Search Results (16)

In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months. Full article

Systemically administered chemotherapy reduces the efficiency of the anticancer agent at the target tumor tissue and results in distributed drug to non-target organs, inducing negative side effects commonly associated with chemotherapy and necessitating repeated administration. Injectable hydrogels present themselves as a potential platform for non-invasive local delivery vehicles that can serve as a slow-releasing drug depot that fills tumor vasculature, tissue, or resection cavities. Herein, we have systematically formulated and tested an injectable shear-thinning hydrogel (STH) with a highly manipulable release profile for delivering doxorubicin, a common chemotherapeutic. By detailed characterization of the STH physical properties and degradation and release dynamics, we selected top candidates for testing in cancer models of increasing biomimicry. Two-dimensional cell culture, tumor-on-a-chip, and small animal models were used to demonstrate the high anticancer potential and reduced systemic toxicity of the STH that exhibits long-term (up to 80 days) doxorubicin release profiles for treatment of breast cancer and glioblastoma. The drug-loaded STH injected into tumor tissue was shown to increase overall survival in breast tumor- and glioblastoma-bearing animal models by 50% for 22 days and 25% for 52 days, respectively, showing high potential for localized, less frequent treatment of oncologic disease with reduced dosage requirements. Full article

Thermosensitive gels based on copolymers (PEG–chitosan, chitosan–polyethylenimine, chitosan–arginine and glycol–chitosan–spermine) are presented as promising polycations for the formation of DNA polyplexes and the potential for the development of drugs with prolonged release (up to 30 days). Being in liquid form at room temperature, such compounds can be injected into muscle tissue with rapid gel formation at human body temperature. An intramuscular depot is formed with a therapeutic agent that provides a gradual release of the drug, such as an antibacterial or cytostatic. The physico-chemical parameters of the formation of polyplexes between polycationic polymers of various compositions and molecular architecture and DNA were studied via FTIR, UV-vis and fluorescence spectroscopy using the dyes rhodamine 6G (R6G) and acridine orange (AO). The competitive displacement of AO from AO-DNA complexes showed that, with a ratio of N/P = 1, most of the DNA is bound to a polycation. During the formation of polyplexes, the DNA charge is neutralized by a polycation, which is reflected in electrophoretic immobility. The cationic polymers described in this work at a concentration of 1–4% are capable of forming gels, and the thermoreversible property is most characteristic of pegylated chitosan. BSA, as a model anionic molecule, is released by half in 5 days from the Chit5-PEG5 gel; full release is achieved in 18–20 days. At the same time, in 5 days, the gel is destroyed up to 30%, and in 20 days, by 90% (release of chitosan particles). For the first time, flow cytometry was used to study DNA polyplexes, which showed the existence of fluorescent particles in a much larger number in combination with free DNA. Thus, functional stimulus-sensitive polymers are potentially applicable for the creation of prolonged therapeutic formulations for gene delivery systems, which were obtained. The revealed regularities appear to be a platform for the design of polyplexes with controllable stability, in particular, fulfilling the requirements imposed for gene delivery vehicles. Full article

A drawback in the development of treatments that can reach the retina is the presence of barriers in the eye that restrain compounds from reaching the target. Intravitreal injections hold promise for retinal delivery, but the natural defenses in the vitreous can rapidly degrade or eliminate therapeutic molecules. Injectable hydrogel implants, which act as a reservoir, can allow for long-term drug delivery with a single injection into the eye, but still suffer due to the fast clearance of the released drugs when traversing the vitreous and random diffusion that leads to lower pharmaceutic efficacy. A combination with HA-covered nanoparticles, which can be released from the gel and more readily pass through the vitreous to increase the delivery of therapeutic agents to the retina, represents an advanced and elegant way to overcome some of the limitations in eye drug delivery. In this article, we developed hybrid PLGA-Dotap NPs that, due to their hyaluronic acid coating, can improve in vivo distribution throughout the vitreous and delivery to retinal cells. Moreover, a hydrogel implant was developed to act as a depot for the hybrid NPs to better control and slow their release. These results are a first step to improve the treatment of retinal diseases by protecting and transporting the therapeutic treatment across the vitreous and to improve treatment options by creating a depot system for long-term treatments. Full article

Glioblastoma (GBM) recurrence after surgical excision has grown to be a formidable obstacle to conquer. In this research, biodegradable thermosensitive triblock copolymer, poly(D, L–lactic acid–co–glycolic acid)–b–poly(ethylene glycol)–b–poly(D, L–lactic acid–co–glycolic acid (PLGA–PEG–PLGA) was utilized as the drug delivery system, loading with micronized temozolomide(micro-TMZ) to form an in situ drug–gel depot inside the resection cavity. The rheology studies revealed the viscoelastic profile of hydrogel under various conditions. To examine the molecular characteristics that affect gelation temperature, ¹H–NMR, inverse gated decoupling ¹³C–NMR, and GPC were utilized. Cryo-SEM and XRD were intended to disclose the appearance of the hydrogel and the micro-TMZ existence state. We worked out how to blend polymers to modify the gelation point (T_gel) and fit the correlation between T_gel and other dependent variables using linear regression. To simulate hydrogel dissolution in cerebrospinal fluid, a membraneless dissolution approach was used. In vitro, micro-TMZ@PLGA–PEG–PLGA hydrogel exhibited Korsmeyer–Peppas and zero–order release kinetics in response to varying drug loading, and in vivo, it suppressed GBM recurrence at an astoundingly high rate. Micro-TMZ@PLGA–PEG–PLGA demonstrates a safer and more effective form of chemotherapy than intraperitoneal TMZ injection, resulting in a spectacular survival rate (40%, n = 10) that is much more than intraperitoneal TMZ injection (22%, n = 9). By proving the viability and efficacy of micro-TMZ@PLGA–PEG–PLGA hydrogel, our research established a novel chemotherapeutic strategy for treating GBM recurrence. Full article

Tacrolimus (FK506) is a common immunosuppressive drug that is capable of suppressing acute rejection reactions, and is used to treat patients after allotransplantation. A stable and suitable serum concentration of tacrolimus is desirable for better therapeutic effects. However, daily drug administration via oral or injection routes is quite inconvenient and may encounter drug overdose or low patient compliance problems. In this research, our objective was to develop an extended delivery system using a thermosensitive hydrogel of poly ethylene glycol, D,L-lactide (L), and ϵ-caprolactone (CL) block copolymer, mPEG-PLCL, as a drug depot. The formulation of mPEG-PLCL and 0.5% PVP-dissolved tacrolimus was studied and the optimal formulation was obtained. The in vivo data showed that in situ gelling is achieved, a stable and sustained release of the drug within 30 days can be maintained, and the hydrogel was majorly degraded in that period. Moreover, improved allograft survival was achieved. Together, these data imply the potential of the current formulation for immunosuppressive treatments. Full article

Peptide-based drug delivery systems have many advantages when compared to synthetic systems in that they have better biocompatibility, biochemical and biophysical properties, lack of toxicity, controlled molecular weight via solid phase synthesis and purification. Lysosomes, solid lipid nanoparticles, dendrimers, polymeric micelles can be applied by intravenous administration, however they are of artificial nature and thus may induce side effects and possess lack of ability to penetrate the blood-brain barrier. An analysis of nontoxic drug delivery systems and an establishment of prospective trends in the development of drug delivery systems was needed. This review paper summarizes data, mainly from the past 5 years, devoted to the use of peptide-based carriers for delivery of various toxic drugs, mostly anticancer or drugs with limiting bioavailability. Peptide-based drug delivery platforms are utilized as peptide–drug conjugates, injectable biodegradable particles and depots for delivering small molecule pharmaceutical substances (500 Da) and therapeutic proteins. Controlled drug delivery systems that can effectively deliver anticancer and peptide-based drugs leading to accelerated recovery without significant side effects are discussed. Moreover, cell penetrating peptides and their molecular mechanisms as targeting peptides, as well as stimuli responsive (enzyme-responsive and pH-responsive) peptides and peptide-based self-assembly scaffolds are also reviewed. Full article

Hydrogels based on poly(caprolactone)–b-poly(ethylene glycol)–b-poly(caprolactone) (PCL–PEG–PCL) have been evaluated extensively as potential injectable fillers or depots for controlled release of drugs. Common drawbacks of these copolymer systems include instability of aqueous solutions and low mechanical strength of gels, issues which are commonly overcome by adding pendant groups to the end of the copolymer chains. Here, a systematic study of the effects of increasing polymer molecular weight (MW) is presented, utilizing PEG blocks of MW 2, 4 or 8 kDa. Triblock copolymers were prepared by the ring-opening polymerization of Ɛ-caprolactone by PEG. Copolymers prepared with PEG MW 2 kDa did not form hydrogels at any copolymer molecular weight. Copolymers prepared with PEG MW 4 kDa formed gels at MW between 11 and 13.5 kDa, and copolymers prepared with PEG MW 8 kDa formed gels at MW between 16 and 18 kDa. Copolymers with PEG block 8 kDa formed hydrogels with high viscosity (17,000 Pa·s) and mechanical strength (G′ = 14,000 Pa). The increased gel strength afforded by increased molecular weight represents a simple modification of the reactants used in the reaction feed without added synthetic or purification steps. Shear-thinning of PCL-PEG-PCL triblock copolymer hydrogels allowed for injection through a standard 23G syringe, allowing for potential use as dermal fillers or drug delivery depots. Full article

In this study, we aimed to develop a multifunctional drug/gene delivery system for the treatment of glioblastoma multiforme by combining the ligand-mediated active targeting and the pH-triggered drug release features of graphene oxide (GO). Toward this end, we load irinotecan (CPT-11) to cetuximab (CET)-conjugated GO (GO-CET/CPT11) for pH-responsive drug release after endocytosis by epidermal growth factor receptor (EGFR) over-expressed U87 human glioblastoma cells. The ultimate injectable drug/gene delivery system was designed by co-entrapping stomatin-like protein 2 (SLP2) short hairpin RNA (shRNA) and GO-CET/CPT11 in thermosensitive chitosan-g-poly(N-isopropylacrylamide) (CPN) polymer solution, which offers a hydrogel depot for localized, sustained delivery of the therapeutics after the in situ formation of CPN@GO-CET/CPT11@shRNA hydrogel. An optimal drug formulation was achieved by considering both the loading efficiency and loading content of CPT-11 on GO-CET. A sustained and controlled release behavior was found for CPT-11 and shRNA from CPN hydrogel. Confocal microscopy analysis confirmed the intracellular trafficking for the targeted delivery of CPT-11 through interactions of CET with EGFR on the U87 cell surface. The efficient transfection of U87 using SLP2 shRNA was achieved using CPN as a delivery milieu, possibly by the formation of shRNA/CPN polyplex after hydrogel degradation. In vitro cell culture experiments confirmed cell apoptosis induced by CPT-11 released from acid organelles in the cytoplasm by flow cytometry, as well as reduced SLP2 protein expression and inhibited cell migration due to gene silencing. Finally, in vivo therapeutic efficacy was demonstrated using the xenograft of U87 tumor-bearing nude mice through non-invasive intratumoral delivery of CPN@GO-CET/CPT11@shRNA by injection. Overall, we have demonstrated the novelty of this thermosensitive hydrogel to be an excellent depot for the co-delivery of anticancer drugs and siRNA. The in situ forming hydrogel will not only provide extended drug release but also combine the advantages offered by the chitosan-based copolymer structure for siRNA delivery to broaden treatment modalities in cancer therapy. Full article

The remarkable number of new molecular entities approved per year as parenteral drugs, such as biologics and complex active pharmaceutical ingredients, calls for innovative and tunable drug delivery systems. Besides making these classes of drugs available in the body, injectable depot formulations offer the unique advantage in the parenteral world of reducing the number of required injections, thus increasing effectiveness as well as patient compliance. To date, a plethora of excipients has been proposed to formulate depot systems, and among those, lipids stand out due to their unique biocompatibility properties and safety profile. Looking at the several long-acting drug delivery systems based on lipids designed so far, a legitimate question may arise: How far away are we from an ideal depot formulation? Here, we review sustained release lipid-based platforms developed in the last 5 years, namely oil-based solutions, liposomal systems, in situ forming systems, solid particles, and implants, and we critically discuss the requirements for an ideal depot formulation with respect to the used excipients, biocompatibility, and the challenges presented by the manufacturing process. Finally, we delve into lights and shadows originating from the current setups of in vitro release assays developed with the aim of assessing the translational potential of depot injectables. Full article

Tacrolimus is an immunosuppressive agent for acute rejection after allotransplantation. However, the low aqueous solubility of tacrolimus poses difficulties in formulating an injection dosage. Polypeptide thermosensitive hydrogels can maintain a sustained release depot to deliver tacrolimus. The copolymers, which consist of poloxamer and poly(l-alanine) with l-lysine segments at both ends (P–Lys–Ala–PLX), are able to carry tacrolimus in an in situ gelled form with acceptable biocompatibility, biodegradability, and low gelling concentrations from 3 to 7 wt %. By adding Pluronic F-127 to formulate a mixed hydrogel system, the drug release rate can be adjusted to maintain suitable drug levels in animals with transplants. Under this formulation, the in vitro release of tacrolimus was stable for more than 100 days, while in vivo release of tacrolimus in mouse model showed that rejection from skin allotransplantation was prevented for at least three weeks with one single administration. Using these mixed hydrogel systems for sustaining delivery of tacrolimus demonstrates advancement in immunosuppressive therapy. Full article

Controlled delivery of gene transfer vectors is a powerful strategy to enhance the temporal and spatial presentation of therapeutic agents in a defined target. Hydrogels are adapted biomaterials for gene delivery capable of acting as a localized depot of genes while maintaining the long term local availability of DNA vectors at a specific location. Supramolecular hydrogels based on cyclodextrins (CDs) have attracted considerable attention as potential biomaterials in a broad range of drug delivery applications. Their unique characteristics of thixotropicity and low cytotoxicity due to their production under mild conditions make them potential candidates to form injectable delivery systems. This work aims to provide an overview of the use of CD-based polypseudorotaxane hydrogels as controlled gene delivery systems for different applications in regenerative medicine. Full article

In this study, we prepared an injectable drug delivery depot system based on a visible light-cured glycol chitosan (GC) hydrogel containing paclitaxel (PTX)-complexed beta-cyclodextrin (β-CD) (GC/CD/PTX) for ovarian cancer (OC) therapy using a tumor-bearing mouse model. The hydrogel depot system had a 23.8 Pa of storage modulus at 100 rad/s after visible light irradiation for 10 s. In addition, GC was swollen as a function of time. However, GC had no degradation with the time change. Eventually, the swollen GC matrix affected the releases of PTX and CD/PTX. GC/PTX and GC/CD/PTX exhibited a controlled release of PTX for 7 days. In addition, GC/CD/PTX had a rapid PTX release for 7 days due to improved water solubility of PTX through CD/PTX complex. In vitro cell viability tests showed that GC/CD/PTX had a lower cell viability percentage than the free PTX solution and GC/PTX. Additionally, GC/CD/PTX resulted in a superior antitumor effect against OC. Consequently, we suggest that the GC/CD system might have clinical potential for OC therapy by improving the water solubility of PTX, as PTX is included into the cavity of β-CD. Full article

Ordered mesoporous silica (OMS) is a very interesting nanostructured material for the design and engineering of new target and controlled drug-delivery systems. Particularly relevant is the interaction between OMS and proteins. Large pores (6–9 nm) micrometric particles can be used for the realization of a drug depot system where therapeutic proteins are adsorbed either inside the mesopores or on the external surface. Small pores (1–2 nm) mesoporous silica nanoparticles (MSNs), can be injected in the blood stream. In the latter case, therapeutic proteins are mainly adsorbed on the MSNs’ external surface. Whenever a protein-OMS conjugate is prepared, a diagnostic method to locate the protein either on the internal or the external silica surface is of utmost importance. To visualize the fine localization of proteins adsorbed in mesoporous silica micro- and nanoparticles, we have employed specific transmission electron microscopy (TEM) analytical strategies based on the use of gold nanoparticles (GNPs) conjugates. GNPs are gaining in popularity, representing a fundamental tool to design future applications of MSNs in nanomedicine by realizing theranostic nanobioconjugates. It may be pointed out that we are at the very beginning of a new age of the nanomaterial science: the “mesoporous golden age”. Full article

Biodegradable polymer-based injectable in situ forming depot (ISD) systems that solidify in the body to form a solid or semisolid reservoir are becoming increasingly attractive as an injectable dosage form for sustained (months to years) parenteral drug delivery. Evaluation of long-term drug release from the ISD systems during the formulation development is laborious and costly. An accelerated release method that can effectively correlate the months to years of long-term release in a short time such as days or weeks is economically needed. However, no such accelerated ISD system release method has been reported in the literature to date. The objective of the current study was to develop a short-term accelerated in vitro release method for contraceptive levonorgestrel (LNG)-containing ISD systems to screen formulations for more than 3-month contraception after a single subcutaneous injection. The LNG-containing ISD formulations were prepared by using biodegradable poly(lactide-co-glycolide) and polylactic acid polymer and solvent mixtures containing N-methyl-2-pyrrolidone and benzyl benzoate or triethyl citrate. Drug release studies were performed under real-time (long-term) conditions (PBS, pH 7.4, 37 °C) and four accelerated (short-term) conditions: (A) PBS, pH 7.4, 50 °C; (B) 25% ethanol in PBS, pH 7.4, 50 °C; (C) 25% ethanol in PBS, 2% Tween 20, pH 7.4, 50 °C; and (D) 25% ethanol in PBS, 2% Tween 20, pH 9, 50 °C. The LNG release profile, including the release mechanism under the accelerated condition D within two weeks, correlated (r² ≥ 0.98) well with that under real-time conditions at four months. Full article