Drug Release Study of Chitosan-Based Nanoparticles PDF

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Universitas Padjadjaran

Yedi Herdiana, Nasrul Wathoni, Shaharum Shamsuddin, Muchtaridi Muchtaridi

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drug release nanoparticles chitosan drug delivery

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This review article explores the drug release characteristics of chitosan-based nanoparticles (CSNPs). It discusses various factors influencing the release rate, such as composition, method of preparation, and interactions between components. The study highlights the importance of kinetic models in understanding and optimizing drug delivery using CSNPs.

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Heliyon 8 (2022) e08674 Contents lists available at ScienceDirect Heliyon jour...

Heliyon 8 (2022) e08674 Contents lists available at ScienceDirect Heliyon journal homepage: www.cell.com/heliyon Review article Drug release study of the chitosan-based nanoparticles Yedi Herdiana a, Nasrul Wathoni a, e, Shaharum Shamsuddin b, c, Muchtaridi Muchtaridi d, e, * a Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia b School of Health Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia c USM-RIKEN Interdisciplinary Collaboration on Advanced Sciences (URICAS), 11800, USM, Penang, Malaysia d Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia e Functional Nano Powder University Center of Excellence (FiNder U CoE), Universitas Padjadjaran, Indonesia A R T I C L E I N F O A B S T R A C T Keywords: Recently, multifunctional drug delivery systems (DDSs) have been designed to provide a comprehensive approach Multifunction delivery system with multiple functionalities, including diagnostic imaging, targeted drug delivery, and controlled drug release. Bi-phasic release Chitosan-based drug nanoparticles (CSNPs) systems are employed as diagnostic imaging and delivering the drug Burst release to particular targeted sites in a regulated manner. Drug release is an important factor in ensuring high repro- Controlled release ducibility, stability, quality control of CSNPs, and scientific-based for developing CSNPs. Several factors influence drug release from CSNPs, including composition, composition ratio, ingredient interactions, and preparation methods. Early, CSNPs were used for improving drug solubility, stability, pharmacokinetics, and pharmaco- therapeutics properties. Chitosan has been developed toward a multifunctional drug delivery system by exploring positively charged properties and modifiable functional groups. Various modifications to the polymer backbone, charge, or functional groups will undoubtedly affect the drug release from CSNPs. The drug release from CSNPs has a significant influence on its therapeutic actions. Our review's objective was to summarize and discuss the relationship between the modification in CSNPs as multifunctional delivery systems and drug release properties and kinetics of the drug release model. Kinetic models help describe the release rate, leading to increased effi- ciency, accuracy, the safety of the dose, optimizing the drug delivery device's design, evaluating the drug release rate, and improvement of patient compatibility. In conclusion, almost all CSNPs showed bi-phasic release, initial burst release drug in a particular time followed controlled manner release in achieving the expected release, stimuli external can be applied. CSNPs are a promising technique for multifunctional drug delivery systems. 1. Introduction Throughout the treatment cycle, the primary aim of drug therapy for any disease is to obtain and sustain the drug's optimal therapeutic con- Nanomedicine is rapidly evolving toward multifunctional DDSs, and centration at the site of action. PNPs can control the release of drugs over it can be used as a diagnostic tool, targeted delivery, and a controlled a long period, thus increasing the therapeutic index of pharmacology delivery system. Nanomedicine has been engineered to be incredibly activity of agents. PNPs' enhanced bioavailability and less adverse small, allowing them to travel more easily inside the human body while effects result in favorable anticancer outcomes as compared to free possessing structurally unique, chemical, electronic, magnetic, electrical, medicines [8,9]. and biological properties [1, 2, 3]. Advantages of nanomedicine are in Characterization of NPs is critical to ensure the desired behaviour in vivo long-circulating in vivo, improved drug bioavailability, breaking vitro and in vivo. The in vitro release rate and mechanism profile are through biological barriers , enhancing deep-tissue penetration, and strongly influenced by the structure, composition, composition ratio, and cancer cell uptake. Furthermore, active targeting and the effects of pas- interaction between drug and polymer. This information accom- sive targeting enable polymeric nanoparticles (PNPs) to specifically modates a scientific and predictive approach to the design and devel- target cancer cells by detecting the expression of surface receptors on opment of DDSs. In vitro release studies are generally indirect measures of tumours [4, 5, 6, 7]. drug availability in the early stages of product development, quality control to support batch release clinically and biologically effective, * Corresponding author. E-mail address: [email protected] (M. Muchtaridi). https://doi.org/10.1016/j.heliyon.2021.e08674 Received 26 August 2021; Received in revised form 8 October 2021; Accepted 22 December 2021 2405-8440/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). Y. Herdiana et al. Heliyon 8 (2022) e08674 assessment of formulation factors, and manufacturing methods that thus regarded as a future carrier of drugs and medicinal products. affect bioavailability. The advantage characteristics can reduce a load of medicine and time for Chitosan (CS) is a natural, hydrophilic, positively charged polymer patient convenience. with easy fabrication, good biocompatibility, and similarity of flexibility to natural tissue [2,6,11,13]. Drug release from CSNPs is governed by 2.1. Drug release from polymeric nanoparticles polymer swelling, adsorbed drugs, drug diffusion, polymer erosion or degradation, and a combination of erosion and degradation [14,15]. The therapeutic window is well-defined as the region between the CSNPs have been extensively used for bioactive compounds because minimum toxic concentration (MTC) and minimum effective concen- of their high physicochemical stability, ability to enhance the bioavail- tration (MEC). A single big dosage of a medicine has hazardous ability, non-toxicity, and potential targeted. CSNPs are used as a adverse effects and quickly drops below the MEC (Figure 1). If there is diagnostic tool, targeted drug delivery, and a controlled delivery system more excellent stability in the plasma's drug levels, multiple adminis- [17,18]. CS modifications may be carried out using functional groups by tration of a particular formulation can help; however, noncompliance can various physical and chemical processes like grafting, crosslinking, be a problem if patients are dosed intermittently. Long-term release of complexation, and mixing with polymers. Modification or adding zero-order drugs is being pursued in practice. However, excessive release other substances to the formulation, such as crosslinker, copolymer, can reduce the therapeutic efficacy, resulting in delayed drug delivery conjugates, or drug, is needed to reach multifunction DDSs. The encap-. Hence, pulsatile or stimulus-responsive drug administration is sulated drug in CSNPs is typically formed through hydrogen bonds, Van investigated [27,29]. der Waals interactions including hydrophobic and electrostatic in- Several factors influence drug release, including drug composition teractions, or monomer polymerization. This modification of CS will (drug, polymer, and adjuvants) and preparation method. The mechanism have consequences in changing CSNPs properties, specialty drug release. by which a drug pulls away from its carrier is summarized below CSNPs have shown great potential with extensive use in active substance (Figure 2). All factors will give different properties to the final NPs administration, diagnostics, and other sectoral uses , including per- product, namely swelling ability, matrix density, and degradation prop- sonal medicine. These advances raise questions about the safety of erties. The drug release from PNPs is affected by swelling of polymers, NPs. Nanotoxicological studies are needed to produce safe NPs and a diffusion of adsorbed materials, diffusion of the drug through a polymer comprehensive toxicity study of existing NPs. The availability of matrix, polymer erosion or degradation, and a combination of erosion safe and non-toxic polymers or materials attracts them, due to its and degradation [30, 31, 32]. biodegradable and biocompatible qualities. Cs was determined to be An essential step in bringing benefits to PNPs is the characterization generally harmless, like mesoporous carbon nanoparticles, organosilica of their complicated release phase since it is distant from conventional and hydroxyapatite (HAP) nanoparticles. DDSs. Additionally, while generating NPs, it is necessary to identify and 2. Polymeric nanoparticles comprehend the unique processes and complications involved in the release process and their differentiation and comprehension of their NPs are made of solid polymer carriers in submicron size (10–1000 respective characteristics. Controlled release of a drug from a carrier nm). PNPs can overcome the biological barriers, protecting and may be achieved by: delivering a drug to target cells [24,25]. The PNPs can be formulated as dendrimers, micelles, nanogels, and nanocapsules. PNPs are widely used 2.1.1. Diffusion-controlled release for controlled release in the pharmaceutical industry, using different The most applicable mechanism for drug release is the diffusion formulations and manufacturing methods [14,15]. PNPs offer a control mechanism. The diffusion mechanism occurs when the drug or remarkable guarantee that they exhibit outstanding physicochemical active substance passes through the polymer NPs matrix, which acts as a properties - size, surface load, hydrophilicity, and hydrophobia - and are controlled release device. The rate of drug release decreases when the Figure 1. Multiple dosing results in plasma drug concentration profiles (green line) and zero-order release (orange line). Two minimum toxic concentration (MTC) levels form the range, and the MEC displays the therapeutic windows. 2 Y. Herdiana et al. Heliyon 8 (2022) e08674 Figure 2. Mechanism of drug release from PNPs. active agent has a longer mileage [27,34,35]. The substance moves matrix. Still, the diffusion constant does not affect them. The Weibull through the interior of the polymer matrix towards the release medium. model seems most applicable to describe the release process. The Weibull The diffusion barrier is formed by polymer chains, which restrict the drug model appears to be flexible enough to account for the influence of sys- from moving. Swelling or erosion may also be associated with diffusion. tem characteristics on the release process and is more suitable for Mathematically, diffusion is described by Fick's Law of Diffusion. determining the drug release profile of swellable PNPs in vivo. Some assumptions must be made to obtain Fick's law parameters, such as maintaining a pseudo-steady state during the release process, the 2.1.3. Erosion and degradation-controlled release diameter of the drug particles less than the average distance of the Polymer erosion involves swelling, diffusion, and dissolution. Erosion diffusion of the drug through the polymer matrix, and the media around is divided into (a) Homogeneous erosion occurs when polymers erode the NPs in sink conditions [36,37]. The drug molecules will be distrib- uniformly throughout the matrix, (b) Heterogeneous erosion occurs uted throughout the polymer matrix because no membrane acts as a when polymers erode from the surface to the inner core. Polymer diffusion barrier in a matrix-type system. This system will show a high breakdown can be triggered by the surrounding media or by the presence initial release rate, followed by a decreased release rate related to the of enzymes and the pH of the media, the content of the polymer, and diffusion distance of the drug molecule with the solution medium [4,27, water absorption. The drug release is regulated by the type of polymer, 38]. The relationship between the release rate increases and the diffusion internal bonding, adjuvant, and the shape and size of the NPs. coefficient is Directly proportional, as the release rate increases as the Because of the distance of water diffusion and the domain size of crys- diffusion coefficient increases. tallization, polymer breakdown is considerably accelerated in small-scale An osmotic-controlled release is found in the PNPs with a semi- NPs [27,43]. The polymer may show no normal surface erosion but permeable membrane, which relies on water and polymer chains relax- shows signs of mass degradation [27,44]. Biodegradable polymeric sys- ing. Removing the drugs from the drug-loaded core will allow water to tems are preferred because the breakdown results of compounds can be flow into the carrier (with a high drug concentration). Maintenance of safely removed from the body without harming the body in the long run constant concentration gradient, the zero-order release profile is reached. The pharmaceutical drug-polymer conjugates are released by hy- [27,38]. Hydrophilic polymers can form a gel when a water-bearing drolytic or enzymatic cleavage at target tissues. The cleavage rate gov- hydrophilic system is added to the water system. The polymer will erns the kinetics of drug release. absorb water, will expand, and then diffuse. 2.1.4. Stimuli-controlled release 2.1.2. The swelling-controlled release Drug release can use internal or external stimuli. Internal stimuli are The polymer chains break down when the polymer interacts with the directed directly at diseased tissue and have been shown to increase the surrounding media, releasing the medication from the polymer matrix. selectivity of drug action. This requires the incorporation of appropriate Before the polymer degrades, it swells. Diffusion is affected by hy- substances into PNPs that are activated by certain endogenous stimuli. drophilicity, degree of swelling, and density of polymer chains [15,41]. PNPs offer tumour-targeting selectivity and efficiency, as is the tumour Swelling of the polymer matrix occurs by a non-Fickian diffusion process, microenvironment (e.g. pH and redox). External stimuli are applied where the active substance is delivered concurrently via erosion and through external factors such as temperature, electromagnetic and diffusion. The relaxation constant affects the matrix swelling device with magnetic fields, or ultrasonic waves. This strategy is advantageous in slab, spherical and cylindrical geometries. The more significant the value terms of delivering drugs exactly to the destination and minimizing side of the relaxation constant, the slower the drug is released from the effects [46,47]. 3 Y. Herdiana et al. Heliyon 8 (2022) e08674 2.2. In vitro release methods for nanoparticles differences in DM are found in arrangement, container size, and molec- ular weight (MW) cut-off. The in vitro release of the NPs must take pH and agitation into ac- The NPs in an inverted dialysis setup are swirled to reduce the count. The administration of NPs depends on the target location [48, 49, unstirred water layer in the outer compartment. The interior compart- 50]. During in vitro release studies, agitation is required to keep the ment is sampled for drug release testing (Figure 5). Adjoining dialysis dosage forms from aggregating. The release media is influenced by the arrangement, where the dialysis membrane separates the donor and solubility, stability of the drug, the test's sensitivity, and the test pro- recipient cells, sampling is carried out from the recipient cell and the cedure. The in vitro method is also used in sampling and buffer replace- vertical Franz diffusion cell, containing the same medium stirred with a ment techniques [12,45,51]. To ensure the quality of the CSNPs, in vitro magnetic stirrer. release analysis is very important, but currently, no compendial stan- dards or regulations apply. Direct comparisons between different systems 2.3. Modeling drug release are difficult due to the variety of testing methods [12,45,51]. Drug release from NPs can be assessed using: Drug release from NPs plays an essential role in determining its pharmacological effects. The drug release kinetics of NPs is an a. Sample and Separate (SS). important feature of the formulation and as a quality control one. In vitro release kinetics is also a prerequisite to look for in vitro-in vivo (IVIVC) SS is the simplest, practical, popular method for determining the drug correlations, which will be an illustration of the performance of in vivo release of NPs. The NPs containing the drug is suspended in a container formulations. Drug release data under simulated physiological with a fixed amount of release medium, then analyzed accordingly conditions is essential in preclinical development, and will serve as the (Figure 3). Various factors such as vessel size, agitating, sample separa- basis for evaluation of drug formulations and regulatory approvals. tion methods, and sampling volume may be adjusted. The amount of Prediction of in vivo drug release through in vitro methods for nano- media needed for the release study determines the type of container used formulations is becoming widely developed. Mathematical models [12,52]. have many advantages, including predicting drug release mechanisms, assisting in formulation development, and building controlled drug b. Continuous Flow (CF) release systems. The dosage forms of NPs are complicated, and the assessment of drug release is complex. Therefore, the use of in vitro drug A fluid cell containing the sample, a pump, and a water bath is a release data to predict and characterize drug substances' in vivo perfor- continuous-flow device in closed or open-end configurations (Figure 4). mance can be considered the rational development of controlled release The media constantly circulates through the column containing the NPs formulations [42,55,56]. in a closed system, then the amount of drug re-leased is analyzed The models are The Korsmeyer-Peppas model, Higuchi Model, First- accordingly. order Release Kinetics Model, Zero-order Release Kinetics Model, Wei- The literature on the technique of using the CF method in nano- bull Release Model, Two-film Theory Mathematical Model. particulate dosage forms is still rare. The flow rate is determined by the type of pump and filter used. The CF approach replaces the media using 3. Chitosan-based nanoparticles closed-loop and open systems. Low flow rates indicate slow or incom- plete release from NPs. 3.1. Chitosan c. Dialysis Method (DM) CS is a widely available, sustainable biomaterial for health care product development and tissue engineering [58,59]. CS has been proven The DM is the most widely used method for determining drug release biodegradable, bio-compatible, biorenewable, non-toxic, non-allergenic, from NPs dosage forms. The dosage forms are physically separated, bioadhesive, does not contain anti-genic properties and is environmen- allowing for convenient sampling at regular intervals. In the literature, tally friendly [41,58,60]. CS has antibacterial, anti-tumor properties and Figure 3. Sample and separate method [12,52]. 4 Y. Herdiana et al. Heliyon 8 (2022) e08674 Figure 4. Continuous flow methods. Figure 5. Dialysis method. was classified as GRAS (generally recognized as safe) by the FDA in 2001 bioactive molecules, such as antigens, antibodies, enzymes, cytokines,. and polyanionic polymers. CS can interact with the blood coagu- The biodegradation profile will affect the drug release so that it be- lation process (e.g., platelets, red blood cells, coagulation factors), comes the basis for the selection of natural polymers. Drug release from accelerating hemostasis, increasing monocyte/macrophage migration, natural polymers takes place relatively quickly from NPs because they and stimulating collagen synthesis. CS with a regulated degree of decompose within a few hours. In contrast, synthetic polymers provide deacetylation strongly affects cell-polymer interaction on cell death by prolonged drug release because they can withstand degradation in the breaking the cell membrane. CS prevents tumour cell growth by prolif- body for long periods of time, days or even weeks. CS consists of erating cytolytic T lymphocytes because of its anti-tumour effect and covalently linked monosaccharide units, in the manufacture of NPs bone regeneration approach. The molecular structure of CS is providing stability or adequacy of functional groups and ease of func- similar to that of collagen and can be applied to mimic the extracellular tionalization [62,63]. matrix. CS is a naturally positively charged polysaccharide (polycation CS has three different functional groups: primary alcohol, secondary polymer) [64, 65, 66], has a good affinity for negatively charged alcohol, and –NH2 groups, which inhibit the growth of various bacteria 5 Y. Herdiana et al. Heliyon 8 (2022) e08674 and fungi. Functional groups are helpful in biosensors, separation 4) Across intestinal epithelial cell layer membranes, tissue engineering, and wastewater treatment. Through ion exchange and complex reactions, they can adsorb various metal ions Amphiphilic polymers such as n-octyl-n-arginine-CS, arginine- through their amino group chelation sites. Changes in pH, concen- modified CS (CS–N-Arg), or amphiphilic CS derivatives with arginine tration, MW, degree of crosslinking, CS polymerization, and poly- may facilitate drug transport through the intestinal epithelial cell layer dispersity index (PDI) will determine the overall characteristics of CS. polymers [14,69]. CS can be fabricated into various nano-morphologies (nanofilms, nanofibers, NPs, nanocapsules, nanomembranes, nano- 5) Dual-delivery system sponges, nanoscaffolds, and hydrogels) [60,70]. CS is extensively researched in the preparation of NPs drug delivery and release control. A dual-delivery method for biodegradable bone grafts constructed by CS can interact with negatively charged polymers, macromolecules, and inserting CS microspheres in calcium sulfate is capable of effectively certain in-organic polyanions. Synthetic polymers normally advantage loading and releasing antibiotics and growth agents concurrently. from high but adaptable mechanical properties, while they often suffer from poor biocompatibility and/or biodegradability. 6) Targeting CS is generally amorphous which is almost insoluble in water due to strong intermolecular hydrogen bonds between polymer chains. How- In vitro cytotoxicity and in vivo anticancer effect of Doxorubicin ever, CS can dissolve in aqueous solution when the pH is below 6, due to Transferrin palmitoyl Glycol CS (DOX-TF-PGCS) demonstrated that DOX- protonation of the amino groups. Increasing the solubility in alkaline HGC could avoid the toxicity of the free drug after systemic adminis- solutions can be done by several chemical modifications, including the tration. attachment of the carboxymethyl group to the CS structure and retaining its cationic structure. CS is a natural sugar, and is highly bioactive, 7) Control release showing it as a cell-compatible drug carrier. CSNPs produced in this study could be used for sustain release with 3.2. Chitosan nanoparticles amiodarone and may serve as a paradigm for regulated administration of a variety of antiarrhythmic medications. CSNPs are used for developing the stimuli-responsive NPs to carry Numerous methods have been proposed to enhance CS characteristics chemo drugs to deliver specifically at cancer locations without causing and expand its application range, including crosslinking, graft copoly- any toxicity to normal cells. Because of excellent biocompatibility, merization, complexation, chemical modification, and blending. durability, low toxicity, simple preparation methods, and versatility of administration routes, CSNPs give several benefits. Due to the 3.2.1. Preparing methods activation of the RES, CSNPs might be extremely unstable in the systemic CSNPs can divide into three groups based on their preparation circulation. methods (Figure 6) : (a) Self-assembled, hydrophobic chains are Drug encapsulation is a critical area of biomedicine because it pro- spontaneously collected to form reservoirs for drugs that dissolve in vides numerous benefits such as increased drug stability, distribution, aqueous phases, while hydrophilic chains act as shells around the nucleus activity, and bioactivity expansion by preventing pharmaceuticals from affected by the aqueous phase ; (b) Ionic crosslinked, electrostatic premature degradation, all of which are linked with low side effects. interaction is used to create ionic crosslinked NPs by using the cationic CSNPs inhibit bacterial growth and antibacterial function and inhibit property of CS (the backbone's amino groups) interact with a polyanionic bacterial uptake by the stomach and intestines. crosslinker such as tripolyphosphate (TPP), CaCl2, Na2SO4. The Many research shows that CSNPs and their derivates have broad- physical characteristics of the NPs (surface size and charge) are easily spectrum efficacy in biomedical purposes, enhancing solubility, stabil- adapted to the processing parameters of the ionic crosslinking, which ity, and bioavailability for the hydro-phobic drug. The other using for a impacts the encapsulation efficiency and drug release. (c) Poly- diagnostic tool, targeted drug delivery, and a controlled delivery system, electrolyte complexes, If CS is mixed with negatively charged poly- for example: electrolyte in a solution and the polymer chain interact to form a CSNPs polyelectrolyte complex. The manufacturing procedure is simple and 1) Improve the pharmacokinetics and pharmacodynamics profile. does not use toxic reagents. When CS is mixed with a negatively charged polyelectrolyte in solution, the polymer chains interact with each other to PEGylated CSNPs are contributing long-circulating and targeted form a strong but reversible electrostatic network without the use of accumulation of rosuvastatin. Compared to CSNPs, PEGylation crosslinking. decreased macrophage identification of the NPs, allowing them to circulate continuously in the blood for a more extended period. 3.2.2. Chemical modifications PEGylated is an ideal graft forming polymer due to its solubility in water The effectiveness of native CS transfection is low due to in vivo in- and organic solvents, low toxicity, high biocompatibility, and biode- stabilities and insufficient cellular release. Developing effective delivery gradability. The novel amphiphilic CSNPs may serve as effective systems needed chemical modifications. First, NPs based on CS carriers for hydrophobic medicines used in tissue engineering. derivatives can be chemically modified because of hydroxyl, acetamido, and amine functional groups [87,88]. Second, CS polymer con- 2) Diagnosis of cancer cells/photoimaging. jugates/complexes, conjugation, or the addition of functional polymers in CS can mask CS weakness and achieve more efficient transfection. CSNPs are used as a photodiagnostic agent for cancer cells, as a Modified CS is used to modulate the carrier's functionality to adjust de- transporter of 5-aminoluvanonic acid inside the cell and over the lipo- livery properties to those required for the desired application. philic obstacle, to inhibit bacterial absorption of 5-ALA, and as a source of CS contains three types of reactive functional groups, an amino group PpIX. on the C-2 position for each deacetylated unit and primary and secondary hydroxyl groups at the C-6 and C-3 positions, respectively, for each 3) Overcome biological barrier. repeating unit. CS has been modified mainly to improve solubility and therefore widen its applications. The most investigated and promising CS CSNPs form ionic connections with endothelial cells, allowing med- derivatives are quaternized alkyl CS (e.g., trimethyl CS), N-alkyl and N- icines to penetrate the BBB through adsorptive transcytosis. benzyl CS, N-acyl CS (acetyl, propionyl, butyryl, hexanoyl, octanoyl, 6 Y. Herdiana et al. Heliyon 8 (2022) e08674 Figure 6. Preparation methods and chemical modifications of CS. lauroyl, palmitoyl, benzoyl), N-carboxyalkyl, and aryl CS (e.g., N-car- MW and decreasing crystallinity of CS by random deacetylation generally boxymethyl and N-carboxybenzyl CS), O-carboxyalkyl (e.g., O-carbox- increases its solubility in dilute acids and allows processing of its solution ymethyl CS) and N-carboxyacyl- CS (derived from anhydrides such as into various bead shapes. maleic, succinic, glutaric, phthalic anhydride), phosphorylated CS and thiolated CS (CS-thioglycolic acid, CS-2- iminothiolane) [63,77]. 2) Glass Transition (Tg) CS derivatives are semi-synthetic aminopolysaccharides with unique properties, various marvellous functionalities, and a wide range of ap- Polymers, copolymers, biopolymers, and polymer-based composites plications in research and industrial areas. all have a glass transition temperature. Tg drops in some circumstances when the interaction between the polymer and the nanofiller develops 3.2.3. Key factors in CSNPs development free surfaces and expands in size due to the attractive interactions formed by the wetted interface. Their glass transition temperature in- 1) Crystallinity fluences the polymer physicochemical properties of the polymer [14,95]. Tg was determining if the amorphous region is in “glasslike” or Since CS is a heterogeneous polymer consisting of D-glucosamine and “rubberlike” condition. The polymer is in a “glasslike” condition if the N-acetyl-D-glucosamine units, its properties depend on its structure and state is below Tg and is affected by low flexibility and low diffusion rate. composition. Partial alignment of the polymer molecular chains, The polymer is in a “rubberlike” condition if the state is above Tg [14,95]. which affects the physical and chemical properties of the polymer. This condition will allow for faster water and drug molecule mass Polymers that have high crystallinity are high melting, low flexibility, transfer throughout the matrix. Developing effective PNPs needs a bal- and low solvent penetration. Polymer crystallinity refers to the propor- ance between crystalline and amorphous states [14,96,97]. If the tran- tion of the crystalline region in the polymer sample to the amorphous sition between 140 and 150 degrees Celsius is a β relaxation transition, region [14,91]. Water molecules can pass across amorphous areas, which the degree of deacetylation, which is proportional to the quantity of side are permeable. The monomers' composition regulates the crystallinity group (acetamino or amino group), will effect this transition. If the and affects flexibility, swelling, solubility, and degradation rates. When transition between 140 and 150  C is part of the α relaxation, the degree low MW polymers are used, A high crystalline degree leads to slower of deacetylation has no effect on Tg, since the relaxation simply refers to drug release conditions. In high MW, the effect on drug release is reduced the motion of segments in the main chain. [92,93]. The glass transition temperatures of the nanocomposite matrices are The quantification of crystallinity is the crystallinity index (CI) utilized to investigate the effect of nanofillers on their thermal charac- calculated from the connection between the distinctive X-ray diffraction teristics. Thermal property variations as a function of loading are also peaks. Quantitative CI is important because these properties affect utilized to infer changes in the molecular packing of polymer chains due swelling, porous, hydration, and absorption. According to the source and to the polymer-nanofiller interface. Incorporating NPs disrupts the chain arrangement, CS exists in three polymorphic phases with varying CS chains, resulting in a decrease in the system's free volume. As a result, degrees of crystallinity (α, β, and ϒ). CS is a semi-crystalline polymer that the polymer's properties, such as free volume and chain conformation, is commercially available, while CI is a function of DD. deviated from their bulk behaviour. The solubility of CS in aqueous solution and its capacity to form complexes depend mainly on the degree of deacetylation and crystal- 3) Molecular Weight linity. The less deacetylated the sample, the higher the crystallinity. CS chain packaging and crystallinity are important parameters in the CS classification can be divided into oligochitosan (16 kDa), low MW- utilization in various fields. CS (LMW) (>16 kDa–190 kDa), medium MW-CS (MMW) (>190 The method used to synthesize CS from chitin determines its crys- kDa–300 kDa), and high MW-CS (HMW).) (>300 kDa). This division is tallinity; solid CS synthesized from chitin has a more amorphous struc- not yet universal. MW affects CS bioactivity. The lower the MW ture than CS synthesized using the suspension method. Reducing the indicates the more significant bioactivity. The degree of deacetylation 7 Y. Herdiana et al. Heliyon 8 (2022) e08674 and MW are the main parameters affecting wound healing efficiency and rate. Copolymers with hydrophobic and hydrophilic moieties often pro- antimicrobial properties. vide more predictable physical properties such as drug release rates [35, The lower the MW the higher the solubility, CS with MW below 9 kDa 107]. shows much better solubility in water. CS above 30 kDa still require acid The solubility and polycationic characteristics of CS are essential for to dissolve in water. Acetic acid most popular, many acid can also the production of further derivatives. They are typically strong bases, dissolve CS in water, except for phosphoric acid. with a pKa of 6.3 for the main amino group. As a result, these bio- MW of degraded polymer affects the release and Cmax of the drug in polymers are soluble in diluted acidic solutions with a pH of 6. Hþ ions in plasma. Low MW CS polymer is more soluble, less viscous, less crystal- medium protonate the -NH2 group, forming (NH3)þ at low pH values. As line, degrades faster. Low MW polymers have high elasticity, and the a consequence of this transformation, the CS structure was converted into matrix is more plastic, causing the pore size to increase. a polycationic polymer. When the pH reaches 6.0, deprotonation occurs, Low MW polymers produce smaller NPs, resulting in altered drug rendering CS insoluble. release kinetics, longer exposure to the bloodstream, reduced accu- Significant research has been carried out to improve polymer mem- mulation in the liver and spleen, and more efficient drug delivery. branes' hydrophilic and anti-fouling properties, such as modification Cellular toxicity is dependent on the concentration and MW of with other polymers through mixing the polymer with a third compound CSNPs , meaning lower toxicity is associated with less MW and. vice versa. The higher weight CS molecules are broken down and completely to a 6) Size lower level. Carbon (44.11%), Nitrogen (7.97%), and Hydrogen (6.84%) are the main constituents of CS. Determination of particle size and morphology are two important parameters in nanotechnology. Sreekumar et al. evaluated the 4) Degree of deacetylation (DD) effect of several factors, namely the chitosans degree of acetylation and the degree of polymerisation, degree of space occupancy, polymer con- DD of CS is determined by the ratio between the N-acetyl-D-glucos- centration, and degree of crosslinking with TPP (NH2/PO4 molar ratio) amine and D-glucosamine units. The CS structure is exclusive on the ability of chitosans to form substances by ionic crosslinking and because the primary amine is at the C-2 position of the glucosamine the effect of such parameters on the average hydrodynamic diameter of residue, increasing its functionalization. DD indicates the concen- the particles formed. tration of the amino group in the molecule and the protonation level of As the amount of TPP increased, so did the number of TPP mole- the -NH2 functional group. The degree of deacetylation determines cules available to attach to the free amino groups in chitosan. The the properties of CS, namely hydrophobicity, solubility, and toxicity. The anion may have been introduced to the nanoparticle during creation to manufacturing conditions used to make CS have an effect on its DD and promote cross-linking between chitosan chains, which would account MW. CS in the market has a DD of between 70% and 85% , soluble in for the decrease in CSNPs size as TPP increased. Internal cross-linking acidic medium but insoluble at neutral medium. improves the strength of the chitosan chains inside the particle, further The degree of deacetylation to form different assemblies and vesicles condensing and shrinking it. Cross-linking decreases the amount of. The lower DD promotes the absorption function of the molar available primary amino groups on CS, hence preventing nanoparticles compounds. DD CS regulates its physicomechanical features. from self-aggregating. This is consistent with the fact that the nano- Although medium/high MW CS with acetylation degree less than 40% particles are smaller and have a lower PDI value. This interaction will tend to agglomerate, CS with acetylation ranging from 40% to 60% has been defined in terms of polymeric micelles, which helps to un- are soluble even at physiological pH. derstand the chitosan polymer and cross-linker dynamics in our system A higher DD indicates a stronger biologic effect. to realize the bio-. logical effect of CS and water solubility. The pH of chitosan used also favored the formation of smaller-sized The polycationic amino groups give CS mucoadhesive properties, nanoparticles. The pH of the CS utilized encouraged the creation of prolonging the time spent at the target region and thereby boosting nanoparticles with a smaller diameter. Due to a lesser degree of amine membrane absorption. protonation, chitosan chains are more constricted at pH 5 than in more The critical step in production is that the acetamide group is con- acidic settings. Whenever cross-linked with TPP, a highly compressed CS verted to an amino group during deacetylation of the C-2 position of chain produces particles that are much denser. However, adding TPP chitin (-NH2). DD is an important parameter affecting the structural and reduces the pH of the CNP solution, resulting in increased protonation of functional properties of polymers and the specific materials that follow amine groups. Protonation may cause the ionic bonds between the chi- them. tosan and the TPP in CSNPs to break down, resulting in agglomeration of the nanoparticles. Centrifugation resulted in a reduction in the size of 5) Polarity CSNPs. NPs size influences particle biodistribution, excretion and medication CS, a naturally occurring linear copolymer of β-(1→4)-2-acetamido- delivery. Small molecule (5nm) NP is readily removed by the kidneys, D-glucose and β- (1→4)-2-amino-D-glucose processed by partial deace- resulting in slower blood circulation. The liver and spleen ultimately tylation of chitin [104,105]. CS is a compound that combines electro- remove larger particles. Degradation rate impacts particle dispersion static stabilization due to its positive charge and steric stabilization.. Due to the protonation of amino groups, its hydrophilic character enables high solubility in acidic conditions. The existence of a surface 3.3. Surface properties of CSNPs charge and the potential of altering the molecule using electrostatically charged chemicals stimulate the usage of CS. Several strategies have been established for surface engineering To develop effective DDS polymers, factors affecting solubility such as (modification, functionalization, and grafting) of various NPs. The chemical properties, structure, and degree of crystallinity must be potential of CS as a cationic polymer provides fascinating properties considered. regarding interactions with oppositely charged materials, especially Polymolecularity generally increases with MW and branched struc- mucosal surfaces (via sugar groups such as sialic acid) and nucleic acids ture, leading to an increase in hydrophilicity. Hydrophobic drug release. Increasing the content of amine groups with the possibility of is controlled by surface erosion of polymers; The ratio of hydrophobic to chemical modification will increase the selectivity and adsorption ca- hydrophilic qualities in the polymer backbone determines its breakdown pacity. 8 Y. Herdiana et al. Heliyon 8 (2022) e08674 Strategies for developing for surface engineering CSNPs. toxic nanotransporters, opening the door for biological applications of CSNPs. 1. CSNPs have polycanionic NPsthat interact negatively with the cell membrane and enhancing drug absorption. They are not ideal for 2. Surface roughness: NPs with a rougher surface have a greater con- systemic delivery, however, since they bind to proteins and cells in centration and interact with more proteins following intravenous the blood and are quickly opsonized and removed by the renal sys- injection (IV). tem, resulting in embolism. CSNPs samples were formed through the cross-linking of chitosan chains via amino group ionic interactions. CSNPs can be found either in nanocapsules or nanosphere (Figure 7). The fraction of free primary amino groups remaining in the CSNPs Drug release usually occurs when the polymer degrades and diffuses. The charge on the PNP surface is important, which can affect. its penetration. Positively charged NPs and negatively charged cell Polymers can be used to engineer the pore surface chemistry as a membranes interact electrostatically, will direct the internalization of place for the adsorption of NPs. Porosity can be varied pore size, ratio, endocytotic NPs. Positively charged particles also showed higher and shape. The polymer material is crosslinked, which will promote macrophage uptake and clearance compared to neutral surface charge better stability in various conditions such as extreme pH or temperature NPs, and showed higher toxicity than anionic and neutral NPs.. PNPs may have a drug encapsulated within or surface-adsorbed on Charged particles can also have a negative effect on the integrity of their polymeric core. The hydrophilic, hydrophobic arrangement the BBB. The NP charge also affects protein corona formation, which of the polymer interface will affect the interaction with the surrounding also affects receptor binding. The zeta potential involves determining fluid, especially in wettability. Organic and inorganic nanomaterials will the surface charge. give a high difference for pore-forming. NPs properties affect the rate of releases such as porous, porosity, surface area, and biodegradation The surface of CS-derived NPs usually has a positive charge. The rate. The drug is entrapped through the surface of the matrix or is scat- polycationic CS molecule has a strong interaction with the surface of tered within it. Because of its large surface area, a porous stationary microbial cells, causing a gradual shrinking of the cell membrane and phase would be an excellent stationary phase for analyte molecule ultimately cell death. Similarly, the bactericidal activity of CS is ascribed adsorption. The research indicates that tiny molecules may have a larger to electrostatic interactions between the (NH3)þ CS groups and the initial burst release rate owing to their trapping capacity or surface ab- phosphoryl groups of the cell membrane component phospholipid. Pol- sorption. ycationicity of CS interacts with anionic surface antigen components (lipopolysaccharides and proteins) of microorganisms, contributing to 3. Small substances and proteins such as transferrin albumin antibodies intracellular response: changes in the permeability barrier. It also inhibits are used as active targeting moieties to specifically target tumor tissue bacterial development by blocking nutrient access into the cell and. binding to DNA, preventing protein and RNA production. 4. A variety of natural and synthetic polymers, including as PEG, PEI, Using a charged polysaccharide derivative enabled the scientists to polyglycerols, hydrophilic polyacrylates, CS, and dextran, are stealth- modify the surface charge of the nanocapsules and improve their sta- inducing molecules (prolonging the drug plasma half-life and bility. Acute oral toxicity studies demonstrated the capsules were non- improving the accumulation of these NPs in the target tissue). Figure 7. Type of biodegradable NPs. 9 Y. Herdiana et al. Heliyon 8 (2022) e08674 Due to the high instability of CSNPs in the systemic circulation as a functions, undesirable in drug delivery applications. Drug release result of RES activation, the NP surface is often modified with poly- from CSNPs is more pH-dependent. The drug's pKa and pH values and the ethylene glycol (PEG), a hydrophilic polyether molecule that has been release media were expected to influence release behaviour. At shown in vitro and in vivo to be non-toxic to brain cells. By inhibiting NCs higher pH, crosslinking will be reduced, the extent to which the coun- from interacting with cellular or serum proteins, PEG may help minimize terion converts positively charged amino groups (NHþ 3 ) of CS into the cytotoxicity and macrophage uptake. Finally, since the CS structure has a unionized state [76,131]. NPs were kept in a shrinkage state and drug low solubility and permeability at physiological pH, functionalizing it released due to the attractive electrostatic interaction between anions helps reduce systemic adverse effects while increasing drug loading and and CS. cellular uptake and managing drug release. Furthermore, at an acidic pH, the electrostatic attraction between The NPs surface chemistry may be further complicated by controlled protonated amine groups and H2O molecules was more significant, dis- ligand exchange. One example of ligand exchange is to change the NPs solves CS polymers, resulting in NPs matrix erosion and rapid drug surface from hydrophobic to hydrophilic. NPs synthesized in nonaqueous release. NPs swelled significantly and even dissociated rapidly, media covered with long-chain ligands (such as trioctylphosphine oxide, resulting in the quick model drug release. The cumulative release oleic acid, and oleylamine) are hydrophobic. of drugs from CSNPs could indicate that drug release was faster at lower pH than at neutral or higher pH. 5. Label/drug binding scaffolds provides drug binding sites, light sen- George et al. discovered a much faster rate of release in polymer sitizers, and imaging molecules. conjugates at the of 5.0 than at 6.8 and 7.4. Protonation under acidic conditions will increase swelling in an acidic medium could account for 3.4. Biocompatibility these release characteristics. The swelling of CSNPs, at a higher pH value (7.4) may increase, which would allow release media to penetrate CSNPs have large surface area, zeta potential and provides superior deeper into the polymer matrix, converting the glassy polymer to a activity. The precise and unique characteristic feature of CS such as rubbery state. Drug molecules were able to diffuse out of the CSNPs biodegradability, biocompatibility, very low-toxicity and more quickly and release quickly. non-immunogenicity make this a good vehicle for drug administration Adding polymer conjugates such as L-Histidine (HIS), Alginate, and. Chitosan is highly biocompatible; it does not lead to allergic re- Emulsification and Ionotropic Gelation Technique have opposite charges actions or rejection and is degraded to nontoxic amino sugars in tissues could more stabilize charge and control release against different pH. Chitosan nanoparticle is a drug carrier with the some advantage of slow Due to the –NH2 groups (-NH3 þ) protonation, CS is highly positively and controlled drug release, which improves drug solubility and stability, charged at low pH, The interaction of Hþ ions (at acidic pH) with cations efficacy and reduces toxicity. Nanoparticles are generally made up of on the CS surface, which limits the polymer's hydrolysis, may explain biocompatible polymers, to reduce their rapid clearance from circulation why drug release from NPs occurs quicker in a neutral environment than by the reticuloendothelial system. in an acidic one. The mechanism of drug release from CSNPs: (a) Release of adsorbed 4. Drug release from CSNPs or trapped drug in the surface layer of particles; (b) Diffusion through the swollen rubber matrix, and (c) Release caused by polymer erosion, The drug release from CSNPs has a significant influence on its ther- breakdown, hydrolysis, or degradation of the NPs backbone, resulting in apeutic actions. long-term drug release. Drug release from CSNPs shows a charac- Different shapes and sizes of CSNPs impact releases of the drug due to teristic biphasic pattern characterized by a rapid initial release followed their physicochemical properties. The ability to absorb water or the rate by a slow-er, controlled-release [39,68,76,125,136,137]. In the case of and rate of degradation, chemical composition, MW, solubility, and the hydrogel, the biphasic form of discharge is more prominent. crystallinity of the materials that make up the NPs, will affect the release The drug that is absorbed and trapped in the surface layer of CSNPs of the NPs. Even drug-drug or drug-polymer interactions appear to dissolves immediately upon contact with the media. This phenomenon significantly affect drug release from the delivery system. CSNPs are causes an explosive effect. The structure of the CSNPs carrier will influ- used to regulate release, increase the bioavailability of degraded sub- ence the kinetics of drug release. If the NPs are in the form of nano- stances and enhance absorption of hydrophilic drugs at target sites. capsules, they will show a low initial burst release. The small size of the The process of making CSNPs can be done by crosslinking with anions, CSNPs will also indicate an initial blast release. The NPs diameter de- precipitation, complex coacervation, modified emulsification, ionotropic creases, the specific surface area increases, and the path length to the glassing, precipitation-chemical glutaraldehyde crosslinking, and ther- drug surface decreases. CSNPs can be modified to reduce initial blast mal crosslinking. The choice of manufacturing method depends on the release, Zheng et al. modified conventional PLGA microspheres with requirements of the particle size, thermal and chemical stability of the alginate and CS. Interfacial deposition of hydrophobic polymers drug molecule, reproduction of the kinetic release profile, stability, and was used to create nanocapsules. Drug release is also regulated utilizing a residual toxicity of the final product. mixture of nanospheres and nanocapsules. The release of the drug from the polymer can be regulated by one of The bi-phasic release type helps determine the release pattern, the following mechanisms: (a) The surface of the polymer matrix is especially achieving therapeutic levels rapidly and maintaining eroded, (b) the breaking of polymer bonds at the surface or in the bulk of controlled release. The pattern of bi-phasic drug release also occurs the matrix, or (c) Diffusion of the loaded drug. In many cases, a mixture of in CSNPs, which are made by crosslinking (ionically and covalently). On the three procedures can be used to release the drug. conjugated CSNPs demonstrated a faster release, roughly twice that of The release of the drug from CSNPs is also influenced by pH due to the unconjugated CSNPs. solubility of CS. CS derivatives can design the release of the drug in The kinetic analysis of drug release from CSNP can be carried out by accordance with the expected pharmacokinetic profile of the drug. mathematical models such as the zero-order model, first-order model, the To see the effect of CSNPs modification, see Table 1. Higuchi model, the Hixson-Crowell cube root law, the Baker-Lonsdale In the ionic gelation method, crosslinking is formed by hydrogen time kinetics equation, and the Peppas exponential model. The bonding between the polar groups on the polymer chains. In contrast, diffusion-controlled release kinetics were investigated using the crosslinking is formed by covalent bonds between different functional zero-order, first-order, and Higuchi models. The Hixson-Crowell model groups on the polymer chains facilitated by special crosslinking agents was used to study dissolution-type release kinetics due to changes in. They were covalently crosslinking agents formaldehyde, glutar- surface area or particle diameter. As shown in Table 1, the model aldehyde or genipin, or other compounds with several reactive chemical release from CSNPs has various models: the zero-order , 10 Y. Herdiana et al. Heliyon 8 (2022) e08674 Table 1. Drug release from CSNPs. Preparing CS Composition Agents of Drugs Result of Research Drug Release Assay Effect Drug Release Models Reference Method Self-aggregated. Carboxymethyl CS Curcumin d ¼ 41.27 nm and 87.35 SS methods The highest release (CMC)-based nm. Monodispersed rates of curcumin in nanocarriers simulated intestinal systems (pH ¼ 6.86) Ionic gelation CS-Alginate NPs Doxorubicin d ¼ 100 nm in size Dialysis methods The release of DOX in DOX is quickly released method. (DOX) CS-Alginate NPs was in the initial 10 h then retarded significantly slower or/and due to the controlled for the next encapsulation. 72 h Polyelectrolyte Salecan-CS. Vitamin C (VC) It was observed an SS methods The swelling is great The release mechanism complex (PEC) interconnected, highly influence on the agreed well with the porous architecture. controlled release of Ritger-Peppas model VC. Emulsification Encapsulated CS Capsaicin (CAP) (d) ¼ 180 nm and Dialysis methods. CSNPs controlled and Release kinetics and Ionotropic NPs Efficient Entrapment sustained release of followed the Weibull gelation 70% CAP. model with Fickian technique diffusion Ionic crosslinked Freeze-dried CS Diclofenac Porous CS scaffolds SF methods A swelling-dependent Release kinetics scaffolds sodium loaded with model drug release is affected by followed Higuchi diclofenac sodium significant changes in model with Fickian pore size and porosity. diffusion Crosslinking affects increasing compactness and decreasing overall porosity. The ionic gelation CS and alginate Lovastatin (LS) d ¼ 68 nm–171.8 nm SS methods The NPs' drug release Hixson-Crowell model. method NPs rate is pH and LS is quickly released lovastatin content- from the NPs in the dependent. initial 10 h Ionic gelation CS porous NPs Oil Red O and Denser hydrogels and SF methods A fast release for 1 h, method Rhodamine B. Highly interconnected then reaching the macropores, around equilibrium 50–200 nm and concentration relatively uniformly around 50–100 nm, Ionic interaction CS NPs Double-stranded Irregular morphology, SS methods DS and CS Quickly released from with dextran siRNA d ¼ 353–1083 nm. concentration the NPs in the initial sulfate (DS) as a A more negatively influenced the size of 6h crosslinker charged DS was added NPs. Ionic gelation CSNPs. Hydrocortisone Nonspherical. d ¼ 243  SF method, A Franz The swelling ratios quickly released from method (HC) 12 nm to 337  13 nm diffusion cell increase with the pH of the NPs in the initial incubating media was 6h increased. Particle size and EE (Entrapment Efficiency) of HC loaded as the CS concentration was increased. Ionic gelation CSNPs Ganciclovir d ¼ 121.20  2.7 and EE The assay was carried The incorporation of Higuchi model quickly method (GCV) ¼ 85.15  1.1% out in diffusion cell GCV into CSNPs results released from the NPs apparatus in in enhanced in the initial 10 h phosphate buffer pH permeability, which 6.8. may, in turn, increase the overall oral absorption of the drug. Polymer Glucose- CS NPs Doxorubicin Spherical d ¼ 187.9 nm Dialysis method After incubation for 30 first, the release profile conjugation (GCNPs), (DOX) and a -15.43 mV h, the accumulative was mainly a diffusion- release rates of DOX/ controlled process of GCNPs and DOX/ DOX molecules from CSNPs were 19% and the hydrophobic 21%, respectively. micro-domains; second, the sustained and constant release, maintain the drug concentration at a therapeutic level. (continued on next page) 11 Y. Herdiana et al. Heliyon 8 (2022) e08674 Table 1 (continued ) Preparing CS Composition Agents of Drugs Result of Research Drug Release Assay Effect Drug Release Models Reference Method Polymer Functionalized Naringenin, The nanohybrid Drug release was Improved stability due The Korsmeyer – Conjugates nanohybrid Quercetin and hydrogels exhibited conducted for the to HIS conjugation and Peppas model, a non- hydrogel using L- Curcumin. highly porous three- optimal drug-loaded the pH gives a steady Fickian diffusion-based Histidine (HIS) dimensional crosslinked condition using 100 swelling rate. quickly mechanism, polymer conjugated CS structures as a result of mL of buffer medium released from the NPs erosion. Drug release the electrostatic (PBS buffers with 2% in the initial follow by kinetics from CHGZ interaction between the Tween 80 at controlled release hydrogel predicted a conjugated polymeric physiological pH non-Fickian diffusion- backbone and the ZnO conditions of 5.0, 6.8, based mechanism NPs and 7.4). The drug along with a molecular release was quantified diffusion mechanism. periodically by analyzing the buffer release medium using UV–Vis spectroscopy up to 12 h. Polymer L-leucine Diltiazem a bi-modal distribution, SS method The higher The Korsmeyer-Peppas conjugates. conjugated CS hydrochloride d ¼ 32 nm, and 388.74 dispersibility was model, Fickian NPs. (DH) nm. attributed to the L- diffusion. A big initial leucine conjugate and burst followed by hydrophobic roughly 1–2 weeks of crosslinks' amphiphilic sustained release. environment, and the release profile reflects the more significant swelling. Conjugates CS–steroid Diosgenin Dialysis Methods The steroid releases Zero-order kinetics Reaction. conjugates NPs monoesters pH-dependent and the during the first 12 h. hydrolysis of the ester linkage between the steroid and CS. Hixson-Crowell , Higuchi , Weibull , and the deacetylation , crosslinking agents used for NPs preparation, Korsmeyer-Peppas. concentrations, enzymes , and the media's pH. Incubation of Table 1 shows that CSNPs can transport drugs with efficient loading NPs with lysozyme resulted in a decrease in the size of the NP. Increased and controlled drug release. Two processes can make the drug loading in lysozyme concentration accelerates the reduction in NPs size. The CSNPs: coalescence simultaneously as particle preparation and incuba- degradation rate of glutaraldehyde crosslinked CS NPs was faster than tion (after particle formation). In this case, drug loading is done by the TPP crosslinked CSNPs, both high and low MW. This degradation adding the drug during the NPs formulation process. promotes higher drug release [61,136]. The amount of surface charge decreased significantly after drug The drug release from the CSNPs can be set to the oral delivery sys- filling, but all remained positively charged (empty, conjugated, and drug- tem. As showed by Liu et al., curcumin is released at the fastest con- laden). The surface charge reduction is because of the accumulation of centration in the simulated intestinal system (pH ¼ 6.86), meeting the some drugs on the surface. The adsorbed drug will determine the standard of oral drug administration. These findings imply that NPs surface smoothness of the CSNPs, in which drug molecules occupy the are more suited to the basic environment of the colon, colon, and rectal fully porous hydrogel. HIS-CHGZ hydrogels include histidine and have a mucosa than they are to the acid environment. smoother drug-loaded surface than non-conjugated hydrogels. CUR, Drug release from CSNPs systems is dependent on the degree of which is very hydrophobic, has a rather rough surface, followed by NRG crosslinking, the morphology, the size, the density of the particulate and QE. system, the physicochemical characteristics of the drug, and the presence The greater the drug loading, the more the drug dissolved in the of an adjuvant in this research. Additionally, in vitro release is dependent hydrated polymeric matrix, resulting in a higher diffusional driving force on the pH, polarity, and enzyme content of the dissolving medium. and quicker drug release from the conjugate NPs. This phenome- pH-responsive delivery devices may take advantage of the body's pH non is similar to the release of another hydrophilic drug from CSNPs.: gradients between normal and malignant tissue, or between extracellular propranolol hydrochloride, sodium diclofenac, Diltiazem HCl, and space and particular cell compartments. Previously, we synthesized pH- vitamin C. Apart from showing higher drug release rates, conju- responsive CS-tripolyphosphate NPs loaded with doxorubicin (DOX- gated NPs also continued to release drug for a period of twice as long as CS-NPs). Additionally, we examined its antiproliferative efficacy in vitro other CSNPs because of the higher percentage of a drug charge and the against a variety of tumor cells. The improved anti-tumor efficacy of hydrophobic environment predominating to the surface. The these NPs in vitro is examined in this study, using conditions that timing of drug release can be engineered via encapsulation and simulate both physiological (pH 7.4) and tumor extracellular environ- air-drying. Shrinkage and thickness of the structure caused by the drying ments (pH 6.6). CS-NPs were synthesized through ionotropic gelation process can inhibit diffusion. In general, drug release follows more using the pH-sensitive adjuvant 77KS, which is derived from the amino than one type of mechanism, as shown in Table 1. acid lysine. Drug release from CSNPs was determined by the particle morphology, The multifunctional components used to change the surface of NPs for size, extent of crosslinking, the active substance's physicochemical oral administration have the potential to generate “smart” NPs with pH- characteristics, pH, polarity of the dissolution matrix, and enzymes' triggered and tailored release mechanisms. presence. Chemical and enzyme catalysis are the primary mechanisms by There are many reports about the dangers of nanoparticles, espe- which CS is degraded, with the latter being the predominant process in cially those that dominate metal and metal oxide NPs. After acute sys- vivo. The degradation of CS depends on the MW, degree of temic exposure, the mediating NP toxicity in target organs are reactive 12 Y. Herdiana et al. Heliyon 8 (2022) e08674 oxygen species (ROS) in liver, spleen and kidney, DNA damage resulting Declarations in cell cycle arrest and apoptosis, modification of protein structure and function and impaired inflammation of membrane integrity [22,147, Author contribution statement 148], inhibiting antioxidant effects, and mitochondrial dysfunction. Metal and metal oxide NPs such as silver, zinc, copper oxide, All authors listed have significantly contributed to the development uraninite, and cobalt oxide have also been found to cause DNA damage and the writing of this article.. Gold NPs may induce kidney injury, which can be amplified synergistically as a consequence of interactions with chemicals or Funding statement medications. In general, most NPs tend to accumulate in mono- nuclear phagocytic system organs such as liver and spleen, resulting in This work was supported by Minister of Research and Higher Edu- toxic effects on exposure to nanoparticles including monocytes, plate- cation for funding this project through grant number 1207/UN6.3.1/ lets, leukocytes, dendritic cells, and macrophages [151,152]. For CSNPs PT.00/2021 and Universitas Padjadjaran Academic Leadership Grants there have been no reports showing symptoms such as metal and metal 2021 grant number 2021 1959/UN6.3.1/PT.00/2021. oxide NPs. Due to the nature of biocompatibility and non-toxic properties. Data availability statement 5. Future perspectives No data was used for the research described in the article. In the future decades, the true influence of new polymeric NPs Declaration of interests statement technologies on clinical trials will be obvious. Although specifically receptive to disease pathology, the next generation of nano-enabled drug The authors declare no conflict of interest. delivery products will increase medication performance, patient compliance, and therapeutic success. The use of stimuli-responsive ma- Additional information terials allows for more precision control of drug release kinetics and sites. When designing stimuli-responsive systems and manufacturing chal- No additional information is available for this paper. lenges, other factors must be considered, such as that few of these ma- terials have been tested in vivo. However, emerging technologies have a References long way to go before being transformed into clinically practical J.K. Patra, G. Das, L.F. Fraceto, E.V.R. Campos, M.D.P. Rodriguez-Torres, products. L.S. Acosta-Torres, L.A. Diaz-Torres, R. Grillo, M.K. Swamy, S. 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