have long intra-cartilage residence time in both healthy and arthritic cartilage via weak-reversible binding with negatively charged aggrecans. mAv's intra-cartilage mean uptake was found to be 112× and 33× the equilibration bath concentration in healthy and arthritic (50% GAG depleted) cartilage, respectively. mAv was conjugated with Dexamethasone (mAv-Dex), a broad-spectrum glucocorticoid, using a combination of hydrolysable ester linkers derived from succinic anhydride (SA), 3,3-dimethylglutaric anhydride (GA) and phthalic anhydride (PA) in 2:1:1 M ratio that enabled 50% drug release within 38.5 h followed by sustained release in therapeutic doses over 2 weeks. A single 10 μM low dose of controlled release mAv-Dex (2:1:1) effectively suppressed IL-1α-induced GAG loss, cell death and inflammatory response significantly better than unmodified Dex over 2 weeks in cartilage explant culture models of OA. With this multi-arm design, <1 μM Avidin was needed – a concentration which has been shown to be safe, preventing further GAG loss and cytotoxicity. A charge-based cartilage homing drug delivery platform like this can elicit disease modifying effects as well as facilitate long-term symptomatic pain and inflammation relief by enhancing tissue specificity and prolonging intra-cartilage residence time of OA drugs. This nano-construct thus has high translational potential for enabling intra-cartilage delivery of a broad array of small molecule OA drugs and their combinations to chondrocytes, enabling OA treatment with a single injection of low drug doses and eliminating toxicity issues associated with multiple high dose injections.

Graphene Quantum Dots and Their Applications in Bioimaging, Biosensing, and Therapy.

Graphene quantum dots (GQDs) are carbon-based, nanoscale particles that exhibit excellent chemical, physical, and biological properties that allow them to excel in a wide range of applications in nanomedicine. The unique electronic structure of GQDs confers functional attributes onto these nanomaterials such as strong and tunable photoluminescence for use in fluorescence bioimaging and biosensing, a high loading capacity of aromatic compounds for small-molecule drug delivery, and the ability to absorb incident radiation for use in the cancer-killing techniques of photothermal and photodynamic therapy. Recent advances in the development of GQDs as novel, multifunctional biomaterials are presented with a focus on their physicochemical, electronic, magnetic, and biological properties, along with a discussion of technical progress in the synthesis of GQDs. Progress toward the application of GQDs in bioimaging, biosensing, and therapy is reviewed, along with a discussion of the current limitations and future directions of this exciting material.

Exploring Multicompartment Plug Flow–Based Model Approach in Biopharmaceutics: Impact of Stomach Setting and the Estimation of the Fraction Absorbed of Orally Administered Basic Drugs

There has been an increasing interest in accurate prediction of human pharmacokinetics of drug candidates to reduce cost and increase productivity during research and development. Modeling efforts have primarily focused on predicting drug absorption after oral administration because it is the most desired route for small molecule drug delivery. Despite significant progress in the field, the fraction of dose absorbed (Fa) is still considered to be a challenging parameter to predict. In recent years, compartment and transit models have become increasingly popular because of their effectiveness. A multicompartment plug flow–based model in which the stomach is assigned as a single compartment has been built. However, this model was found to be less accurate in estimating stomach solubilization of basic drugs under certain conditions and leads to false-negative results. Therefore, a modified multicompartment approach was developed by dividing the stomach into 4 compartments allowing the model to better mimic the physiological conditions. This approach was found to be more precise in estimating Fa for basic drugs compared to the previous approach. Based on this finding, it is believed the aforementioned approach should also be applicable to all compartmental-based models when similar issues are encountered.

Silk Fibroin-Based Biomaterials for Biomedical Applications: A Review.

Since it was first discovered, thousands of years ago, silkworm silk has been known to be an abundant biopolymer with a vast range of attractive properties. The utilization of silk fibroin (SF), the main protein of silkworm silk, has not been limited to the textile industry but has been further extended to various high-tech application areas, including biomaterials for drug delivery systems and tissue engineering. The outstanding mechanical properties of SF, including its facile processability, superior biocompatibility, controllable biodegradation, and versatile functionalization have allowed its use for innovative applications. In this review, we describe the structure, composition, general properties, and structure-properties relationship of SF. In addition, the methods used for the fabrication and modification of various materials are briefly addressed. Lastly, recent applications of SF-based materials for small molecule drug delivery, biological drug delivery, gene therapy, wound healing, and bone regeneration are reviewed and our perspectives on future development of these favorable materials are also shared.