Polymeric Drug Delivery Systems Research Articles

Polymeric Drug Delivery System Based on Pluronics for Cancer Treatment.

Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.

Efficient delivery of hydrophobic drug, Cabazitaxel, using Nanodisc: A nano sized free standing planar lipid bilayer

Several new drug candidates have emerged as potential cancer therapeutics with the advent of drug discovery. The hydrophilic drug candidates have easily translated to chemotherapy via oral or intravenous administration methods, whereas efficient drug delivery vehicles for hydrophobic drugs have been an area of concern. This has resulted in an increasing interest in the nano-sized polymer and lipid-based drug delivery systems due to their enhanced distribution, bioavailability, and therapeutic value. In this study, the efficiency of membrane scaffold protein (MSP) embedded POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) nanodiscs has been investigated as a hydrophobic drug delivery vehicle. Synthesized nanodiscs with an average diameter of 27.03 ± 1.5 nm were loaded with different hydrophobic drugs and evaluated for biocompatibility and drug release kinetics. The drug loading was found to be proportional to the hydrophobicity (LogP) of the drugs. Drug loaded nanodiscs showed sustained drug release till 24 h which was preceded by initial burst release. Drug delivery efficacy of cabazitaxel loaded nanodiscs (NDCBT) was tested by in vitro cytotoxicity assay, cell cycle arrest analysis, and spheroid growth inhibition study. We achieved significant enhancement of autophagy mediated cell death using NDCBTs when compared to free drug. Similarly, NDCBTs were able to induce approximately 20% higher toxicity in 3D spheroids model.

A one-step in vitro continuous flow assessment of protein release from core-shell polymer microcapsules designed for therapeutic protein delivery

Developing accurate methods for the assessment of therapeutic protein release from polymer drug delivery systems (microcapsules, microspheres, nanoparticles, 3D-printed systems) is of paramount importance for new formulation development. The most straightforward method for protein release assessment is spectrophotometric analysis of the release medium surrounding the formulation. However, direct spectrophotometric analysis is inapplicable to formulations releasing interfering compounds (co-encapsulated drugs, additives) absorbing light in the same spectrum as proteins. Conventional protein release assays also require frequent release medium sampling and replacement, which reduces their accuracy. We propose a one-step method to assess protein release from core/shell microcapsules eliminating the need for sampling and allowing selective real-time protein quantitation in the release medium. To prevent spectral interferences, released protein is differentiated from interfering compounds by employing a colorimetric protein assay reagent, forming a colour complex selectively with the protein, as the release medium. To eliminate sampling, we employed a continuous flow closed loop set-up, where the release medium is constantly circulating between microcapsule-containing tank and spectrophotometer. A series of colorimetric protein assay reagents (bromocresol green, tetrabromophenol blue, eosin B, eosin Y, biuret) were evaluated in terms of their applicability as the release medium in described system. Only biuret reagent was found compatible with proposed method due to formation of color complex stable over extended period of time and low adsorption to microcapsules. Presented method allowed effective evaluation of albumin release from alginate-polyethersulfone microcapsules with accuracy equal to conventional ‘sample and separate’ technique. Albumin release followed first-order kinetics with plateau reached after 19 h.

Drug Release Kinetics from Nondegradable Hydrophobic Polymers Can Be Modulated and Predicted by the Glass Transition Temperature.

Controlling drug release kinetics within a desired therapeutic window is the central task when designing polymeric drug delivery systems. Complex polymer chemistries have often been explored to control water penetration, polymer degradation rate, or the mesh network size of delivery systems. Here, a simple parameter for controlling the release rate and duration of nondegradable hydrophobic polymers is discovered. A systematic study involving 59 polymers and multiple drugs demonstrates that the glass transition temperature, Tg , is a critical factor that dictates drug release kinetics from nondegradable hydrophobic polymers. Drug release rate exhibits a unique and simple linear correlation of (T - Tg )0.5 despite variability of polymer structure and type. An empirical model established based on the special correlation can accurately simulate and predict drug release kinetics from polymers saving substantial time typically required to test long-acting drug delivery systems.

Synthesis of a PVA drug delivery system for controlled release of a Tramadol\u2013Dexketoprofen combination

The local administration of analgesic combinations by means of degradable polymeric drug delivery systems is an alternative for the management of postoperative pain. We formulated a Tramadol–Dexketoprofen combination (TDC) loaded in poly(vinyl alcohol) (PVA) film. Films were prepared by the solvent casting method using three different molecular weights of PVA and crosslinking those films with citric acid, with the objective of controlling the drug release rate, which was evaluated by UV–vis spectrometry. Non-crosslinked PVA films were also evaluated in the experiments. Differential scanning calorimetry (DSC) analysis of samples corroborated the crosslinking of PVA by the citric acid. Blank and loaded PVA films were tested in vitro for its impact on blood coagulation prothrombin time (PT) and partial thromboplastin time (PTT). The swelling capacity was also evaluated. Crosslinked PVA films of higher-molecular weight showed a prolonged release rate compared with that of the lower-molecular-weight films tested. Non-crosslinked PVA films released 11–14% of TDC. Crosslinked PVA films released 80% of the TDC loaded (p < 0.05). This suggests that crosslinking films can modify the drug release rate. The blank and loaded PVA films induced PT and PTT in the normal range. The results showed that the polymeric films evaluated here have the appropriate properties to allow films to be placed directly on surgical wounds and have the capacity for controlled drug release to promote local analgesia for the control of postoperative pain.

Reactive Oxygen Species Responsive Polymers for Drug Delivery Systems.

Reactive oxygen species (ROS) play an essential role in regulating various physiological functions of living organisms; however, as the concentration of ROS increases in the area of a lesion, this may undermine cellular homeostasis, leading to a series of diseases. Using cell-product species as triggers for targeted regulation of polymer structures and activity represents a promising approach for the treatment. ROS-responsive polymer carriers allow the targeted delivery of drugs, reduce toxicity and side effects on normal cells, and control the release of drugs, which are all advantages compared with traditional small-molecule chemotherapy agents. These formulations have attracted great interest due to their potential applications in biomedicine. In this review, recent progresses on ROS responsive polymer carriers are summarized, with a focus on the chemical mechanism of ROS-responsive polymers and the design of molecular structures for targeted drug delivery and controlled drug release. Meanwhile, we discuss the challenges and future prospects of its applications.

PH-Responsive Amphiphilic Polyether Micelles with Superior Stability for Smart Drug Delivery.

Despite widespread interest in the amphiphilic polymeric micelles for drug delivery systems, it is highly desirable to achieve high loading capacity and high efficiency to reduce the side effects of therapeutic agents while maximizing their efficacy. Here, we present a novel hydrophobic epoxide monomer, cyclohexyloxy ethyl glycidyl ether (CHGE), containing an acetal group as a pH-responsive cleavable linkage. A series of its homopolymers, poly(cyclohexyloxy ethyl glycidyl ether)s (PCHGEs), and block copolymers, poly(ethylene glycol)-block-poly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-b-PCHGE), were synthesized via anionic ring-opening polymerization in a controlled manner. Subsequently, the self-assembled polymeric micelles of mPEG-b-PCHGE demonstrated high loading capacity, excellent stability in biological media, tunable release efficiency, and high cell viability. Importantly, quantum mechanical calculations performed by considering prolonged hydrolysis of the acetal group in CHGE indicated that the CHGE monomer had higher hydrophobicity than three other functional epoxide monomer analogues developed. Furthermore, the preferential cellular uptake and in vivo therapeutic efficacy confirmed the enhanced stability and the pH-responsive degradation of the amphiphilic block copolymer micelles. This study provides a new platform for the development of versatile smart polymeric drug delivery systems with high loading efficiency and tailorable release profiles.

Polymeric drug delivery systems by additive manufacturing.

Additive manufacturing (AM) is gaining interests in drug delivery applications, offering innovative opportunities for the design and development of systems with complex geometry and programmed controlled release profile. In addition, polymer-based drug delivery systems can improve drug safety, efficacy, patient compliance, and are the key materials in AM. Therefore, combining AM and polymers can be beneficial to overcome the existing limitations in the development of controlled release drug delivery systems. Considering these advantages, here we are focusing on the recent developments in the field of polymeric drug delivery systems prepared by AM. This review provides a comprehensive overview on a holistic polymer-AM perspective for drug delivery systems with discussion on the materials, properties, design and fabrication techniques and the mechanisms used to achieve a controlled release system. The current challenges and future perspectives for personalized medicine and clinical use of these systems are also briefly discussed.

A polymeric micellar drug delivery system developed through a design of Experiment approach improves pancreatic tumor accumulation of calcipotriol and paclitaxel

• The Design of Experiment approach enables faster drug delivery development with pre-defined performance parameters. • The Design of Experiment approach enables the definition of a design space for potential modifications of a delivery system. • Size-controlled micelles facilitate pancreatic tumor accumulation.

Self-assembled micellar nanostructures of ursolic acid-polyethylene glycol (UA-PEG) conjugate as efficient drug transporter system

Polymeric micelle-based drug delivery systems have been extensively studied by researchers due to their nanoscopic size and low toxicity. In this study, we have designed and synthesized an amphiphilic ursolic acid-polyethylene glycol conjugate, which on self-assembly results in micellar nanostructures. We conjugated ursolic acid (UA) with polyethylene glycol monomethyl ether in a single step in the presence of a condensing reagent, DCC/DMAP, and their self-assembly was monitored by DLS and TEM. Further an anticancer drug, doxorubicin (DOX), was encapsulated into the hydrophobic core of the self-assembled nanostructures. Due to strong interactions between DOX and UA, high encapsulation efficiency (85.3%) was obtained. The release pattern of DOX from the loaded nanostructures showed a sustained release of drug over a period of time. The projected system showed responsiveness towards lipase and hence, biodegradability aspect of the nanostructure (UA-PEG) was also investigated by lipase-mediated degradation studies. MTT experiments were also carried out on both normal HEK293 cells and MG-63 cancer cells and showed the non-toxic nature of the projected conjugate. These results ensure the promising potential of the projected system as an efficient drug delivery vehicle specifically to cancers cells in vivo and in vitro.

Robotics, microfluidics, nanotechnology and AI in the synthesis and evaluation of liposomes and polymeric drug delivery systems.

The field of nanotechnology and personalised medicine is undergoing drastic changes in the approach and efficiency of experimentation. The COVID-19 pandemic has spiralled into mass stagnation of major laboratories around the globe and led to increased investment into remote systems for nanoparticle experiments. A significant number of laboratories now operate using automated systems; however, the extension to nanoparticle preparation and artificial intelligence–dependent databases holds great translational promise. The strive to combine automation with artificial intelligence (AI) grants the ability to optimise targeted therapeutic nanoparticles for unique cell types and patients. In this perspective, the current and future trends of automated approaches to nanomedicine synthesis are discussed and compared with traditional methods.Graphical abstract

Evaluating Antibacterial Efficacy and Biocompatibility of PAN Nanofibers Loaded with Diclofenac Sodium Salt.

Side effects of the drugs’ oral administration led us to examine the possibility of using diclofenac sodium (DLF) in a polymeric drug delivery system based on electrospun polyacrylonitrile (PAN) nanofibers, which can be produced cost-effectively and with good applicability for transdermal treatments. The inclusion of DLF in PAN nanofibers increased the nanofiber diameter from ~200 nm to ~500 nm. This increase can be attributed to the increase in the spinning solution viscosity. FTIR spectra confirm the entrapment of the DLF into the PAN nanofibers. X-ray diffraction pattern showed that the inclusion of the DLF in the PAN nanofibers had caused the misalignment in the polymeric chains of the PAN, thus resulting in a decrease of the peak intensity at 2θ = 17o. The DLF loaded PAN nanofibers were efficient against the gram-positive Staphylococcus aureus (S. aureus) and gram-negative Escherichia coli (E. coli), with maximum inhibition zone of 16 ± 0.46 mm for E. coli and 15.5 ± 0.28 mm for S. aureus. Good cell viability ~95% for L929 cells in more extended incubation periods was reported. A gradual release of DLF from the PAN nanofiber was observed and can be attributed to the stability of Pan in PBS medium. Cell adhesion micrographs show that cell-cell interaction is stronger than the cell-material interaction. This type of weak cell interaction with the wound dressing is particularly advantageous, as this will not disturb the wound surface during the nursing of the wound.

Synthesis and characterization of an injectable microparticles integrated hydrogel composite biomaterial: In-vivo biocompatibility and inflammatory arthritis treatment

Polymeric hydrogels and microparticles have been widely used for localized drug delivery applications for the treatment of arthritis. Nonetheless, owing to initial burst drug release, non-specific biodistribution and low retention time at the target site in body, these polymeric drug delivery systems have been found with low in-vivo performance. Hence, the above limitations need to be resolved by designing a smart novel drug delivery system which is the current need in biomedicine. Herein, a novel localized injectable thermoresponsive microparticles embedded hydrogel composite drug delivery system has been developed for the treatment of inflammatory arthritis. In the current study, methotrexate (MTX) loaded alginate microparticles (MTX-Microparticles) are embedded into thermoreversible hydrogel matrix (MTX-MPs-H) prepared by physical blending of sodium hyaluronate and methylcellulose (SHMC). Microparticles-hydrogel composite system exhibited appropriate in-vitro thermoreversibility (sol at 4 °C and gel at 37 °C), biocompatibility (>80 %), hemocompatibility, and controlled drug release profile. The in-vivo biocompatibility studies for 10 days revealed that composite system is non-toxic in nature. The developed MTX-MPs-H composite drug delivery system effectively decreased the swelling/ inflammation of the arthritis affected paw in wistar rats in comparison to only alginate microparticles and pure MTX up to 30 days.

Porous Polymeric Carrier System for Modified Drug Releaseof Boswellic Acid

Microsponges being the polymeric drug delivery systems consist of porous microspheres that can entrap a wide range of active ingredients. Boswellic acid is a pentacyclic triterpenoid having anti-inflammatory, anti-hypertensive, anti-cancer activities. The aim of the study was to develop, characterize and formulate microsponge delivery for topical application. The Microsponges were prepared by quasi emulsion solvent diffusion method using QbD approach. Drug excipient compatibility study was carried out by FT-IR, DSC and XRD. The prepared Microsponges were further evaluated for its physicochemical properties by scanning electron microscopy (SEM), photomicroscopy, transmission electron microscopy (TEM), particle size, zeta potential, and porosity analysis. The optimized Microsponges were incorporated into gel base formulation and evaluated for in-vitro drug release, dissolution studies and ex-vivo permeability studies. Further, microsponge formulations, subjected for animal studies for skin irritation test and clinical efficacy. The present study confirmed the formation of Microsponges of Boswellic acid. It also proves the sustained release of drug through microsponge formation.

Development of novel agent without placental passage to prevent preterm birth by using polymeric micelle drug delivery system

Development of novel agent without placental passage to prevent preterm birth by using polymeric micelle drug delivery system

Poly Lactic-Co-Glycolic Acid- (PLGA-) Loaded Nanoformulation of Cisplatin as a Therapeutic Approach for Breast Cancers.

Despite recent advancements in cisplatin (cis-diamminedichloroplatinum II) and other platinum-based chemotherapeutic drugs for treating solid tumors, their uses are limited by either in terms of toxicity and/or acquired drug resistance. These side effects have a dangerous problem with higher dose for severe patients. To overcome the low therapeutic ratio of the free drug, a polymeric nanoparticle drug delivery system has been explored promoting delivery of cisplatin to tumors. Recently, the applications of nanoparticles (NPs) have been underlined for encouraging the effects of chemotherapeutic drugs in cancerous cells. The intention of this project is to assess the potential of poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) for enhancing the effects of anticancer drug cisplatin. For the purpose, we have synthesized PLGA-cisplatin nanoparticles for increasing its bioavailability and studied the comparative cytotoxicity of free cisplatin and PLGA-cisplatin against MCF-7 cancer cell lines and HEK-293 normal cell lines. We have also analyzed the hallmarks of PLGA-cisplatin-induced apoptosis. The outcomes of this study may provide the possibility of delivery of anticancer drug to their specific site, which could minimize toxicity and optimize the drug efficacy.

Formaldehyde-doxorubicin dual polymeric drug delivery system for higher efficacy and limited cardiotoxicity of anthracyclines

We report the synthesis of a dual delivery system composed of chemically bound pH-responsive formaldehyde polymer prodrugs and pH-responsive doxorubicin loaded nanoparticles to increase the therapeutic index of doxorubicin by working in synergy with formaldehyde to enable the formation of DOX-DNA adducts and limiting the cardiotoxicity of anthracyclines. Polyacrylates bearing 1,2- and 1,3- pendant diols were synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization to conjugate formaldehyde, forming 5- or 6-membered acetal rings with tunable conjugation percentages (1.5–10 wt%) for controlled release in acidic environments of the tumor extracellular matrix. The formaldehyde-conjugated prodrugs are then combined with polyester nanoparticles formed by intermolecular crosslinking via oxime click chemistry of less than 200 nm in size containing 14 wt% encapsulated Doxorubicin (DOX). Release kinetics show a sustained release of both DOX and formaldehyde at pH 5.0, mimicking the low pH of the tumor environment whereas insignificant release was recorded at physiological pH. The cell viability of the dual delivery system combination was evaluated in 4 T1 breast cancer cells resulting in a considerably increase of cell death of about 4-fold compared to free DOX alone. The protective effect of formaldehyde towards DOX- induced damages was observed in Lactate dehydrogenase assays with cardiomyocytes (P1-3). The resulting polymeric delivery system is the first reported example of a DOX and formaldehyde co-administration, demonstrating the potential significant effect of formaldehyde towards an improved anti-cancer efficacy and reduced cardiotoxicity of DOX.

Localized Delivery of Cisplatin to Cervical Cancer Improves Its Therapeutic Efficacy and Minimizes Its Side Effect Profile

Cervical cancer represents the fourth most frequent malignancy in the world among women, and mortality has remained stable for the past 4 decades. Intravenous cisplatin with concurrent radiation therapy is the standard-of-care for patients with local and regional cervical cancer. However, cisplatin induces serious dose-limiting systemic toxicities and recurrence frequently occurs. In this study, we aimed to develop an intracervical drug delivery system that allows cisplatin release directly into the tumor and minimize systemic side effects. Twenty patient biopsies and 5 cell lines treated with cisplatin were analyzed for platinum content using inductively coupled plasma mass spectrometry. Polymeric implants loaded with cisplatin were developed and evaluated for degradation and drug release. The effect of local or systemic cisplatin delivery on drug biodistribution as well as tumor burden were evaluated invivo, in combination with radiation therapy. Platinum levels in patient biopsies were 6-fold lower than the levels needed for efficacy and radiosensitization invitro. Cisplatin local delivery implant remarkably improved drug specificity to the tumor and significantly decreased accumulation in the blood, kidney, and other distant normal organs, compared with traditional systemic delivery. The localized treatment further resulted in complete inhibition of tumor growth. The current standard-of-care systemic administration of cisplatin provides a subtherapeutic dose. We developed a polymeric drug delivery system that delivered high doses of cisplatin directly into the cervical tumor, while lowering drug accumulation and consequent side effects in normal tissues. Moving forward, these data will be used as the basis of a future first-in-human clinical trial to test the efficacy of localized cisplatin as adjuvant or neoadjuvant chemotherapy in local and regional cervical cancer.

PLA/PLGA-Based Drug Delivery Systems Produced with Supercritical CO2-A Green Future for Particle Formulation?

Supercritical carbon dioxide (SC-CO2) can serve as solvent, anti-solvent and solute, among others, in the field of drug delivery applications, e.g., for the formulation of polymeric nanocarriers in combination with different drug molecules. With its tunable properties above critical pressure and temperature, SC-CO2 offers control of the particle size, the particle morphology, and their drug loading. Moreover, the SC-CO2-based techniques overcome the limitations of conventional formulation techniques e.g., post purification steps. One of the widely used polymers for drug delivery systems with excellent mechanical (Tg, crystallinity) and chemical properties (controlled drug release, biodegradability) is poly (lactic acid) (PLA), which is used either as a homopolymer or as a copolymer, such as poly(lactic-co-glycolic) acid (PLGA). Over the last 30 years, extensive research has been conducted to exploit SC-CO2-based processes for the formulation of PLA carriers. This review provides an overview of these research studies, including a brief description of the SC-CO2 processes that are widely exploited for the production of PLA and PLGA-based drug-loaded particles. Finally, recent work shows progress in the development of SC-CO2 techniques for particulate drug delivery systems is discussed in detail. Additionally, future perspectives and limitations of SC-CO2-based techniques in industrial applications are examined.

Polymeric Drug Delivery Systems Bearing Cholesterol Moieties: A Review.

This review aims to provide an overview of polymers comprising cholesterol moiety/ies designed to be used in drug delivery. Over the last two decades, there have been many papers published in this field, which are summarized in this review. The primary focus of this article is on the methods of synthesis of polymers bearing cholesterol in the main chain or as side chains. The data related to the composition, molecular weight, and molecular weight distribution of polymers are presented. Moreover, other aspects, such as forms of carriers, types of encapsulated drugs, encapsulation efficiency and capacity, are also included.