A Tumor Microenvironments‐Adapted Polypeptide Hydrogel/Nanogel Composite Boosts Antitumor Molecularly Targeted Inhibition and Immunoactivation (Adv. Mater. 21/2022)

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

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.

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

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

Currently, multidrug combinations are often used clinically to improve the efficacy of oncology chemotherapy, but multidrug combinations often lead to multidrug resistance and decreased performance, resulting in more severe side effects than monotherapy. Therefore, sequential drug release strategies in time and space as well as nanocarriers that respond to the tumor microenvironment have been developed. First, the advantage of the sequential release strategy is that it can load multiple drugs simultaneously to meet their spatiotemporal requirements and stability, thus exerting synergistic effects of two or more drugs. Second, in some cases, sequential drug delivery of different molecular targets can improve the sensitivity of cancer cells to drugs, control the metabolism of cancer cells, and remodel tumor vasculature. Finally, some drug combinations with built-in release control are used for sequential administration. This paper focuses on the use of nanotechnology and built-in control device to construct drug delivery carriers with different stimulation responses, thus achieving the sequential release of drugs. Therefore, the nano-sequential delivery carrier provides a new idea and platform for the therapeutic effect of various drugs and the synergistic effect among the drugs.

Currently, multidrug combinations are often used clinically to improve the efficacy of oncology chemotherapy, but multidrug combinations often lead to multidrug resistance and decreased performance, resulting in more severe side effects than monotherapy. Therefore, sequential drug release strategies in time and space as well as nano-carriers that respond to the tumor microenvironment have been developed. First, the advantage of the sequential release strategy is that they can load multiple drugs simultaneously to meet their spatiotemporal requirements and stability, thus exerting synergistic effects of two or more drugs. Second, in some cases, sequential drug delivery of different molecular targets can improve the sensitivity of cancer cells to drugs. Control the metabolism of cancer cells, and remodel tumor vasculature. Finally, some drug combinations with built-in release control are used for sequential administration. This paper focuses on the use of nanotechnology and built-in control device to construct drug delivery carriers with different stimulation responses, thus achieving the sequential release of drugs. Therefore, the nano-sequential delivery carrier provides a new idea and platform for the therapeutic effect of various drugs and the synergistic effect among drugs.

The dense extracellular matrix (ECM) of stroma-rich solid tumors acts as a significant barrier to effective chemotherapy by hindering drug penetration. In this study, a supramolecular hydrogel was successfully developed, enabling the codelivery and sequential release of hydrophilic and lipophilic drugs designed to target the ECM. The hydrogel is easy to prepare, has self-healing properties and excellent biocompatibility. Upon administration, the hydrogel first releases pirfenidone to inhibit collagen production, weakening the ECM, followed by the release of paclitaxel, which improves tumor penetration. The effectiveness of this sequential drug delivery system was validated in both oral squamous cell carcinoma and pancreatic cancer models, a classic example of a tumor with abundant ECM. In vitro experiments showed controlled sequential release profiles, whereas in vivo experiments using cell-derived and patient-derived xenograft models revealed that the hydrogel was more effective at tumor suppression compared to traditional methods. Single administration of the hydrogel led to long-term localized drug release, maintaining higher concentrations of chemotherapeutic agents in the tumor tissue and effectively reducing the tumor volume. This study provided a promising strategy to enhance chemotherapy in ECM-dense tumors, offering an efficient and minimally invasive method for localized, sustained-release cancer therapy.

Sequential drug delivery for liver diseases.

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.

Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs

Thermo-sensitive hydrogel-mediated locally sequential release of doxorubicin and palbociclib for chemo-immunotherapy of osteosarcoma

A sequential release of biological cues is of high interest in tissue engineering applications, as both the proliferation and the differentiation of stem cells can be drugged. In previous studies we have shown that particulate films of mesoporous silica particles can be successfully applied for influencing stem cell fates through intracellular drug delivery after particle internalisation by the cells. In this study, we develop this concept towards an enhanced control of the particle uptake kinetics through either adsorption or covalent linking of the mesoporous silica particles to the substrate. Microscopy glass slides were initially functionalized by an aminosilane to which a thin layer of hyaluronic acid was covalently attached through an amide bond. A sub-monolayer of amino-functionalized mesoporous silica nanoparticles with a diameter of 400 nm were then adsorbed to the hyaluronic acid-functionalized surface by adsorption under high-shear conditions. Subsequently, the adsorbed particles were covalently linked to the hyaluronic acid through an amide bond. Corresponding films without the covalent coupling step were used as the control. Muscle stem cells attach and proliferate nicely on all films, and do internalize particles in all cases. However, the kinetics of particle internalization was clearly delayed for the covalently attached particles in comparison to physisorbed particles. Thus, the results imply that tuning of the particle-substrate interactions through linking chemistries is a promising means of achieving sequential particle-mediated drug release from films and that corresponding chemistries should also be applicable for 3D scaffold systems.

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.

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.

Combination chemotherapy has become the primary strategy against cancer multidrug resistance; however, accomplishing optimal pharmacokinetic delivery of multiple drugs is still challenging. Herein, we report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. In acidic tumour environments, the positive charge generated by the protonation of the diisopropylamine moiety facilitated the cellular uptake of the particles. Upon internalization, the acidic endosomal pH condition and intracellular glutathione regulated the sequential release of the drugs in a time-dependent manner, providing a promising therapeutic approach to overcoming drug resistance during cancer treatment.