How Biodegradable Polymers Can be Effective Drug Delivery Systems for Cannabinoids? Prospectives and Challenges.

Cannabinoids are compounds found in and derived from the Cannabis plants that have become increasingly recognised as significant modulating factors of physiological mechanisms and inflammatory reactions of the organism, thus inevitably affecting maintenance of homeostasis. Medical Cannabis popularity has surged since its legal regulation growing around the world. Numerous promising discoveries bring more data on cannabinoids' pharmacological characteristics and therapeutic applications. Given the current surge in interest in the medical use of cannabinoids, there is an urgent need for an effective method of their administration. Surpassing low bioavailability, low water solubility, and instability became an important milestone in the advancement of cannabinoids in pharmaceutical applications. The numerous uses of cannabinoids in clinical practice remain restricted by limited administration alternatives, but there is hope when biodegradable polymers are taken into account. The primary objective of this review is to highlight the wide range of indications for which cannabinoids may be used, as well as the polymeric carriers that enhance their effectiveness. The current review described a wide range of therapeutic applications of cannabinoids, including pain management, neurological and sleep disorders, anxiety, and cancer treatment. The use of these compounds was further examined in the area of dermatology and cosmetology. Finally, with the use of biodegradable polymer-based drug delivery systems (DDSs), it was demonstrated that cannabinoids can be delivered specifically to the intended site while also improving the drug's physicochemical properties, emphasizing their utility. Nevertheless, additional clinical trials on novel cannabinoids' formulations are required, as their full spectrum therapeutical potential is yet to be unravelled.

Self-Immolative Domino Dendrimers as Anticancer-Drug Delivery Systems: A Review.

Worldwide cancer statistics have indicated about 20 million new cancer cases and over 10 million deaths in 2022 (according to data from the International Agency for Research on Cancer). One of the leading cancer treatment strategies is chemotherapy, using innovative drug delivery systems (DDSs). Self-immolative domino dendrimers (SIDendr) for triggered anti-cancer drugs appear to be a promising type of DDSs. The present review provides an up-to-date survey on the contemporary advancements in the field of SIDendr-based anti-cancer drug delivery systems (SIDendr-ac-DDSs) through an exhaustive analysis of the discovery and application of these materials in improving the pharmacological effectiveness of both novel and old drugs. In addition, this article discusses the designing, chemical structure, and targeting techniques, as well as the properties, of several SIDendr-based DDSs. Approaches for this type of targeted DDSs for anti-cancer drug release under a range of stimuli are also explored.

Xanthohumol-A Miracle Molecule with Biological Activities: A Review of Biodegradable Polymeric Carriers and Naturally Derived Compounds for Its Delivery.

Xanthohumol (Xn), a prenylated chalcone found in Hop (Humulus lupulus L.), has been shown to have potent anti-aging, diabetes, inflammation, microbial infection, and cancer properties. Unfortunately, this molecule has undesirable characteristics such as inadequate intake, low aqueous solubility, and a short half-life. To address these drawbacks, researchers have made numerous attempts to improve its absorption, solubility, and bioavailability. Polymeric drug delivery systems (PDDSs) have experienced significant development over the last two decades. Polymeric drug delivery is defined as a formulation or device that allows the introduction of a therapeutic substance into the body. Biodegradable and bioreducible polymers are the ideal choice for a variety of new DDSs. Xn formulations based on biodegradable polymers and naturally derived compounds could solve some of the major drawbacks of Xn-based drug delivery. In this regard, the primary concern of this study is on presenting innovative formulations for Xn delivery, such as nanoparticles (NPs), nanomicelles, nanoliposomes, solid lipid nanoparticles (SLNs), and others, as well as the received in vitro and in vivo data. Furthermore, this work describes the chemistry and broad biological activity of Xn, which is particularly useful in modern drug technology as well as the cosmetics industry. It is also important to point out that the safety of using Xn, and its biotransformation, pharmacokinetics, and clinical applications, have been thoroughly explained in this review.

Dual-Stimuli-Sensitive Smart Hydrogels Containing Magnetic Nanoparticles as Antitumor Local Drug Delivery Systems-Synthesis and Characterization.

The aim of this study was to develop an innovative, dual-stimuli-responsive smart hydrogel local drug delivery system (LDDS), potentially useful as an injectable simultaneous chemotherapy and magnetic hyperthermia (MHT) antitumor treatment device. The hydrogels were based on a biocompatible and biodegradable poly(ε-caprolactone-co-rac-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-rac-lactide) (PCLA-PEG-PCLA, PCLA) triblock copolymer, synthesized via ring-opening polymerization (ROP) in the presence of a zirconium(IV) acetylacetonate (Zr(acac)4) catalyst. The PCLA copolymers were successfully synthesized and characterized using NMR and GPC techniques. Furthermore, the gel-forming and rheological properties of the resulting hydrogels were thoroughly investigated, and the optimal synthesis conditions were determined. The coprecipitation method was applied to create magnetic iron oxide nanoparticles (MIONs) with a low diameter and a narrow size distribution. The magnetic properties of the MIONs were close to superparamagnetic upon TEM, DLS, and VSM analysis. The particle suspension placed in an alternating magnetic field (AMF) of the appropriate parameters showed a rapid increase in temperature to the values desired for hyperthermia. The MIONs/hydrogel matrices were evaluated for paclitaxel (PTX) release in vitro. The release was prolonged and well controlled, displaying close to zero-order kinetics; the drug release mechanism was found to be anomalous. Furthermore, it was found that the simulated hyperthermia conditions had no effect on the release kinetics. As a result, the synthesized smart hydrogels were discovered to be a promising antitumor LDDS, allowing simultaneous chemotherapy and hyperthermia treatment.

Poly(amidoamine) Dendrimer/Camptothecin Complex: From Synthesis to In Vitro Cancer Cell Line Studies.

Camptothecin (CPT), an alkaloid with potent anticancer activity, is still not used in clinical practice due to its high hydrophobicity, toxicity, and poor active-form stability. To address these shortcomings, our research focuses on the encapsulation of this drug in the poly(amidoamine) (PAMAM) dendrimer macromolecule. The PAMAM dendrimer/CPT complex was synthesized and thoroughly characterized. The in vitro drug release study revealed that the drug was released in a slow and controlled manner in acidic and physiological conditions and that more than 80% of the drug was released after 168 h of incubation. Furthermore, it was demonstrated that CPT was released with first-order kinetics and non-Fickian transport. The studies on the hemolytic activity of the synthesized complex indicated that it is hemocompatible for potential intravenous administration at a concentration ≤ 5 µg/mL. Additionally, the developed product was shown to reduce the viability of non-small-cell lung cancer cells (A549) in a concentration- and time-dependent manner, and cancer cells were more susceptible to the complex than normal fibroblasts. Lastly, molecular modeling studies revealed that the lactone or carboxylic forms of CPT had a significant impact on the shape and stability of the complex and that its formation with the lactone form of CPT was more energetically favorable for each subsequent molecule than the carboxylic form. The report represents a systematic and structured approach to develop a PAMAM dendrimer/CPT complex that can be used as an effective drug delivery system (DDS) for the potential treatment of non-small-cell lung cancer.

The Advancement of Biodegradable Polyesters as Delivery Systems for Camptothecin and Its Analogues-A Status Report.

Camptothecin (CPT) has demonstrated antitumor activity in lung, ovarian, breast, pancreas, and stomach cancers. However, this drug, like many other potent anticancer agents, is extremely water-insoluble. Furthermore, pharmacology studies have revealed that prolonged schedules must be administered continuously. For these reasons, several of its water-soluble analogues, prodrugs, and macromolecular conjugates have been synthesized, and various formulation approaches have been investigated. Biodegradable polyesters have gained popularity in cancer treatment in recent years. A number of biodegradable polymeric drug delivery systems (DDSs), designed for localized and systemic administration of therapeutic agents, as well as tumor-targeting macromolecules, have entered clinical trials, demonstrating the importance of biodegradable polyesters in cancer therapy. Biodegradable polyester-based DDSs have the potential to deliver the payload to the target while also increasing drug availability at intended site. The systemic toxicity and serious side-effects associated with conventional cancer therapies can be significantly reduced with targeted polymeric systems. This review elaborates on the use of biodegradable polyesters in the delivery of CPT and its analogues. The design of various DDSs based on biodegradable polyesters has been described, with the drug either adsorbed on the polymer's surface or encapsulated within its macrostructure, as well as those in which a hydrolyzed chemical bond is formed between the active substance and the polymer chain. The data related to the type of DDSs, the kind of linkage, and the details of in vitro and in vivo studies are included.

Development and Comprehensive Characteristics of Thermosensitive Liquid Suppositories of Metoprolol Based on Poly(lactide-co-glycolide) Nanoparticles.

Thermosensitive liquid suppositories (LSs) carrying the model antihypertensive drug metoprolol tartrate (MT) were developed and evaluated. The fundamental purpose of this work was to produce, for the first time, liquid MT suppositories based on biodegradable nanoparticles and optimize their rheological and mechanical properties for prospective rectal administration. The nanoparticle system was based on a biodegradable copolymer synthesized by ring opening polymerization (ROP) of glycolide (GL) and L,L-lactide (LLA). Biodegradable nanoparticles loaded with the model drug were produced by the o/o method at the first stage of the investigation. Depending on the concentration of the drug in the sample, from 66 to 91% of MT was released over 12 h, according to first-order kinetics. Then, thermosensitive LSs with MT-loaded biodegradable nanoparticles were obtained by a cold method and their mechanical and rheological properties were evaluated. To adjust the thermogelling and mucoadhesive properties for rectal administration, the amounts of major formulation components such as poloxamers (P407, P188), Tween 80, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), and sodium alginate were optimized. The in vitro release results revealed that more than 80% of the MT was released after 12 h, following also first-order kinetics. It was discovered that the diffusion process was dominant. The drug release profile was mainly governed by the rheological and mechanical properties of the developed formulation. Such a novel, thermosensitive formulation might be an effective alternative to hypertension treatment, particularly for unconscious patients, patients with mental illnesses, geriatric patients, and children.

A Comprehensive Investigation of the Structural, Thermal, and Biological Properties of Fully Randomized Biomedical Polyesters Synthesized with a Nontoxic Bismuth(III) Catalyst.

Aliphatic polyesters are the most common type of biodegradable synthetic polymer used in many pharmaceutical applications nowadays. This report describes the ring-opening polymerization (ROP) of l-lactide (L-LA), ε-caprolactone (CL) and glycolide (Gly) in the presence of a simple, inexpensive and convenient PEG200-BiOct3 catalytic system. The chemical structures of the obtained copolymers were characterized by 1H- or 13C-NMR. GPC was used to estimate the average molecular weight of the resulting polyesters, whereas TGA and DSC were employed to determine the thermal properties of polymeric products. The effects of temperature, reaction time, and catalyst content on the polymerization process were investigated. Importantly, the obtained polyesters were not cyto- or genotoxic, which is significant in terms of the potential for medical applications (e.g., for drug delivery systems). As a result of transesterification, the copolymers obtained had a random distribution of comonomer units along the polymer chain. The thermal analysis indicated an amorphous nature of poly(l-lactide-co-ε-caprolactone) (PLACL) and a low degree of crystallinity of poly(ε-caprolactone-co-glycolide) (PCLGA, Xc = 15.1%), in accordance with the microstructures with random distributions and short sequences of comonomer units (l = 1.02-2.82). Significant differences in reactivity were observed among comonomers, confirming preferential ring opening of L-LA during the copolymerization process.

Synthesis and Characterization of New Biodegradable Injectable Thermosensitive Smart Hydrogels for 5-Fluorouracil Delivery.

In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)4), as co-initiator and catalyst, respectively. The structure, molecular weight (Mn) and molecular weight distribution (D) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol-gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer-Peppas mathematical models. The obtained results indicate good release control; the kinetics were generally defined as first order according to the predominant diffusion mechanism; and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic; the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy.

Achievements in Thermosensitive Gelling Systems for Rectal Administration.

Rectal drug delivery is an effective alternative to oral and parenteral treatments. This route allows for both local and systemic drug therapy. Traditional rectal dosage formulations have historically been used for localised treatments, including laxatives, hemorrhoid therapy and antipyretics. However, this form of drug dosage often feels alien and uncomfortable to a patient, encouraging refusal. The limitations of conventional solid suppositories can be overcome by creating a thermosensitive liquid suppository. Unfortunately, there are currently only a few studies describing their use in therapy. However, recent trends indicate an increase in the development of this modern therapeutic system. This review introduces a novel rectal drug delivery system with the goal of summarising recent developments in thermosensitive liquid suppositories for analgesic, anticancer, antiemetic, antihypertensive, psychiatric, antiallergic, anaesthetic, antimalarial drugs and insulin. The report also presents the impact of various types of components and their concentration on the properties of this rectal dosage form. Further research into such formulations is certainly needed in order to meet the high demand for modern, efficient rectal gelling systems. Continued research and development in this field would undoubtedly further reveal the hidden potential of rectal drug delivery systems.

Poly(chitosan-ester-ether-urethane) Hydrogels as Highly Controlled Genistein Release Systems.

Polymeric hydrogels play an increasingly important role in medicine, pharmacy and cosmetology. They appear to be one of the most promising groups of biomaterials due to their favorable physicochemical properties and biocompatibility. The objective of the presented study was to synthesize new poly(chitosan-ester-ether-urethane) hydrogels and to study the kinetic release of genistein (GEN) from these biomaterials. In view of the above, six non-toxic hydrogels were synthesized via the Ring-Opening Polymerization (ROP) and polyaddition processes. The poly(ester-ether) components of the hydrogels have been produced in the presence of the enzyme as a biocatalyst. In some cases, the in vitro release rate of GEN from the obtained hydrogels was characterized by near-zero-order kinetics, without "burst release" and with non-Fickian transport. It is important to note that developed hydrogels have been shown to possess the desired safety profile due to lack of cytotoxicity to skin cells (keratinocytes and fibroblasts). Taking into account the non-toxicity of hydrogels and the relatively highly controlled release profile of GEN, these results may provide fresh insight into polymeric hydrogels as an effective dermatological and/or cosmetological tool.

Hydrogels Based on Poly(Ether-Ester)s as Highly Controlled 5-Fluorouracil Delivery Systems-Synthesis and Characterization.

A novel and promising hydrogel drug delivery system (DDS) capable of releasing 5­fluorouracil (5-FU) in a prolonged and controlled manner was obtained using ε­caprolactone­poly(ethylene glycol) (CL-PEG) or rac­lactide-poly(ethylene glycol) (rac­LA-PEG) copolymers. Copolymers were synthesized via the ring-opening polymerization (ROP) process of cyclic monomers, ε­caprolactone (CL) or rac-lactide (rac-LA), in the presence of zirconium(IV) octoate (Zr(Oct)4) and poly(ethylene glycol) 200 (PEG 200) as catalyst and initiator, respectively. Obtained triblock copolymers were characterized by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques; the structure and tacticity of the macromolecules were determined. The relationship between the copolymer structure and the reaction conditions was evaluated. The optimal conditions were specified as 140 °C and 24 h. In the next step, CL-PEG and rac-LA-PEG copolymers were chemically crosslinked using hexamethylene diisocyanate (HDI). Selected hydrogels were subjected to in vitro antitumor drug release studies, and the release data were analyzed using zero-order, first-order, and Korsmeyer-Peppas mathematical models. Controlled and prolonged (up to 432 h) 5-FU release profiles were observed for all examined hydrogels with first-order or zero-order kinetics. The drug release mechanism was generally denoted as non-Fickian transport.

Sterilization process of polyester based anticancer-drug delivery systems.

Recently, growing interest in biodegradable polyesters as drug carriers in the development of innovative anticancer drug delivery systems (DDSs) has been observed. These compounds are thermally unstable, and are therefore, particularly demanding due to the limited number of available sterilization techniques. Furthermore, the DDSs sterilization process is often limited to aseptic filtration. Ensuring aseptic production is very demanding and costly, and it is therefore necessary to work on the application of new sterilization methods. In view of this, this review presents the current state of knowledge regarding the radiation sterilization process of some anticancer drugs as well biodegradable polyester carriers (such as polylactide, polyglycolide, poly(ε-caprolactone), poly(trimethylene carbonate) and co- or terpolymers of lactide, glycolide, ε-caprolactone and trimethylene carbonate). The structural changes in anticancer DDSs under the influence of ionizing radiation and the potential degradation mechanisms of both, polyester carriers and cytostatics during the sterilization process of ionizing radiation as well as their effects on the microstructure and properties of DDSs have been discussed in this paper.

Smart Hydrogels - Synthetic Stimuli-Responsive Antitumor Drug Release Systems.

Among modern drug formulations, stimuli-responsive hydrogels also called "smart hydrogels" deserve a special attention. The basic feature of this system is the ability to change their mechanical properties, swelling ability, hydrophilicity, bioactive molecules permeability, etc., influenced by various stimuli, such as temperature, pH, electromagnetic radiation, magnetic field and biological factors. Therefore, stimuli-responsive matrices can be potentially used in tissue engineering, cell cultures and technology of innovative drug delivery systems (DDSs), releasing the active substances under the control of internal or external stimuli. Moreover, smart hydrogels can be used as injectable DDSs, due to gel-sol transition connected with in situ cross-linking process. Innovative smart hydrogel DDSs can be utilized as matrices for targeted therapy, which enhances the effectiveness of tumor chemotherapy and subsequently limits systemic toxicity. External stimulus sensitivity allows remote control over the drug release profile and gel formation. On the other hand, internal factors provide drg accumulation in tumor tissue and reduce the concentration of active drug form in healthy tissue. In this report, we summarise the basic knowledge and chemical strategies for the synthetic smart hydrogel DDSs applied in antitumor therapy.

Development and Evaluation of Matrices Composed of ß-cyclodextrin and Biodegradable Polyesters in the Controlled Delivery of Pindolol.

Polymer-drug conjugates are currently being more widely investigated for the treatment of hypertension. In view of the above, in the first stage of our work, we used nontoxic ß-cyclodextrin (ß-CD) as effective, simple, inexpensive, and safe for the human body initiator for the synthesis of biocompatible and biodegradable functionalized polymers suitable for the medical and pharmaceutical applications. The obtained polymeric products were synthesized through a ring-opening polymerization (ROP) of ε-caprolactone (CL), d,l-, and l,l- lactide (LA and LLA). The chemical structures of synthesized materials were elucidated based on 1H NMR and solid-state carbon-13 cross-polarization/magic angle spinning nuclear magnetic resonance (13C CP/MAS NMR) analysis, while the incorporation of ß-CD molecule into the polymer chain was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Furthermore, molecular modeling has been applied to investigate the intrachain rigidities and chain architectures for several representative structures. The obtained and thoroughly characterized branched matrices were then used to generate the first ß-cyclodextrin/biodegradable polymer/ß-blocker conjugate through the successful conjugation of pindolol. The conjugates were fabricated by carbodiimide-mediated coupling reaction. The branched biodegradable materials released the drug in vitro in a sustained manner and without "burst release" and thus have the ability to treat different heart diseases.

Overview of the latest developments in the field of drug-eluting stent technology.

Angioplasty with stent implantation is considered to be the basic treatment method of stenosis of blood vessels. The process of stent implantation changed through the years, from stents made only from metals, produced from polymers, to biodegradable ones and those which elute drugs. The purpose of this review is to outline the development of this medical procedure and present the advantages and disadvantages of each type of stent.

Application of Diethylzinc/propyl Gallate Catalytic System for Ring-Opening Copolymerization of rac-Lactide and ε-Caprolactone.

Biodegradable polyesters gain significant attention because of their wide potential biomedical applications. The ring-opening polymerization method is widely used to obtain such polymers, due to high yields and advantageous properties of the obtained material. The preparation of new, effective, and bio-safe catalytic systems for the synthesis of biomedical polymers is one of the main directions of the research in modern medical chemistry. The new diethylzinc/propyl gallate catalytic system was first used in the copolymerization of ε-caprolactone and rac-lactide. In this paper, the activity of the new zinc-based catalytic system in the copolymerization of cyclic esters depending on the reaction conditions was described. The microstructure analysis of the obtained copolyesters and their toxicity studies were performed. Resulted copolyesters were characterized by low toxicity, moderate dispersity (1.19-1.71), varying randomness degree (0.18-0.83), and average molar mass (5300-9800 Da).

Biodegradable synthetic polyesters in the technology of controlled dosage forms of antihypertensive drugs - the overview.

Introduction: Arterial hypertension is a disease of civilization that requires long-term treatment. Recently, growing interest in natural and synthetic polymers as drug delivery vehicles in controlled release dosage forms for improving the efficacy of treatment has been observed. Areas covered: This review introduces biodegradable synthetic polyesters as macromolecular carriers of antihypertensive drugs. Although various, synthetic and natural polymer-drug conjugates and/or polymeric carriers of anticancer drugs are currently under preclinical and clinical studies, there is no such data for antihypertensive drugs. Therefore, it seems appropriate to use such materials for the treatment of hypertension. Expert opinion: There are currently only a few studies describing the use of synthetic polyesters in the arterial hypertension therapy. In order to the fact that there is a high demand for new, effective antihypertensive dosage forms, further studies for such drug carriers are certainly expected. Synthetic polyester carriers could improve the drug bioavailability and its pharmacokinetic properties by altering the pharmaceutical dosage form. This property is particularly useful for drugs with proven pharmacological action, but with limited application due to their inappropriate pharmacological properties. The development of new polymeric materials and technologies affords the opportunity to produce novel synthetic polyester DDSs.

Current state of the polymeric delivery systems of fluoroquinolones - A review.

Recently, growing interest in polymers (natural and synthetic) as drug carriers in controlled release formulations and drug targeting systems that may improve the efficacy of treatment and reduce the side effects of a drug therapy, has been observed. Special attention has been paid to improving the effectiveness of antibiotics, which constitute a very important, often life-saving group of drugs. In this paper, we review polymers as macromolecular carriers of fluoroquinolones, a group of antibiotics with a broad spectrum of activity. We consider both physical intermixtures and chemical conjugates, although we discuss in greater depth the latter type of coupling, in which covalent bonds between drug molecules and polymers occur.

The Effect of Polymer Microstructure on Encapsulation Efficiency and Release Kinetics of Citropin 1.1 from the Poly(ε-caprolactone) Microparticles.

Cationic antimicrobial peptides represent a promising therapeutic option against multidrug-resistant bacteria for the treatment of local infections. However, due to their low stability and potential toxicity, there are limited possibilities for their application in clinical practice. In this study, different poly(ε-caprolactone) (PCL) microparticles (MPs) loaded with citropin 1.1 (CIT) were investigated in order to demonstrate the effect of the polymer microstructure on the encapsulation efficiency (EE) and kinetics of the peptide release from the newly developed devices. The characteristics of the new systems in terms of surface morphology, particle size, EE and zeta potential analysis, as well as the haemolytic activities of the peptide were investigated. The in vitro release kinetics of CIT from the MPs was also investigated. CIT loading was favoured by a high content of negative charged linear polymer chains in the PCL structure. The presence of non-charged, amorphous macrocycle domains results in faster degradation of the PCL matrix. Depending on the crystallinity of the PCL, the peptide release exhibited a near-zero-order or near-first-order profile with no “burst release”. The results indicated that CIT-loaded PCL MPs could potentially be a promising drug delivery system (DDS) for the treatment of local infections.