Biomaterials-mediated sequential drug delivery: Emerging trends for wound healing

Controlled drug delivery systems, that include sequential and/or sustained drug delivery, have been utilized to enhance the therapeutic effects of many current drugs by effectively delivering drugs in a time-dependent and repeatable manner. In this study, with the aid of 3D printing technology, a novel drug delivery device was fabricated and tested to evaluate sequential delivery functionality. With an alginate shell and a poly(lactic-co-glycolic acid) (PLGA) core, the fabricated tubes displayed sequential release of distinct fluorescent dyes and showed no cytotoxicity when incubated with the human embryonic kidney (HEK293) cell line or bone marrow stromal stem cells (BMSC). The controlled differential release of drugs or proteins through such a delivery system has the potential to be used in a wide variety of biomedical applications from treating cancer to regenerative medicine.

Sequential drug delivery for liver diseases.

A pH-responsive polycarbonate nanoplatform enables sequential drug release for enhanced apoptotic cascade synergy in non-small cell lung cancer therapy.

A sequential drug delivery system based on silk fibroin scaffold for effective cartilage repair.

Cancer is a major public health problem and one of the leading causes of death. However, traditional cancer therapy may damage normal cells and cause side effects. Many targeted drug delivery platforms have been developed to overcome the limitations of the free form of therapeutics and biological barriers. The commonly used cancer cell surface targets are CD44, matrix metalloproteinase-2, folate receptors, etc. Once the drug enters the cell, active delivery of the drug molecule to its final destination is still preferred. The subcellular targeting strategies include using glucocorticoid receptors for nuclear targeting, negative mitochondrial membrane potential and N-acetylgalactosaminyltransferase for Golgi apparatus targeting, etc. Therefore, the most effective way to deliver therapeutic agents is through a sequential drug delivery system that simultaneously achieves cellular- and subcellular-level targeting. The dual-targeting delivery holds great promise for improving therapeutic effects and overcoming drug resistance. This review classifies sequential drug delivery systems based on final targeted organelles. We summarize different targeting strategies and mechanisms and gave examples of each case.

Controlled and sequential drug delivery is a strategy to enhance the therapeutic effectiveness of drugs in a variety of biological processes and disease states. While many different drug delivery systems are developed recently, most cannot generate temporally complex delivery profiles of multiple therapeutics. These temporally complex profiles are critical for applications such as bone regeneration and cancer chemotherapy, where an orchestrated delivery of multiple drugs is required for an optimal outcome. Here, we developed three distinct biomaterial systems that each enable on-demand controlled or sequential drug release. These systems are based on varying external stimulus such as magnetic stimulation, radiofrequency heating, and near infrared (NIR) laser irradiation. The first system is a dual compartment hydrogel composed of an outer gelatin partition and an inner alginate ferrogel. While the outer compartment could be loaded with a recruitment factor to recruit and harbor cells, the inner compartment was capable of retaining and releasing a differentiation factor on-demand. The inner compartment was a biphasic ferrogel and stimulation was conducted using a custom magnetic stimulation set up. It was shown that delayed differentiation factor delivery can enhance mMSCs’ osteo-differentiation outcomes using 2D and 3D cell cultures. The second system is a magnetoliposome (ML) integrated hydrogel system. In this design, different sizes of magnetic iron oxide nanoparticles (IONPs) were used to develop two different MLs: ML-A and ML-B. Cationic and zwitterionic lipids were used to form positively charged liposomes that could electrostatically adsorb the IONPs on their surfaces and form MLs. The ratio of IONP/lipid was optimized to form stable ML-A and ML-B structures. These structures were integrated within 3D alginate hydrogels to enhance stability and provide localized drug delivery. As the different MLs could be stimulated at different frequencies, complex delivery profiles could be generated using these MLs in hydrogels. Controlled and delayed releases of a model drug (FITC-Dextran) from ML-A and ML-B in hydrogels were demonstrated. The third system is a single-walled carbon nanotube (SWCNT) liposome complex (CLC) integrated hydrogel. Here, unique NIR absorbance properties of SWCNTs were used to achieve drug release from liposomal structures. DNA sequences were used to wrap SWCNTs to uniformly disperse them in an aqueous solution and provide negative charge on their surface. These DNA-SWCNTs were then mixed with cationic liposomes to form CLCs. Optimal SWCNT to lipid ratio to form stable CLCs were determined. CLCs were then integrated within hydrogel structures and drug release was controlled using

Fabrication of chitosan-polycaprolactone composite nanofibrous scaffold for simultaneous delivery of ferulic acid and resveratrol

A nanocapsular combinatorial sequential drug delivery system for antiangiogenesis and anticancer activities

With hollow mesoporous silica (hMSN) and injectable macroporous hydrogel (Gel) used as the internal and external drug-loading material respectively, a sequential drug delivery system DOX-CA4P@Gel was constructed, in which combretastatin A4 phosphate (CA4P) and doxorubicin (DOX) were both loaded. The anti-angiogenic drug, CA4P was initially released due to the degradation of Gel, followed by the anti-cell proliferative drug, DOX, released from hMSN in tumor microenvironment. Results showed that CA4P was mainly released at the early stage. At 48 h, CA4P release reached 71.08%, while DOX was only 24.39%. At 144 h, CA4P was 78.20%, while DOX release significantly increased to 61.60%, showing an obvious sequential release behavior. Photodynamic properties of porphyrin endow hydrogel (ϕΔ(Gel) = 0.91) with enhanced tumor therapy effect. In vitro and in vivo experiments showed that dual drugs treated groups have better tumor inhibition than solo drug under near infrared laser irradiation, indicating the effectivity of combined photodynamic-chemotherapy.

Toll-like receptor 7/8 agonists, such as imidazoquinolines (IMDQs), are promising for the de novo priming of antitumor immunity. However, their systemic administration is severely limited due to the off-target toxicity. Here, this work describes a sequential drug delivery strategy. The formulation is composed of two sequential modules: a tumor microenvironment remodeling nanocarrier (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4, termed CA4-NPs) and an immunotherapy nanocarrier (apcitide peptide-decorated poly(l-glutamic acid)-graft-IMDQ-N3 conjugate, termed apcitide-PLG-IMDQ-N3 ). CA4-NPs, as a vascular disrupting agent, are utilized to remodel the tumor microenvironment for enhancing tumor coagulation and hypoxia. Subsequently, the apcitide-PLG-IMDQ-N3 could identify and target tumor coagulation through the binding of surface apcitide peptide to the GPIIb-IIIa on activated platelets. Afterward, IMDQ is activated selectively through the conversion of "-N3 " to "-NH2 " in the presence of hypoxia. The biodistribution results confirm their high tumor uptake of activated IMDQ (22.66%ID/g). By augmenting the priming and immunologic memory of tumor-specific CD8+ T cells, 4T1 and CT26 tumors with a size of ≈500 mm3 are eradicated without recurrence in mouse models.

Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell. The nanocarriers exploit storage capacities for drugs based on the high porosity and molecular sieving capabilities of ZIF-8 for sequential drug release. Particularly, large amounts of an anticancer drug (DOX, 607 μg mg-1) and a MDR inhibitor curcumin (CUR, 778 μg mg-1) were sequentially loaded in the mesoporous core via π-π stacking interactions mediated by PDA and in the microporous shell via the encapsulation during ZIF-8 growth. The sustained release of DOX was observed to follow earlier and faster release of CUR by acid-sensitive dissolution of the ZIF-8 shell. Furthermore, the nanoparticles showed good biocompatibility and effective cellular uptake in in vitro evaluations using drug-resistant MCF-7/ADR cancer cells. More importantly, the preferentially released CUR inhibited the drug efflux function of the membrane P-glycoprotein (P-gp), which subsequently facilitated the nuclear transportation of DOX released from the PDA-MSN core, and, in turn, the synergistic effects on killing MDR cancer cells. The hybrid mesoporous-microporous nanocarrier holds great promise for combination chemotherapy applications on the basis of sequential drug release.

Sequential Drug Delivery In article number 2200449, Di Li, Jianxun Ding, Tianmeng Sun, and co-workers develop a tumormicroenvironments-adapted gel composite for sequential drug release to reverse the epithelial–mesenchymal transition of tumor cells and regulate the tumor immune microenvironments, thereby inhibiting tumor growth and metastases. This process is like a painter using a paintbrush to turn a depressed and cold winter into a colorful and vibrant spring.

Microchannel system for rate-controlled, sequential, and pH-responsive drug delivery.

Stimuli-responsive hydrogels possess unique advantages in drug delivery due to their variable performance and status based on the external environment. In the present study, a dual-responsive (pH and reactive oxygen species (ROS)) hydrogel was prepared to realize drug release properties under inflammatory stimulation. By grafting 3-carboxy-phenylboronic acid to the gelatin molecular backbone and cross-linking with poly(vinyl alcohol), we successfully synthesized the inflammation-responsive drug-loaded hydrogels after encapsulation with vancomycin-conjugated silver nanoclusters (VAN-AgNCs) and pH-sensitive micelles loaded with nimesulide (NIM). This novel design not only retained the dynamic functions of hydrogels, such as injectability, self-healing, and remodeling, but also realized sequential and on-demand drug delivery at diabetic-infected wound sites. In this work, we found that the hydrogel exhibited excellent biocompatibility and hemostasis properties owing to the enhanced cell-adhesive property of the gelatin component. The significant antibacterial and anti-inflammatory effect of the hydrogel was demonstrated in an in vitro experiment. Moreover, in the in vivo experiment, the hydrogel was found to play a role in promoting infected wound healing through sequential hemostasis and antibacterial and anti-inflammatory processes. Collectively, this inflammation-responsive hydrogel design containing VAN-AgNCs and NIM-loaded micelles has great potential in the application of chronically infected diabetic wound treatment, as well as in other inflammatory diseases.

The possibility of active laser delivery of a modern chlorine-containing photosensitizing drug “Chloderm” (Chloderm, Russia) under the nail plate by laser radiation with a wavelength of 450 nm for the purpose of photodynamic therapy of onychomycosis is studied. In an in vitro experiment, sequential laser microporation of the nail plate and active delivery of the drug under the nail plate by this laser radiation with an intensity of up to 200 W/cm2 were investigated. The results of studying the absorption spectra of an aqueous solution of Chloderm in the range of 400–900 nm before and after exposure to 450 nm laser radiation are presented. It is demonstrated that sequential laser microporation and active laser drug delivery under the nail plate is possible at laser radiation intensity greater than 178 W/cm2. It is shown that the maximum rate and efficiency of nail plate ablation by 450 nm laser radiation is achieved at an intensity of 200 W/cm2 and is 2750 ± 30 μm/s and 1.47 ± 0.05 μm/mJ, respectively. The delivery rate of Chloderm under the nail plate is 1.15 ± 0.1 mg/s. It is shown that exposure to 450 nm laser radiation at the intensity of 200 W/cm2 for a time sufficient to deliver the drug under the nail plate does not change the extinction coefficient of the drug at the laser wavelength and slightly changes the conformational state of Chloderm.