pH triggered delivery of curcumin from Eudragit-coated chitosan microspheres for inflammatory bowel disease: characterization and pharmacodynamic evaluation

Objective: This investigation deals with the development and evaluation (in vitro and in vivo) of pH triggered Eudragit-coated chitosan microspheres of curcumin (CUR) for treating ulcerative colitis.

Methods: CUR-loaded chitosan microspheres were initially prepared by emulsion cross linking method followed by coating with Eudragit S-100. The pharmacodynamics of the developed formulation was analyzed in mice by acetic acid induced colitis model.

Results: The developed microspheres were of uniform spherical shape with high entrapment efficiency. CUR-chitosan microspheres showed less intense peaks compared to free CUR confirming inclusion of drug within microspheres as revealed by X-ray diffractogram. Uncoated CUR-chitosan microspheres exhibited burst release within initial 4?h while microspheres coated with Eudragit S-100 prevented premature release of CUR and showed controlled release up to 12?h following Higuchi model. In vivo organ biodistribution study showed negligible amount of CUR in stomach and small intestine confirming integrity of microsphere in upper gastrointestinal tract (GIT). In vivo study revealed significant reduction in severity and extent of colonic damage with CUR-loaded microspheres as compared to pure CUR which was further confirmed by histopathological study.

Conclusion: In vitro and in vivo studies proved the developed formulations as a promising system for pH-dependent delivery of drug to colon in ulcerative colitis.     

Design and characterization of chitosan-alginate microspheres for ocular delivery of azelastine

Abstract

The use of mucoadhesive biopolymers is one of the best approaches to prolong the drug residence inside the cul-de-sac, consequently increasing the bioavailability. Thus, the focus of this work was to develop mucoadhesive microspheres to overcome the limitations of ocular drug delivery. The chitosan-sodium alginate microspheres of azelastine hydrochloride were fabricated using modified ionotropic gelation technique. The particle size, zeta potential, entrapment efficiency and drug release kinetics were evaluated and characterized by SEM, FT-IR, DSC, in vitro mucoadhesion and in vivo study. The microspheres had average particle size in the range of 3.55 to 6.70?µm and zeta potential +24.55 to +49.56?mV. The fabricated microspheres possess maximum drug entrapment of 73.05% with 65% mucin binding efficiency and revealed a controlled release over the 8-h period following a non-Fickian diffusion. SEM showed that microspheres were distinct solid with irregular shape. FT-IR and DSC results concluded the drug entrapment into microspheres. In vivo studies on ocular rat model revealed that azelastine microspheres had better efficacy. Chitosan sodium alginate microspheres prepared were in particle size range suitable for ocular purpose. In vitro release and in vivo efficacy studies revealed that the microspheres were effective in prolonging the drug’s presence in cul de sac with improved therapeutic efficacy.     

Sodium fusidate-poly(D,L-lactide-co-glycolide) microspheres: Preparation,characterisation and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis

Purpose: The aim of this study was to prepare poly(D,L-lactide-co-glycolide) (PLGA) microspheres containing sodium fusidate (SF) using a double emulsion solvent evaporation method with varying polymer:drug ratios (1:1, 2.5:1, 5:1) and to evaluate its efficiency for the local treatment of chronic osteomyelitis.

Methods: The particle size and distribution, morphological characteristics, thermal behaviour, drug content, encapsulation efficiency and in vitro release assessments of the formulations had been carried out. Sterilized SF-PLGA microspheres were implanted in the proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. After 3 weeks of treatment, bone samples were analysed with a microbiological assay.

Results: PLGA microspheres between the size ranges of 2.16–4.12?µm were obtained. Production yield of all formulations was found to be higher than 79% and encapsulation efficiencies of 19.8–34.3% were obtained. DSC thermogram showed that the SF was in an amorphous state in the microspheres and the glass transition temperature (T_g) of PLGA was not influenced by the preparation procedure. In vitro drug release studies had indicated that these microspheres had significant burst release and their drug release rates were decreased upon increasing the polymer:drug ratio (p?<?0.05). Based on the in vivo data, rats implanted with SF-PLGA microspheres and empty microspheres showed 1987?±?1196 and 55526?±?49086 colony forming unit of MRSA in 1?g bone samples (CFU/g), respectively (p?<?0.01).

Conclusion: The in vitro and in vivo studies had shown that the implanted SF loaded microspheres were found to be effective for the treatment of chronic osteomyelitis in an animal experimental model. Hence, these microspheres may be potentially useful in the clinical setting.     

Heparin Immobilized Porous PLGA Microspheres for Angiogenic Growth Factor Delivery

Purpose Heparin immobilized porous poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres were prepared for sustained release of basic fibroblast growth factor (bFGF) to induce angiogenesis.Materials and Methods Porous PLGA microspheres having primary amine groups on the surface were prepared using an oil-in-water (O/W) single emulsion method using Pluronic F-127 as an extractable porogen. Heparin was surface immobilized via covalent conjugation. bFGF was loaded into the heparin functionalized (PLGA-heparin) microspheres by a simple dipping method. The bFGF loaded PLGA-heparin microspheres were tested for in vitro release and in vivo angiogenic activity.Results PLGA microspheres with an open-porous structure were formed. The amount of conjugated amine group onto the microspheres was 1.93 ± 0.01 nmol/mg-microspheres, while the amount of heparin was 95.8 pmol/mg-microspheres. PLGA-heparin microspheres released out bFGF in a more sustained manner with a smaller extent of initial burst than PLGA microspheres, indicating that surface immobilized heparin controlled the release rate of bFGF. Subcutaneous implantation of bFGF loaded PLGA-heparin microspheres in mice significantly induced the formation of new vascular microvessels.Conclusions PLGA microspheres with an open porous structure allowed significant amount of heparin immobilization and bFGF loading. bFGF loaded PLGA-HP microspheres showed sustained release profiles of bFGF in vitro, demonstrating reversible and specific binding of bFGF to immobilized heparin. They also induced local angiogenesis in vivo in an animal model.     

Biodegradable microspheres of ketorolac tromethamine for parenteral administration

Ketorolac tromethamine loaded microspheres were prepared using two different polyesters, namely poly (lactic acid) and poly (glycolic acid) by solvent evaporation technique. The morphology of microspheres was analysed by scanning electron microscopy. In vitro release profiles of these microspheres were studied in phosphate buffered saline pH 7.4. The release kinetics of ketorolac tromethamine from the microspheres was evaluated by fitting the release data to the zero-order, Higuchi and korsemeyer-peppas equations. All microspheres showed initial burst release, followed by fickian diffusion of drug through microspheres. These microspheres were formulated as parenterals to have controlled release system.     

Improved Activity of a New Angiotensin Receptor Antagonist by an Injectable Spray-Dried Polymer Microsphere Preparation

Purpose. To characterize and evaluate in vitro and in vivo the release mechanisms involved in spray-dried biodegradable microspheres having differents Poly(D,L-lactide) blend formulations and containing an antihypertensive drug (L-158,809). Methods. Microspheres and blended polymers were characterized by DSC, SEM, confocal laser microspcopy and size analysis. In vitro release studies were evaluated by using microspheres made from various blends of high and low molecular weight polymer. In vivo studies were evaluated by L-158,809 antagonist ATI function versus the shift of the normal dose-response curve of blood pressure induced by Angio-tensine II. Results. The average yield of L-158,809 microspheres (10% (w/w)) was 95% of the theoritical loading. The average diameter of the microspheres was from 1 to 3 micrometers. In all release experiments, a significant burst effect (< 15%) was observed followed by a near zero-order release kinetics. In vivo studies with two different formulations show a strong shift of angiotensin II dose-response curve. Conclusions. The release kinetics and photomicrographs suggest that the system is best described as a multi-parameter controlled released system in which the drug is molecularly dispersed. In vivo results demonstrating the controlled release of L-158,809.     

Targeted delivery of diclofenac sodium via gelatin magnetic microspheres formulated for intra-arterial administration

In the present work, we have attempted to deliver diclofenac sodium to a target site by intra-arterial injection of gelatin magnetic microspheres and subsequent localization using an external magnet. Drug-loaded magnetic microspheres were prepared by emulsification/cross-linking method, characterized by drug loading, magnetite content, size distribution, optical microscopy, scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) analysis, differential scanning calorimetry (DSC), X-ray diffraction (XRD), absence of glutaraldehyde by gas chromatography, and in vitro release studies. The targeting efficiency and the therapeutic efficacy of microspheres were studied in vivo in rabbits. The microspheres showed drug loading of 9.1, 18.7, 24.9% w/w, magnetite content of 27.8–28.9% w/w with an average size range of 25–30.6 μm, depending upon the drug–polymer ratio. They were spherical in nature as evidenced by optical microscopy and SEM. FT-IR, DSC, and XRD studies revealed the absence of drug–polymer interaction. Gas chromatography confirmed the absence of residual glutaraldehyde. The microspheres were able to prolong the drug release over 24–30 days and the application of sonication during in vitro release study has slightly increased the release rate. After intra-arterial administration of microspheres, 77.7% of injected dose was recovered at the target site which revealed good targeting efficiency. The microspheres effectively reduced joint swelling, but lesser extent than the oral diclofenac sodium in high dose, in antigen induced arthritic rabbits without producing gastric ulceration which was observed in rabbits treated with oral diclofenac sodium.     

Development of gelatin microspheres loaded with diclofenac sodium for intra-articular administration

We have previously reported on the targeting of diclofenac sodium in joint inflammation using gelatin magnetic microspheres. To overcome complications in the administration of magnetic microspheres and achieve higher targeting efficiency, the present work focuses on the formulation of gelatin microspheres for intra-articular administration. Drug-loaded microspheres were prepared by the emulsification/cross-linking method, characterized by drug loading, size distribution, scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), gas chromatography, and in vitro release studies. The targeting efficiency of microspheres was studied in vivo in rabbits. The microspheres showed drug loading of 9.8, 18.3, and 26.7% w/w with an average size range of 37–46 µm, depending upon the drug–polymer ratio. They were spherical in nature and free from surface drug as evidenced by the SEM photographs. FT-IR, DSC, and XRD revealed the absence of drug–polymer interaction and amorphous nature of entrapped drug. Gas chromatography confirms the absences of residual glutaraldehyde. The formulated microspheres could prolong the drug release up to 30 days in vitro. About 81.2 and 43.7% of administered drug in the microspheres were recovered from the target joint after 1 and 7 days of postintra-articular injection, respectively, revealing good targeting efficiency.     

Evaluation of polyanhydride microspheres for basal insulin delivery: Effect of copolymer composition and zinc salt on encapsulation,in vitro release,stability, in vivo absorption and bioactivity in diabetic rats

The potential of poly 1,3-bis-(p-carboxyphenoxy) propane-co-sebacic acid (p(CPP:SA)) microspheres was investigated for controlled delivery of basal insulin. CPP:SA copolymers with molar compositions of 20:80, 40:60, and 50:50 were synthesized, characterized, and used in the fabrication of microspheres by water-in-oil-in-water double emulsion solvent evaporation technique. Insulin stability was assessed using various analytical methods and in vivo insulin absorption and bioactivity were studied in diabetic rats. Microspheres exhibited smooth surfaces and mean particle size ranged from 41.5 to 49.8 µm. Insulin encapsulation efficiency (EE) and in vitro release kinetics were influenced by the molar ratios of CPP:SA copolymer. Increasing CPP content and addition of zinc oxide increased EE, reduced burst release, and prolonged insulin in vitro release over a month. Dimer aggregates were observed for insulin encapsulated in CPP:SA 50:50 microspheres and addition of zinc oxide prevented dimer formation. Subcutaneous administration of CPP:SA 50:50 microspheres in diabetic rats controlled insulin release over a month, and the released insulin was bioactive as determined by lowering blood glucose levels. The results indicate that CPP:SA microspheres controlled insulin release in vitro and in vivo over a month and the released insulin was conformationally and chemically stable, and bioactive. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4237–4250, 2009     

Formulation,evaluation and 32 full factorial design-based optimization of ondansetron hydrochloride incorporated taste masked microspheres

Abstract

Context: Masking the bitter taste of Ondansetron hydrochloride (ONS) may improve palatability, acceptance and compliance of ONS products.

Objective: ONS-loaded, taste-masked microspheres were prepared with a polycationic pH-sensitive polymer and 3² full factorial design (FFD) was applied to optimize microsphere batches.

Materials and methods: Solvent evaporation, in acetone--methanol/liquid paraffin system, was used to prepare taste-masked ONS microspheres. The effect of varying drug/polymer (D/P) ratios on microspheres characteristics were studied by 3² FFD. Desirability function was used to search the optimum formulation. Microspheres were evaluated by FTIR, XRD and DSC to examine interaction and effect of microencapsulation process. In vitro taste assessment approach based on bitterness threshold and drug release was used to assess bitterness scores.

Results: Prepared ONS microspheres were spherical and surface was wrinkled. ONS was molecularly dispersed in microspheres without any incompatibility with EE100. In hydrochloric acid buffer pH 1.2, ONS released completely from microsphere in just 10?min. Contrary to this, ONS release at initial 5?min from taste-masked microspheres was less than the bitterness threshold.

Conclusion: Full factorial design and in vitro taste assessment approach, coupled together, was successfully applied to develop and optimize batches of ONS incorporated taste-masked microspheres.     

Effect of PLGA hydrophilia on the drug release and the hypoglucemic activity of different insulin-loaded PLGA microspheres

The effects of viscosity and hydrophilic characteristics of different PLGA polymers on the microencapsulation of insulin have been studied in vitro and in vivo after subcutaneous administration to hyperglycemic rats. Hydrophilic PLGA polymers produced a higher burst effect than the hydrophobic ones. Moreover, an incomplete insulin release was observed with the hydrophilic PLGA polymers in comparison with the hydrophobic ones. An explanation for that incomplete release can be the development of polymer-insulin interactions associated to the polymer hydrophilic/hydrophobic character, as detected by DSC analysis. Differences in the release rate of microsphere formulations lead to differences in the hypoglycemic action and the weight of animals. Hydrophobic PLGA was able to prolong the hypoglycemic action up to 4 weeks which is at least double than that obtained with hydrophilic PLGA of a similar viscosity. Comparing insulin microspheres with an immediate release formulation, microspheres can increase insulin relative bioavailability up to four times.     

Amphotericin B microspheres: A therapeutic approach to minimize toxicity while maintaining antifungal efficacy

Amphotericin B microsphere formulations with and without addition of polyethylene glycol 2000 in cross-linked bovine serum albumin were prepared. Amphotericin B microspheres were characterized for particle size (<5 µm), zeta potential (～30 mV) and drug interaction by DSC and FTIR and were found to be stable formulations. Drug release profiles for these microspheres revealed that the release was primarily by diffusion. In vitro toxicity as assessed by release of haemoglobin and potassium demonstrated no toxic effect as compared with conventional solution formulation. Antifungal activity in vitro was comparable to solution formulation when tested by broth dilution method.     

In vitro release of adriamycin from drug-loaded albumin and haemoglobin microspheres

Abstract

Release of adriamycin from albumin and haemoglobin microspheres has been determined in vitro using a flow through system. Release from cross-linked albumin microspheres is controlled by the percentage of glutaraldehyde used but release profiles of spheres of 23, 41 and 60 μm diameter were virtually superimposable. Not all of the adriamycin is released from the microspheres over 20 h; as biodegradation occurs in vivo after 24 h the amount of drug remaining in the system at 20 h is likely to be principally released by degradation of the protein matrix in vivo. Estimates of the retained adriamycin vary from 16–26 per cent for albumin (n = 3) and 30 per cent for haemoglobin (n = 1).     

Synthesis and characterization of new derivatives of alginic acid and evaluation of their iron(III)-crosslinked beads as potential controlled release matrices

Abstract

Context: The excellent gelling and safety profiles of alginic acid combined, however, with drawbacks of its ionotropically crosslinked beads (i.e. their quick release of loaded drugs) prompted us to chemically modify alginic acid.

Objective: Alginic acid was chemically conjugated with four amines of varying hydrophilic-hydrophobic properties (i.e. tris(hydroxymethyl)methyl-, allyl-, benzyl- or pentyl-amines) in an attempt to enhance the drug release profiles from respective metal crosslinked beads.

Materials and methods: Chemical conjugation procedures were performed using dicyclohexylcarbodiimide as a coupling agent and the resulting new derivatives were characterized using proton nuclear magnetic resonance (¹H NMR), infrared (IR) spectroscopy and differential scanning calorimetry (DSC). These modified polymers were used to prepare iron (III)-crosslinked beads loaded with folic acid as model drug, which were tested in vitro to assess their folic acid release profiles.

Results and discussion: Interestingly, the resulting beads accessed enteric release kinetics, with tris(hydroxymethyl)methyl-amide alginic conjugate producing most pronounced enteric profile.

Conclusion: The results suggest the possibility of achieving controlled drug release from alginate-based beads via facile chemical modification of alginic acid.     

PLGA and PHBV Microsphere Formulations and Solid-State Characterization: Possible Implications for Local Delivery of Fusidic Acid for the Treatment and Prevention of Orthopaedic Infections

Purpose  To develop and characterize the solid-state properties of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) microspheres for the localized and controlled release of fusidic acid (FA). Methods  The effects of FA loading and polymer composition on the mean diameter, encapsulation efficiency and FA released from the microspheres were determined. The solid-state and phase separation properties of the microspheres were characterized using DSC, XRPD, Raman spectroscopy, SEM, laser confocal and real time recording of single microspheres formation. Results  Above a loading of 1% (w/w) FA phase separated from PLGA polymer and formed distinct spherical FA-rich amorphous microdomains throughout the PLGA microsphere. For FA-loaded PLGA microspheres, encapsulation efficiency and cumulative release increased with initial drug loading. Similarly, cumulative release from FA-loaded PHBV microspheres was increased by FA loading. After the initial burst release, FA was released from PLGA microspheres much slower compared to PHBV microspheres. Conclusions  A unique phase separation phenomenon of FA in PLGA but not in PHBV polymers was observed, driven by coalescence of liquid microdroplets of a DCM-FA-rich phase in the forming microsphere. Electronic supplementary material   The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Preparation,characterization and in vitro release properties of ibuprofen-loaded microspheres based on polylactide,poly(϶-caprolactone) and their copolymers

In this paper, ibuprofen was encapsulated into microspheres by oil-in-water (o/w) emulsion solvent evaporation method. Biodegradable polymers with certain compositions and characteristics such as polylactide (PLA), poly(?-caprolactone) (PCL) and their block copolymer were used to prepare the microspheres. The results indicate that, under the same processing conditions, the drug entrapment efficiency was similar (～80%) for microspheres prepared with PLA and P(LA-b-CL) (78.7/21.3 by mole), but it was only 25.4% for PCL microspheres. The in vitro drug release rate decreased in the order of PCL, P(LA-b-CL) (78.7/21.3 by mole) and PLA microspheres. PCL microspheres showed more serious burst release during the first day (almost 80%) than P(LA-b-CL) (50%) and PLA microspheres (18%). The complete ibuprofen release duration from the last two kinds of microspheres exceeded 1 month. Characterization of the microspheres by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and polarized optical microscope (POM) revealed that ibuprofen was amorphous in PCL microspheres and partially crystalline in P(LA-b-CL) and PLA microspheres. The different release behaviour of ibuprofen from the three kinds of microspheres could be attributed to the different crystallinity of the studied polymers and drug dispersion state in polymer matrices. All the above results suggest that the copolymer with a certain ratio of lactide to ?-caprolactone could have potential applications for long-term ibuprofen release.     

Preparation and testing of cefquinome-loaded poly lactic-co-glycolic acid microspheres for lung targeting

The aim of this study was to prepare cefquinome-loaded poly lactic-co-glycolic acid (PLGA) microspheres and to evaluate their in vitro and in vivo characteristics. Microspheres were prepared using a spry drier and were characterized in terms of morphology, size, drug-loading coefficient, encapsulation ratio and in vitro release. The prepared microspheres were spherical with smooth surfaces and uniform size (12.4?±?1.2?μm). The encapsulation efficiency and drug loading of cefquinome was 91.6?±?2.6 and 18.3?±?1.3%, respectively. In vitro release of cefquinome from the microspheres was sustained for 36?h. In vivo studies identified the lung as the target tissue and the region of maximum cefquinome release. A partial lung inflammation was observed but disappeared spontaneously as the microspheres were removed through in vivo decay. The sustained cefquinome release from the microspheres revealed its applicability as a drug delivery system that minimized exposure to healthy tissues while increasing the accumulation of therapeutic drug at the target site. These results indicated that the spray-drying method of loading cefquinome into PLGA microspheres is a straightforward method for lung targeting in animals.     

Formulation and in vitro evaluation of ethyl cellulose microspheres containing zidovudine

The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of zidovudine using ethyl cellulose as the retardant material with high entrapment efficiency and extended release. Microspheres were prepared by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion method. A mixed solvent system (MSS) consisting of acetonitrile and dichloromethane in a 1:1 ratio and light liquid paraffin were chosen as primary and secondary oil phases, respectively. Span 80 was used as the surfactant for stabilizing the secondary oil phase. The prepared microspheres were white, free flowing and spherical in shape and characterized by drug loading, infrared spectroscopy (IR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release studies were performed using PH 7.4 phosphate buffer. The drug loaded microspheres showed 41–55% of entrapment and release was extended up to 18–20?h. The infrared spectra and DSC and DTA thermograms showed stable character of zidovudine in the drug loaded microspheres and revealed the absence of drug-polymer interactions. SEM studies showed that the microspheres are spherical and porous in nature. Data obtained from in vitro release were fitted to various kinetic models and high correlation was obtained in the Higuchi model. The drug release was found to be diffusion controlled.     

Recent advances in testing of microsphere drug delivery systems

ABSTRACT

Introduction: This review discusses advances in the field of microsphere testing.

Areas covered: In vitro release-testing methods such as sample and separate, dialysis membrane sacs and USP apparatus IV have been used for microspheres. Based on comparisons of these methods, USP apparatus IV is currently the method of choice. Accelerated in vitro release tests have been developed to shorten the testing time for quality control purposes. In vitro-in vivo correlations using real-time and accelerated release data have been developed, to minimize the need to conduct in vivo performance evaluation. Storage stability studies have been conducted to investigate the influence of various environmental factors on microsphere quality throughout the product shelf life. New tests such as the floating test and the in vitro wash-off test have been developed along with advancement in characterization techniques for other physico-chemical parameters such as particle size, drug content, and thermal properties.

Expert opinion: Although significant developments have been made in microsphere release testing, there is still a lack of guidance in this area. Microsphere storage stability studies should be extended to include microspheres containing large molecules. An agreement needs to be reached on the use of particle sizing techniques to avoid inconsistent data. An approach needs to be developed to determine total moisture content of microspheres.     

Characterization and antitumor efficacy of poly(L-lactid acid)-based etoposide-loaded implants

Etoposide is widely used in the chemotherapy of a variety of malignancies. But the strong lipophilicity, poor bioavailability, and severe side effects of etoposide limit its clinical application. The aim of this study was to develop sustained-release etoposide-loaded implants and evaluate antitumor activity of the implants after intratumoral implantation. We prepared the implants containing etoposide, poly(L-lactid acid) and polyethylene glycol 4000 by the direct compression method. The implants were characterized regarding drug-excipient compatibility, content uniformity, morphology, sterility, in vitro, and in vivo release profiles. Then the antitumor activity of the implants was tested in xenograft model of A549 human non-small cell lung cancer. SEM images displayed smooth surface of the implant and indicated that etoposide was homogeneously dispersed in the polymeric matrix. The results of content uniformity met the requirements of the Chinese Pharmacopoeia. Both in vitro and in vivo release profiles of the implants were characterized by high burst release followed by sustained release of etoposide. Intratumoral implantation of etoposide-loaded implants could efficiently delay the tumor growth. Furthermore, increasing the dose of implants led to higher tumor suppression rate without adding systemic toxicity. These results indicated that etoposide-loaded implants have significant antitumor efficacy in xenograft model without dose-limiting side effects and they possess a strong potential to be used as an intratumoral chemotherapy option for lung cancer treatment.