A randomized controlled trial for comparing efficacy and safety between intraarticular polynucleotide and hyaluronic acid for knee osteoarthritis treatment.

Although the use of intra-articular polynucleotide (IA PN) injection as a viscosupplement for knee osteoarthritis (OA) treatment has been proposed, its efficacy and safety compared to high molecular weight hyaluronic acid (HMWHA) injection has not yet been established. The present double-blind, multicenter, randomized controlled trial aimed to investigate the efficacy and safety of IA PN injection compared to IA HMWHA injection. A total of 60 patients (15 men, 45 women, 64.5 ± 7.5 years) with knee OA (Kellgren-Lawrence grade 1-4) were randomly allocated to each group. All patients were given three IA injections of PN (n = 30) or HMWHA (n = 30) at intervals of 1 week. The primary endpoint was the change rate in weight-bearing pain (WBP) 16 weeks from the baseline. The secondary endpoint included multiple measurements: the change rate in WBP rate at 8 weeks; the change rate in pain level at rest and during walking at 8 and 16 weeks; the Korean-Western Ontario and McMaster University Osteoarthritis index; the Euro-Quality of Life-5 Dimension; Clinical Global Impression, Patient Global Impression at 8 and16 weeks, and total consumption of rescue medicine. The mean change rate in the WBP at 16 weeks from the baseline was - 54.0 ± 38.1% in the IA PN group and - 42.8 (± 35.8%) in the IA HMWHA group, and there was no significant difference between the two groups (p = 0.296). All secondary endpoints related with pain and functional outcome also showed no significant difference between the two groups. Pain at the injection site and swelling were reported as adverse events, and the incidence was similar between the two groups. IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be useful alternative to IA HMWHA for the treatment of knee OA.

Hyperbaric oxygenation therapy improve recovery in early or late vascular occlusion generates by tissue fillers.

INTRODUCTION: Aesthetic medicine is characterized by the efficacy and safety of treatments. Although sometimes adverse events could be occurred, in this case vascular occlusion is the most serious of them. The tissue is deprived of oxygen and there is a possibility of necrosis, so it is necessary to remove the tissue filler and promote oxygenation. OBJECTIVE: We propose the hyperbaric oxygenation treatment to oxygenate the tissue after vascular occlusion generated by a tissue filler such as Hyaluronic Acid. RESULTS: We show how hyperbaric oxygenation treatment is an adjuvant therapy after vascular occlusion, improving tissue regeneration and prevent or limit scars or sequelae. CONCLUSION: Hyperbaric oxygenation treatment is a safe and effective method to treat vascular accident, improving tissue oxygenation in early cases and improving tissue regeneration in cases with necrosis.

Effects of a Topical Growth Factor Regimen Following Pre-elected Cosmetic Facial Injection Procedures.

BACKGROUND: There are limited studies evaluating topical cosmetic skincare products following cosmetic facial injections. OBJECTIVE: An open-label study assessed a novel medical-grade topical skincare regimen following cosmetic facial injections. METHODS: The study enrolled 20 women with moderate to severe facial photodamage who used non–physician-dispensed skincare products and pre-elected to receive facial neuromodulator and hyaluronic acid (HA) dermal filler injections. All subjects continued regular skincare through week 4 after facial injection, then switched to the novel regimen (growth factor product, TNS Advanced+; day/night antioxidant serum system, Lumivive; HA-based hydrator, HA5; and basic skincare components) through week 16. RESULTS: At week 4, significant (P≤0.05) improvements from baseline were seen for multiple investigator-graded skin quality parameters, including overall photodamage, tactile roughness, and skin tone evenness, as well as fine and coarse lines/wrinkles. After switching to the novel regimen, additional significant improvements in overall skin quality and forehead, cheek, and perioral fine lines/wrinkles were observed at week 8 (all P≤0.05 vs week 4), which continued through week 16. CONCLUSION: This study highlights the importance of topical skincare in conjunction with cosmetic facial injections to holistically optimize overall skin quality and appearance. J Drugs Dermatol. 2023;21(1): doi:10.36849/JDD.7160.

Efficacy, Safety, and Accuracy of Intra-articular Therapies for Hand Osteoarthritis: Current Evidence.

The lifetime risk of symptomatic hand osteoarthritis (OA) is 39.8%, with one in two women and one in four men developing the disease by age 85 years and no disease-modifying drug (DMOAD) available so far. Intra-articular (IA) therapy is one of the options commonly used for symptomatic alleviation of OA disease as it can circumvent systemic exposure and potential side effects of oral medications. The current narrative review focuses on the efficacy and safety profiles of the currently available IA agents in hand OA (thumb-base OA or interphalangeal OA) such as corticosteroids and hyaluronic acid (HA), as well as the efficacy and safety of IA investigational injectates in phase 2/3 clinical trials such as prolotherapy, platelet-rich plasma, stem cells, infliximab, interferon-? and botulinum toxin, based on the published randomized controlled trials on PubMed database. The limited published literature revealed the short-term symptomatic benefits of corticosteroids in interphalangeal OA while long-term data are lacking. Most of the short-term studies showed no significant difference between corticosteroids and hyaluronic acid in thumb-base OA, usually with a faster onset of pain relief in the corticosteroid group and a slower but greater (statistically insignificant) pain improvement in the HA group. The majority of studies in investigational agents were limited by small sample size, short-term follow-up, and presence of serious side effects. In addition, we reported higher accuracy rates of drug administrations under imaging guidance than landmark guidance (blind method), and then briefly describe challenges for the long-term efficacy and prospects of IA therapeutics.

Hyperbaric oxygen therapy for treatment of a late presenting ischaemic complication from hyaluronic acid cosmetic filler injection.

Vascular compromise and resulting ischaemic injury are known rare complications of cosmetic filler injections. Most hyaluronic acid vascular compromises present early and can be treated effectively by hyaluronidase. Here we present a case of ischaemic wound and mucosal necrosis after cosmetic facial hyaluronic acid injection that appeared within hours of injection but was not diagnosed and treated for 5 days. At day 5, the patient was treated with hyaluronidase injection immediately followed by 14 sessions of daily hyperbaric oxygen therapy (HBOT). Despite the delayed treatment, the patient had essentially complete recovery and the hyperbaric therapy was overall well-tolerated. Our case report suggests that hyaluronidase injection with concurrent daily HBOT sessions may be effective to allow recovery from late-presenting filler ischaemic complication. Furthermore, given the safety profile of HBOT, we suggest a more deliberate approach to this modality as a therapeutic adjunct by cosmetic practitioners when similar complications arise.

Effects of Calf Blood-Deproteinized Extract Ophthalmic Gel Combined with Sodium Hyaluronate Eye Drops on Conjunctival Hyperemia Score and Tear Film Stability in Patients with Dry Eye.

Objective: The aim of this paper is to research the impact of calf blood-deproteinized extract ophthalmic gel combined with sodium hyaluronate eye drops on conjunctival hyperemia score and tear film stability in patients having dry eye. Methods: 144 patients having dry eye disease who were hospitalized from July 2018 to July 2021 were chosen as the research targets, which were composed of the control group and research group on the basis of the sequences of hospitalization, and each has 72 cases. The sodium hyaluronate eye drops were gained in the control one. In accordance with the control one, the study ones were given the combined treatment with eye drops of sodium hyaluronate. Treatment of calf blood-deproteinized extract ophthalmic gel, the scores of conjunctival hyperemia, tear film stability, visual function, curative effect, and their adverse reactions were observed and made comparisons among the two groups. Results: After the treatments of 2 weeks and later 1 month, the numerical values of the conjunctival hyperemia were fewer in the categories which had been mentioned above, and in contrast with the control one (P < 0.05), the numerical values of the conjunctival hyperemia in the study one were distinctly fewer. The data of SIt, BUT, and the heights of the central tear river of the lower eyelid were higher than those before cure. In comparison with the control one, the FL of the study one was distinctly lower, and the heights of SIt, BUT, and the central tear river of the lower eyelid were obviously better than the control one (P < 0.05). After therapy, the visual contrast sensitivity of the patients in two categories at 6.4 c/d and 12c/d increased in comparison with those before treatment, and the visual contrast sensitivity of the study group at 6.4 c/d and 12c/d was apparently higher than the data of control one (P < 0.05); the effective rate of treatment in the study one was 97.22%, which had a higher situation than the control one, 88.89% (P < 0.05); the probability of occurrence of the negative events in the study one after treatment was 4.17%, which was distinctly below the control one, 15.28% (P < 0.05). Conclusion: In order for the treatments of patients having dry eye disease, the use of calf blood-deproteinized extract ophthalmic gel having the combinations with eye drops of sodium hyaluronate can enhance the extent of visual impairment and conjunctival hyperemia with effect and improve the stability of tear film, with significant safety and high efficiency.

Alopecia After Cosmetic Injection Procedures: A Review.

BACKGROUND: Cosmetic procedures for antiaging carry inherent risks of adverse events. One that has not yet been well characterized is transitory or permanent alopecia. This is attributable to numerous mechanisms including pressure, ischemia, inflammation, and necrosis. Cases of postcosmetic procedure alopecia have been reported after mesotherapy as well as hyaluronic acid filler, deoxycholic acid, and botulinum toxin injections. OBJECTIVE: This review serves to describe the currently known causes of postcosmetic procedure alopecia and the mechanisms by which alopecia is attained. Furthermore, this review highlights the risk of unregulated mesotherapy injections for cosmetic enhancement and to bring attention to the increasing number reports of alopecia after these procedures. METHODS: A systematic review of the literature from 2000 to 2022 was conducted looking for keywords such as "alopecia," "cosmetic procedures," "mesotherapy," and "hyaluronic acid" in Google Scholar and PubMed. RESULTS: Ten articles met the criteria set forth in the authors' literature review. Many of the procedures resulted in partial or complete resolution of alopecia. CONCLUSION: Alopecia after cosmetic injection procedures is an underreported adverse effect. More research is needed to further characterize the risk of alopecia after mesotherapy and other injection procedures.

Effects of hyaluronic acid filler injection for non-surgical rhinoplasty on first impressions and quality of life (FACE-Q scale).

BACKGROUND: The nose is a central visual feature of the face leading many patients wishing to improve their facial esthetic appearance to undergo rhinoplasty. Increasingly more patients are seeking non-surgical alternatives such as hyaluronic acid filler injections. These treatments have the ability to profoundly impact patients' esthetic appearance and first impressions. OBJECTIVE: To evaluate the effects of hyaluronic acid filler injection in non-surgical nasal augmentation on first impressions, quality of life, and to evaluate treatment efficacy in reducing the height of the nasal dorsal convexity. METHODS: Ten female subjects underwent small-particle hyaluronic acid filler injection into the nasal soft tissues. Photographs of the subjects were taken at baseline and post-treatment after achieving an optimal correction result. Patients reported satisfaction with outcomes using a validated patient-reported outcome measurement tool. Blinded evaluators were used to assess first impressions across specifically defined categories using the baseline and post-treatment photographs. The height of the pre and post-injection nasal dorsal convexity was compared. RESULTS: All patients experienced a statistically significant reduction in the height of their dorsal nasal convexity. There was significant improvement in patient-reported outcomes based on all measures of the FACE-Q scale. A total of 224 evaluators completed blinded assessments of first impressions. Mean first impressions in all eight categories, along with overall first impression score showed statistically significant improvement following treatment. CONCLUSION: Hyaluronic acid filler injections for non-surgical nasal reshaping are a safe and effective method to improve perceived first impressions and to improve patient-reported self-esteem and esthetic satisfaction with their nose.

The efficacy and tolerability of pollen extract in combination with hyaluronic acid and vitamins in the management of patients affected by chronic prostatitis/chronic pelvic pain syndrome: a 26 weeks, randomized, controlled, single-blinded, phase III study.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains a challenging clinical condition to manage. Here, we evaluate the efficacy and tolerability of a new treatment option (suppositories) containing pollen extract in combination with hyaluronic acid and vitamins in the management of patients with CP/CPPS. METHODS: In this prospective, randomized, controlled, single-blinded, phase-III study we enrolled CP/CPPS patients between March and December 2019. Participants were randomized (1:1) to the following treatment groups: 1) pollen extract suppositories 1 daily for 10 days; or 2) ibuprofen 600 mg 1 tablet in the morning for 10 days. At the enrolment time and at the follow-up evaluations (3, 6 months), all patients completed baseline questionnaires ([National Institutes of Health Chronic Prostatitis Symptom Index [NIH-CPSI] and Quality of Well-Being [QoL]) and underwent urological examination and microbiological evaluation. The primary endpoint was the quality-of-life assessment with Patients' Reported Outcomes (PROs). RESULTS: One hundred and eighty-seven patients were screened. Finally, one hundred and twenty-four patients (mean age 34.6±3.9 years) were randomly allocated to the new pollen extract treatment (N.=63) or ibuprofen (N.=61) groups. At the end of follow-up examinations 56/63 group 1 patients (88.8%) showed a significant reduction of the NIH-CPSI total score, compared with 17/61 (27.8%) in group 2 (P<0.0001). Group 1 patients also reported a higher improvement in terms of PROs, when compared with the control group and group 1 patients reported a significant reduction of leucocyte count at the Meares-Stamey Test (-12; -4; P<0.001). Only mild adverse events were reported in the two groups and adverse events were less frequent in the pollen extract suppositories group. CONCLUSIONS: The combination of pollen extract with hyaluronic acid and vitamins is more effective than ibuprofen in improving symptoms and Quality of Life in patients affected with CP/CPPS and has less side effects.

Hyaluronic Acid Compound Filling Plus Mesotherapy vs Botulinum Toxin A for the Treatment of Horizontal Neck Lines: A Multicenter, Randomized, Evaluator-Blinded, Prospective Study in Chinese Subjects.

BACKGROUND: Although energy devices and botulinum toxin A (BTX-A) can alleviate age-related laxity, ptosis, and platysmal bands, they have limited efficacy on horizontal neck lines. OBJECTIVES: The purpose of this study was to investigate the efficacy, safety, and subject satisfaction of a combined treatment of non-cross-linked hyaluronic acid (HA) compound filling plus mesotherapy for the correction of horizontal neck lines, in comparison with BTX-A. METHODS: This multicenter, randomized, evaluator-blinded, prospective study enrolled female patients with moderate-to-severe horizontal neck lines corrected with either 2 or 3 sessions of of non-cross-linked HA compound filling plus mesotherapy or 1 session of BTX-A injection. Improvement of the neck lines grades, Global Aesthetic Improvement Scale (GAIS), patient satisfaction, and adverse events (AEs) were evaluated and compared at 1, 3, 6, and 10 months after the final treatment. RESULTS: Twenty-five patients received HA filling plus mesotherapy and 23 received BTX-A injection. Compared with BTX-A, the HA compound filling plus mesotherapy significantly improved the horizontal neck lines grades on all follow-up visits (P = 0.000). Cases of different baseline grades (2, 2.5, and 3) demonstrated similar outcomes. The GAIS and patients' satisfaction ratings were significantly higher for the HA filling plus mesotherapy treatment group (P = 0.000). Significantly higher pain ratings, higher incidence, and longer recovery of AEs (erythema, edema, and ecchymosis) were noticed in the combined treatment group (P < 0.001). No serious AEs occurred. CONCLUSIONS: Compared with BTX-A, combined treatment with HA compound filling plus mesotherapy significantly improved moderate-to-severe horizontal neck lines and achieved a high level of patient satisfaction.

Oral intake of a new full-spectrum hyaluronan improves skin profilometry and ageing: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Skin aging is a physiological condition which leads to structural and functional changes in skin. Common signs of aging are the gradual decrease of hyaluronic acid (HA) in the skin and the appearance of wrinkles. Therefore, effective HA supplementation could counteract HA deficiency and improve skin parameters, providing a safe profile for use which is easily incorporated into daily routine. OBJECTIVES: To evaluate a food supplement containing a wide range of hyaluronans of different molecular weights (full-spectrum hyaluronan [FS-HA]) in order to ameliorate skin conditions in adult females. MATERIALS & METHODS: Sixty subjects showing mild-to-moderate skin aging signs were enrolled in a double-blind, randomized, placebo-controlled clinical trial to receive 200 mg/day of FS-HA (ExceptionHYAL® Star), or placebo, for 28 days. Dermatological parameters were evaluated at T0d and T28d. Product efficacy and tolerance were further evaluated using a self-assessment questionnaire. In addition, HA serum levels were weekly evaluated in a proportion of enrolled subjects. RESULTS: After only 28 days, subjects in the active arm showed a statistically significant improvement in all evaluated dermatological parameters related to skin aging. Skin became more hydrated (+10.6%) and protected from dehydration, with a decrease in both wrinkle depth (-18.8%) and volume (-17.6%) and increase in elasticity and firmness (+5.1%). Instrumental results were further confirmed by self-assessment questionnaire outcomes. CONCLUSION: Administration of a food supplement based on innovative hyaluronans from bio-fermentation, characterized by a wide range of molecular weights, resulted in a quick and significant amelioration of typical signs of skin aging.

Use of hyaluronidase in plastic surgery: A review.

Hyaluronidase is a family of enzymes that degrade hyaluronic acid (HA). It is found to increase vascular permeability and temporarily disrupt the extracellular matrix, promoting diffusion of substances through tissues. Alongside its applications in ophthalmology, obstetrics and gynaecology, musculoskeletal medicine, radiology and drug and fluid administration, hyaluronidase has a number of roles in the field of plastic surgery. The popularity of HA fillers in recent years has led to an increase in the usage of hyaluronidase in the treatment of filler-related complications. The purpose of this article is to review the current and future uses of hyaluronidase within the field of plastic surgery. Hyaluronidase is used as an adjunct to local anaesthetics in skin infiltration, skin graft harvesting, tumescent analgesia, managing complications of dermal fillers, treatment of extravasation injury, prevention and management of oedema, treatment of ganglion and management of scars. However, it has some limitations. Hyaluronidase is known to interact with a number of common medications. Several case reports also highlight the risk of allergic reaction to the substance. Although rare and usually mild, hyaluronidase has the potential to cause anaphylaxis. Other adverse effects include bruising and swelling. Overall, hyaluronidase appears to be a very safe, cheap and effective medication for a variety of uses in the field of plastic surgery and beyond.

Mandibular osteomyelitis after hyaluronic acid injection.

BACKGROUND: Mandibular osteomyelitis after filler injection is extremely rare. AIMS: We reported a case of mandibular osteomyelitis after hyaluronic acid injection. PATIENTS: A 33-year-old woman received 1 mL hyaluronic acid injection on her chin 1 year ago, after which her chin kept swelling and painful, and gradually ulcerated with pus flowing out. She received antibiotics, debridement procedures, negative pressure wound therapy, and hyperbaric oxygen therapy without symptoms improved. Cone-beam computed tomography scan showed local bone destruction, sequestrum formation, and tissue calcification on the right mandible body. The patient was diagnosed with mandibular osteomyelitis and received local curettage for the removal of necrotized bone. RESULTS: Literature search found no case reports on mandibular osteomyelitis after filler injection so far. CONCLUSION: Minimizing the risk of contamination and infection is strictly required during the filler injection process. Once the patient shows signs of incurable mandibular infection postoperation, clinicians should consider the possibility of osteomyelitis.

Ophthalmoplegia with skin necrosis after a hyaluronic acid filler injection.

Hyaluronic acid filler injection is commonly used for aesthetic purposes. However, many clinicians neglect the possibility of developing vascular occlusion and its devastating sequelae. Besides visual loss after iatrogenic ophthalmic artery occlusion, ophthalmoplegia without blindness is rare but may occur. Here, we report a 23-year-old woman with ptosis, lateral deviation of the right eye, and skin necrosis after hyaluronic acid filler injection. After hyaluronidase injection and steroid pulse therapy, ptosis and eye movement were completely restored. Skin necrosis was treated with a human epithelial growth factor ointment, followed by Nd:YAG laser. Complete healing with minimal scar was achieved.

Treatment of skin soft tissue embolism after hyaluronic acid injection for injection rhinoplasty in Asian patients.

INTRODUCTION: The purpose of this manuscript is to investigate the treatment of skin soft tissue embolization or vascular occlusion after the injection of hyaluronic acid (HA) for Injection Rhinoplasty (IR) in Asians with a special interest in the time occurrence of the occlusion. METHODS: A total of 35 cases were evaluated after receiving HA injections for IR who presented with a vascular occlusive event. They were divided into three stages based on the time to embolization. Immediate, ≤5 hours; early, ≤3 days; and late, >3 days. There were two cases of immediate, 28 deemed early, and five late. Methods to prevent tissue necrosis are reviewed in the manuscript based on these stages. RESULTS: Skin color gradually recovered to normal after 11 treatments in 11 patients with mild embolization. No ischemic aggravation or skin necrosis was observed in 19 patients with moderate embolization; red scarring was seen in two and hypertrophic scar with uneven skin color in one patient. The five patients in the severe category had longer healing, more red scars, and more hypertrophic scarring. CONCLUSION: The treatment of skin soft tissue embolization or vascular occlusion after HA IR in Asians can be effected by identifying the stage and degree of embolization and treating appropriately with the outlines presented in this manuscript.

Hyaluronidase inhibits reactive adipogenesis and inflammation of colon and skin.

In this study we evaluated the role of hyaluronan (HA) in reactive adipogenesis, a local expansion of preadipocytes that provides host defense by release of antimicrobial peptides. We observed that HA accumulated during maturation of adipocytes in vitro and was associated with increased expression of preadipocyte factor 1, zinc finger protein 423, and early B cell factor 1. Although HA is normally abundant in the extracellular matrix, a further increase in HA staining occurred in mice at sites of reactive adipogenesis following injury of colon by dextran sodium sulfate or injury of skin from infection with Staphylococcus aureus. HA also abundantly accumulated around adipocytes seen in the colons of patients with inflammatory bowel disease. This HA was necessary for adipocyte maturation because digestion of HA by administration of soluble hyaluronidase or transgenic expression of hyaluronidase 1 inhibited adipogenesis in vitro and in vivo. Furthermore, hyaluronidase also suppressed inflammation of both skin and colon and decreased antimicrobial peptide expression by developing preadipocytes. This resulted in increased bacterial transit across the epithelial barrier despite decreased tissue injury from inflammation. These observations suggest HA plays an important role in reactive adipogenesis and host defense after injury.

Pulsed-dye laser as a novel therapeutic approach for post-filler bruises.

Fillers have become popular worldwide as the demand for enhancements in rejuvenating effects and esthetic improvements is continually increasing. With broader applications and the increasing number of cosmetic procedures using fillers, more filler-related complications are being reported. These filler-related complications range from mild bruising to severe vascular complications. Because of the severe and irreversible outcomes of vascular complications, treatment protocols for such complications are being investigated and updated actively. However, not much attention is paid to mild bruises that develop after filler injections. Simple observation is the treatment of choice for bruises in current filler complication protocols. In the present study, the possible effect of a pulsed-dye laser (PDL) on bruises is reported, with a case report of a female patient who received PDL treatment for a bruise that developed after a filler injection.

Gastric cancer combination therapy: synthesis of a hyaluronic acid and cisplatin containing lipid prodrug coloaded with sorafenib in a nanoparticulate system to exhibit enhanced anticancer efficacy and reduced toxicity.

PURPOSE: Gastric cancer is one of the most common human epithelial malignancies, and using nanoparticles (NPs) in the diagnosis and treatment of cancer has been extensively studied. The aim of this study was to develop hyaluronic acid (HA) containing lipid NPs coloaded with cisplatin (CDDP) and sorafenib (SRF) for the treatment of gastric cancer. MATERIALS AND METHODS: HA and CDDP containing lipid prodrug was synthesized using polyethylene glycol (PEG) as a linker (HA-PEG-CDDP). HA-PEG-CDDP and SRF were entrapped into the lipid NPs by nanoprecipitation method (H-CS-NPs). The physicochemical and biochemical properties such as size, zeta potential, and drug release pattern were studied. In vitro viability was also evaluated with MKN28 and SGC7901 human gastric cancer cells. In vivo testing including biodistribution and accumulation in tumor tissue was applied in gastric tumor-bearing mice to confirm the inhibition of gastric cancer. RESULTS: H-CS-NP has a particle size of 173.2±5.9 nm, with a zeta potential of -21.5±3.2 mV. At day 21 of in vivo treatment, H-CS-NPs inhibited the tumor volume from 1,532.5±41.3 mm3 to 259.6±16.3 mm3 with no obvious body weight loss. In contrast, mice treated with free drugs had body weight loss from 20 to 15 g at the end of study. CONCLUSION: The results indicate that H-CS-NPs enhanced the antitumor effect of drugs and reduced the systemic toxicity effects. It could be used as a promising nanomedicine for gastric cancer combination therapy.