Among the biodegradable polymers developed for the formulation of polymeric nanoparticles, PLGA has attracted considerable attention and is widely used for its appealing characteristics, such as outstanding biocompatibility, favorable biodegradation, and FDA and EMA approval. PLGA-based delivery systems have demonstrated significant promise in treating bone tumors (Table 2).

Studies have shown that these systems provide controlled drug release, which can enhance their therapeutic efficacy while reducing the side effects associated with traditional chemotherapy. Additionally, PLGA-based systems have demonstrated high biocompatibility and biodegradability, which makes them ideal for long-term use for bone tissue engineering applications. Salerno et al. developed alendronate (ALN)-conjugated PLGA nanoparticles loaded with doxorubicin (DOX) for treating bone metastases from breast cancer (Salerno et al., 2010), and the obtained ALN-PLGA-DOX nanoparticles had good biocompatibility and the ability to target tumor-induced osteolytic sites (Cenni et al., 2008; Pignatello et al., 2009; Pignatello, 2011; Cenni et al., 2012; Thamake et al., 2012; Yin et al., 2016). In vivo studies showed that the ALN-PLGA-DOX nanoparticles could reduce the incidence of tumor metastasis and decrease the number of osteoclasts at tumor sites in mice. Gdowski et al. prepared ALN-conjugated PLGA nanoparticles loaded with cabazitaxel for enhanced drug delivery to the bone microenvironment (Figure 3). These bone-targeted PLGA-ALN nanoparticles significantly reduced tumor burden and pain in the tumor-bearing limbs of mice (Gdowski et al., 2017), representing a promising strategy for treating metastatic bone cancer. These results suggest that ALN-conjugated PLGA nanoparticles deserve further evaluation as practical for delivering anti-cancer drugs to bone tumors.

Bortezomib shows significant anti-tumor activity in multiple myeloma. Swami et al. (Swami et al., 2014) found that bortezomib/PLGA nanoparticles inhibited myeloma growth in mice (Figure 4). Modifications of nanoparticle surface with PEG prevent clearance by the reticuloendothelial system. The Bortezomib-loaded ALN-PLGA-PEG nanoparticles exhibited good retentive, accumulative, and bone-homing properties. The zoledronate (ZOL)-conjugated PLGA-PEG-DOX nanoparticles also showed prolonged circulation half-life, reduced hepatic uptake, significantly longer tumor retention, and more effective prevention of multiple myeloma growth (Chaudhari et al., 2012). Similar observations of enhanced cellular uptake and increased tumor regression in mice (Li et al., 2019a; Yuan et al., 2020) were found for multiple drug-loaded PLGA-ZOL nanoparticles (Figure 5), demonstrating the conjugation of PLGA with a bisphosphonate with anti-tumor agents can be served as a potential treatment for osteosarcoma.

Intravenous administration of ifosfamide (IFS) is indicated as the mainstay of treatment for osteosarcoma. Chen et al. enclosed ifosfamide in a conjugate of dextran and PLGA to evaluate its anti-cancer activity towards osteosarcoma tumor cells (Figure 6). The resulting particles showed a more significant promotion of cell death and apoptosis and superior in vitro anti-cancer activity compared to the free ifosfamide (Chen et al., 2015), suggesting that the PLGA nanoparticles obtained could be a possible therapeutic approach for treating osteosarcoma. Due to the complex microenvironment and drug resistance mechanisms of cancer, single-agent cancer therapy remains unsatisfactory (Liu, 2009; Bar-Zeev et al., 2017). Combination therapies are promising strategies to improve treatment efficacy and decrease adverse events (Xiao et al., 2017). The combined administration of more than one chemotherapeutic agent can produce synergistic suppression of cancer cells. Wang et al. encapsulated etoposide (ETP) and paclitaxel (PTX) into PLGA nanoparticles to investigate the synergistic effect of the combination regimen to promote apoptosis as a treatment for osteosarcoma (Wang et al., 2015). The resulting PLGA-PTX-ETP nanoparticles exhibited potent anti-cancer effects in MG63 and Saos-2 cancer cells in a time- and concentration-dependent manner. Co-administration of PTX and ETP led to the arrest of the cell cycle and enhanced cell apoptosis. The findings revealed that the combination significantly improved the treatment efficacy of the anti-cancer drugs. The combination of nanoparticles has a more significant inhibition effect, which will be beneficial for systemic cancer treatment. In conclusion, multi-drug PLGA nanoparticles will be a highly anticipated anti-cancer delivery system for treating osteosarcoma.

Melatonin has potent antioxidant, immunomodulatory, anti-proliferative, and tumor-suppressive properties (Moradkhani et al., 2020). Studies have shown that melatonin significantly inhibits tumor cell growth and can reduce chemotherapy drugs’ side effects (Bondy and Campbell, 2018; Gurunathan et al., 2021). Melatonin has a short half-life, which prolong its pharmacological effect. Altındal et al. used an emulsion-diffusion-evaporation method to encapsulate melatonin in PLGA nanoparticles, and MG-63 cells were significantly inhibited by melatonin/PLGA nanoparticles (Altındal and Gümüşderelioğlu, 2016). The results laid the foundation for studying melatonin/PLGA as an adjunct to conventional chemotherapy for osteosarcoma.

Salinomycin (SAL) has a highly selective anti-cancer activity. However, its low solubility in water reduces its therapeutic effect. To overcome this limitation, Irmak et al. encapsulated SAL in PLGA nanoparticles and evaluated the anti-cancer effect of the resulting delivery system. The results showed that PLGA/SAL nanoparticles could reduce proliferation and promote apoptosis of MG-63 cells more than SAL. The nanoparticles were also able to induce caspase-3 expression and inhibit that of β-catenin (Wnt/β-catenin pathway) and c-myc genes in osteosarcoma cancer cells, thus achieving a synergistic anti-cancer effect (Irmak et al., 2020). The findings showed that PLGA/SAL nanoparticles were faster and more effective than free SAL in eliminating osteosarcoma cells.

PLGA-carbon nanotube (CNT) conjugates provide binding targets for the caspase-3 (CP3) to form a CNT-PLGA-CP3 coupling that can effectively transduce cells and inhibit cell proliferation for up to 1 week at doses down to 0.05 μg/mL. These results are critical in demonstrating the ability of gene delivery using PLGA-functionalized CNTs for cell fate regulation (Cheng et al., 2013). The PLGA nanoparticles loaded with other anti-cancer agents, such as sclareol (Cosco et al., 2019), castalin (Zhang et al., 2022), and simvastatin (Venkatesan et al., 2019; Jin et al., 2021a), also present potent anti-cancer activity, indicating that PLGA nanoparticle delivery systems have promising potential for treating bone cancers.

Although PLGA-based nanoparticles have been intensively explored for targeted cancer therapeutics because they promise to improve and prolong the efficacy of conventional anti-cancer drugs with fewer adverse effects, they suffer from limitations, including clearance by the reticuloendothelial system and insufficient penetration capacity to tumor cells (Zhang et al., 2016; Wang et al., 2020a). Membrane extracted from tumor cells could be employed for coating nanoparticles to achieve homologous targeting (Sun et al., 2016). Furthermore, nanoparticles coated with tumor membranes exhibited high conjugative capacity and specific uptake into homologous tumor cells, leading to lower levels of immune-clearance after routine administration (Harris et al., 2019). To take advantage of homologous targeting and minimized immunological clearance, Cai et al. prepared paclitaxel (PTX) loaded PLGA nanoparticles encapsulated in osteosarcoma cell membranes and macrophage membranes for the targeted delivery of chemotherapeutic agents to osteosarcoma (Cai et al., 2022). In vitro studies demonstrated that PTX-PLGA nanoparticles enhanced the PTX uptake by the tumor cells and caused apoptosis in the osteosarcomas. They showed excellent tumor-targeted activity and significant tumor growth inhibition and were less toxic than free PTX. The research offers a targeted delivery approach for osteosarcoma therapy. The human osteosarcoma cell membrane-coated PLGA nanoparticles loaded with IR780 significantly improved endocytosis in vitro and tumor accumulation in vivo and induced considerably apoptosis and iron phagocytosis in HOS cells by excessive accumulation of ROS (Figure 7). At the same time, the PLGA-IR780-loaded nanoparticles-guided PDT also significantly inhibited tumor growth in vivo (Wang et al., 2022a).

Polymeric micelles are nanometer-sized (5–100 nm) colloidal particles that readily self-assemble from amphiphilic polymers (Jones and Leroux, 1999; Movassaghian et al., 2015). Over the past 20 years, polymeric micelles have received considerable research focus in drug delivery, with particular emphasis on their possible uses in the main areas of delivering drugs, including drug solubilization, controlled drug release, and drug targeting (Croy and Kwon, 2006; Miyata et al., 2011; Ahmad et al., 2014). Polymer micelles have gained attention as a novel approach to treating and diagnosing cancer due to various advances compared to conventional drug delivery. These include the following key advantages, 1) improved drug solubility: many anti-cancer drugs have poor solubility, which can limit their effectiveness. Polymeric micelles can enhance drug solubility, allowing for improved drug delivery and efficacy; 2) selective targeting: polymeric micelles can be engineered to target specific cells or tissues, including cancer cells. This allows for more precise drug delivery and reduces the risk of off-target effects; 3) reduced toxicity: Polymeric micelles can help reduce the toxicity by minimizing their exposure to healthy cells and tissues, reducing the risk of side effects and improving patient outcomes; 4) enhanced circulation time: polymeric micelles can increase the circulation time of drugs in the body, allowing for sustained drug release and improved therapeutic efficacy; 5) enhanced accumulation of anti-cancer drugs in the tumor: Their enhanced permeability and retention (EPR) effects allow them to accumulate in the tumor microenvironment. Overall, the advantages of polymeric micelles make them promising for treating cancers (Biswas et al., 2016; Yu et al., 2019b; Majumder et al., 2020; Ghosh and Biswas, 2021; Hari et al., 2023). One clinically successful micelle formulation is Genexol, which is paclitaxel encapsulated in a polylactic acid polymer micelle and was approved in Korea in 2007 for treating breast, lung, and ovarian cancer (Egusquiaguirre et al., 2012; Cabral and Kataoka, 2014; Deshmukh et al., 2017; Kar et al., 2020; Norouzi and Hardy, 2021).

PLGA-based polymer micelles have demonstrated significant promise in treating bone cancers (Table 3). Research studies have shown that these micelles can effectively deliver anti-cancer drugs to tumor locations and increase the effectiveness of the drugs. In addition, PLGA-based polymeric micelles have also been found to enhance drug solubility and bioavailability, thereby reducing the side effects associated with chemotherapy. For example, PEG–PLGA micelles were used to encapsulate the gallium (III)-diflunisal complex for treating osteosarcoma, and the results showed that the resulting nanoparticle formulations were 5,645 times more potent against osteosarcoma than doxorubicin and cisplatin. The nanoparticle formulation also induced nuclear damage to DNA, downregulation of cyclooxygenase-2, and caspase-driven apoptosis (Passeri et al., 2023).

Liu developed chitosan (CS)-conjugated PLGA micelles loaded with docetaxel (DOC) and alendronate (ALN) to increase the therapeutic efficiency in osteosarcoma cells. CS-conjugated PLGA with dual-drug-loaded (DTX and ALN) micelles exhibited typical time-dependent cellular uptake and also showed higher cytotoxicity in MG-63 cells in comparison to blank micelles, which were found to be safe and biocompatible. The findings suggested that the combined loading of DTX and ALN into micelles enhances the therapeutic efficacy of the formulation for osteosarcoma therapy (Liu et al., 2016).

Cisplatin (CDDP) is a potent anti-cancer drug commonly used in the treatment of osteosarcoma, but the efficacy of CDDP is limited by severe undesirable side effects such as renal toxicity and neurotoxicity. The formulation of CDDP in polymer micelles is anticipated to reduce the adverse related impact while improving efficacy. Liu et al. encapsulated CDDP in ALN-PLGA micelles (PLD) conjugated with dextran (DX) to enhance the specificity of the delivered system for bone tumor cells and improve the efficacy of osteosarcoma treatment. In vitro cellular cytotoxicity tests showed that PLD/CDDP micelles had outstanding anti-cancer activity and exhibited substantial cellular uptake via an endocytic-mediated mechanism. In comparison with free CDDP, PLD/CDDP had a marked apoptosis effect on MG63 cancer cells. The most important thing, PLD/CDDP demonstrated the most pronounced anti-tumor efficacy and the highest tumor inhibition, suggesting excellent anti-cancer potential in osteosarcoma. Taken together, the PLD/CDDP micelles significantly improve the anti-cancer activity of CDDP in osteosarcoma cells, and PLD-containing CDDP formulations may represent a most promising and efficacious therapeutic approach for the control of osteosarcoma (Liu et al., 2015).

Miller et al. developed PEG-PLGA micelles for the co-delivery of PTX and ALN, which synergistically target bone metastases from breast cancer. In vitro results have shown that the PTX-PLGA-ALN micelles have almost identical cytotoxic as well as anti-angiogenic features to those of the free drugs. Furthermore, in a model of mCherry-infected tibia cancer, PTX-PLGA-ALN micelles achieved superior efficacy and safety compared to free PTX. The results showed that the selective accumulation of the PTX-PLGA-ALN micelles in the tumors resulted in a higher inhibition of tumor growth than the controls (Miller et al., 2013).

Mithramycin A (MTM), a natural chrysophanol polyketide, has been used to treat several types of cancer. Despite its efficacy, serious adverse effects have hindered its use in clinical practice at the concentrations necessary to achieve a beneficial therapeutic outcome. Estupiñán et al. provided MTM-loaded PLGA micelles for efficient nano-delivery of MTM. These MTM nano delivery systems mimic the potent anti-tumor efficacy of free MTM in both liposarcoma and chondrosarcoma models. As with free MTM, nanocarrier-delivered MTM also effectively suppressed SP1-mediated signaling. This suggests they may provide a safer delivery option for MTM that could be investigated for clinical use in the future (EstupiñánRendueles et al., 2021).

These studies suggest that PLGA-based polymeric micelles have great potential for treating bone cancers and could provide a promising alternative to traditional chemotherapy. At the same time, further exploration is necessary to fully understand the potential of these micelles in the treatment of bone cancer. The initial results are promising and suggest they may be a viable treatment option.

PLGA-based hydrogels have shown great promise in the therapy of bone tumors. These hydrogels can be loaded with drugs or other therapeutic agents and implanted into the bone, where they slowly release the medicine over time. This approach allows accurate and selective drug delivery directly to the cancer cells with minimal adverse effects on surrounding normal tissues (Jin et al., 2021b; Liao et al., 2021). The FDA-approved PLGA-PEG-PLGA triblock copolymer is a candidate for the local delivery vehicle to bone tumors (Marques and Kumar, 2022). Ma et al. developed a novel strategy for osteosarcoma therapy using PLGA-PEG-PLGA hydrogel to release a combination of drugs, such as MTX, CDDP, and DOX (Figure 8). The results showed that the hydrogels co-loaded with multiple drugs displayed cytotoxicity that was synergistic towards the tumor cells in vitro. Following injection into Saos-2 osteosarcoma xenografts, drug-loaded hydrogels provided the most potent tumor suppression in vivo for 16 days (Ma et al., 2015). Furthermore, systemic toxicity was reduced, and no significant injury. Thus, local co-administration via a PLGA-PEG-PLGA hydrogel may be a viable therapy to enhance the treatment efficacy of osteosarcoma. The authors also used PLGA-PEG-PLGA hydrogel for local delivery of PLK1shRNA/polyether-modified polyethylene glycol (PEI-Lys) complex and DOX for osteosarcoma therapy. The resulting drug delivery system showed significant and synergistic effects in inducing osteosarcoma cell apoptosis when cultured with Saos-2 and MG63 osteosarcoma cells. Following subcutaneous injection of the drug delivery system adjacent to Saos-2 osteosarcoma in nude mice, the hydrogels demonstrated more excellent anti-tumor activity in vivo (Ma et al., 2014). In particular, the combined in vivo therapy resulted in almost total inhibition of tumor proliferation for 16 days without significant organ damage, suggesting that co-delivery of PLK1 shRNA and DOX by PLGA-PEG-PLGA hydrogels might offer the opportunity for effective therapy of osteosarcoma in the clinic.

To develop a more effective combination therapy for treating osteosarcoma, Yang et al. used PLGA-PEG-PLGA as a vehicle to deliver DOX and β-cyclodextrin-curcumin (CD-CUR) to the target tumor in a controlled manner. The co-delivery system demonstrated superior anti-tumor efficacy and a greater capacity to induce apoptosis. Similarly, local PLGA-PEG-PLGA combination treatments exhibited a greater anti-tumor efficiency in vivo as compared to free DOX + CD-CUR or single-agent strategies (Yang et al., 2020). In another research, a PLGA-PEG-PLGA hydrogel loaded with DOX and CDDP was utilized for local combination chemotherapy of osteosarcoma. The resulting hydrogel was degradable and biocompatible. In vitro cell viability assays showed that the hydrogels co-loaded with DOX and CDDP exhibited synergistic anti-proliferative effects as well as high tumor growth inhibition efficiency. The in vivo experimental results indicated that the PLGA-PEG-PLGA hydrogel for local combination chemotherapy promoted increased tumor necrosis and enhanced the modulation of the expression of apoptosis-related genes (Si et al., 2022), indicating synergistic anti-tumor effectiveness in vivo with low systemic toxicity. These results indicated that persistent local co-delivery of DOX and CDDP via PLGA-PEG-PLGA hydrogels could be a promising approach to effectively treating osteosarcoma in the clinic.

Although PLGA-PEG-PLGA hydrogels have shown considerable therapeutic promise in local cancer treatment, the maximum tolerated dose (MTD) of these strategies is still unclear. To address this issue, Yang et al. employed PLGA-PEG-PLGA hydrogels loaded with DOX to evaluate the MTD of DOX in the local treatment of osteosarcoma (Yang et al., 2018). The hydrogels exhibited favorable injectable and biodegradable properties in vivo, with significantly prolonged drug residence time at the tumor location. The results showed that the local administration of DOX at 5.0 mg/kg could not suppress tumor-sustained growth or extend the survival duration, while the local administration of DOX at 30 mg/kg showed intense activity in suppressing tumor growth but also caused severe weight loss. At the same time, the local administration of DOX at 15 mg/kg showed markedly higher anti-tumor potency and extended average survival time as compared to free DOX (15 mg/kg). The improved MTD and reduced systemic toxicity of DOX administered with hydrogels will offer a potential therapy for osteosarcoma.

Recently, local DDS based on bone scaffolds has attracted increasing interest. Drug-loaded scaffolds can generate high local drug concentrations to eradicate residual tumor cells. This approach promises to prevent tumor recurrence and reduce systemic adverse events more effectively than intravenous drug delivery. The right biomaterial can both treat tumors and promote bone regeneration. Compared to natural polymers, synthetic polymers offer adjustable properties for bone scaffolds, allowing the control of molecular weight or functional group ratios to modulate mechanical strength, degradation, and other properties. Among synthetic polymers, PLGA is the most commonly used to fabricate porous scaffolds due to its controlled biodegradability, limited toxicity, and potential capabilities. PLGA-based scaffolds have been developed for the localized delivery system to treat bone tumors and regenerate bone (Sarigol-Calamak and Hascicek, 2018; Wang et al., 2022b).

Using a 3D printing technique at low temperatures, Li et al. fabricated a scaffold composed of PLGA/β-TCP incorporating salvianolic acid B. Their results indicated that incorporating SB could promote the osseointegration of the obtained scaffolds by enhancing the effect of salvianolic acid B on angiogenesis and osteogenesis (Lin et al., 2019). However, the acidic product produced by the degradation of PLGA may cause an inflammation, which the incorporation of CaP materials can eliminate (Zhao et al., 2020b; Liang et al., 2020; Sokolova et al., 2020). In comparison to conventional chemotherapy, magnetic hyperthermia and photo-thermal therapy are attracting more attention because of their low invasive potential and high specificity. Li et al. fabricated a magnetic scaffold of PLGA, Fe₃O₄, and HA nanoparticles (Li et al., 2019b). It was found that the resulting scaffolds could raise the internal temperature to 47°C and induce substantial tumor cell apoptosis in vitro. In addition, the scaffolds showed an excellent osteogenic capacity to allow new bone to be regenerated in the defect site, with the result that bone volume/total was significantly higher than the untreated group (Li et al., 2019b). Wang et al. (Wang et al., 2020b)used black phosphorus nanosheets, DOX, and hydrophilic osteogenic peptides as photo-thermal agents, chemotherapeutic agents, and osteogenic factors, respectively, blended with 𝛽-TCP nanoparticle and PLGA for 3D printing to obtain drug delivery scaffolds for the treatment of bone tumor resection-induced defects (Figure 9). BDPTP scaffolds can cause tumor cell death in vitro and tumor clearance in vivo. The scaffold has a photo-thermal effect, and laser radiation with a wavelength of 808 nm can raise the BDPTP scaffold temperature to 60°C within 10 min. The MG63 cells attached to the scaffold were nearly eliminated after 1 day of culturing, the tumor disappeared after 4 days, and the tumor recurrence rate in vivo was low by combining chemotherapy and photo-thermal treatment. The in vivo experiments showed that the scaffold promoted new bone growth through its osteoinductive and osteogenic inductive effects (Wang et al., 2020b). Therefore, as a multi-functional platform, BDP-PT scaffolds can promote apoptosis and bone tissue regeneration in bone cancer, thereby meeting the clinical need of treating bone cancer.

Bone regeneration after resection of tumor tissue still faces a vast clinical obstacle in the therapy of bone defects, the therapeutic approaches that promote bone regeneration while being antimetastatic are of great interest. s. Hu et al. prepared drug delivery scaffolds by encapsulating BPQDs in PLGA nanoparticles and mixing them with wood/silk hydrogels to achieve adequate mechanical strength, bone formation, and tumor treatment (Hu et al., 2022). The drug delivery scaffolds further potently enhanced osteogenesis in vivo by efficiently enhancing bone mesenchymal stem cells’ growth, differentiation, and migration (Hu et al., 2022). More important, the BPQDs in the drug delivery scaffolds could suppress osteoclast differentiation and exert photo-thermal activity on spinal tumor metastasis (Hu et al., 2022). Significant inhibition of the growth of human osteosarcoma cells in vitro and reduction of tumor progression in vivo was also observed with the nanohydroxyapatite/collagen scaffolds filled with DOX-PLGA nanoparticles (Rong et al., 2016). These researches offer potential evidence for the possible treatment application in clinics for bone regeneration and bone metastasis ablation.

To overcome the difficulties of tumor reoccurrence and extensive bone defect, Long et al. designed an innovative multi-functional PLGA/Mg scaffold for the comprehensive postoperative management of osteosarcoma (Long et al., 2021), which resulted in the total inhibition of tumor reoccurrence when exposed to near-infrared laser radiation as well as the successful repair of bone defects in vivo (Long et al., 2021). In addition, the PLGA/Mg scaffold loaded with β-tricalcium phosphate (β-TCP) also exhibited both osteogenic and angiogenic capabilities, which had a synergetic effect in promoting the new bone generation and strengthening the quality of newly regenerated bone (Lai et al., 2019). The innovative PLGA/Mg scaffolds exhibited superior performance in suppressing postoperative osteosarcoma recurrence and regenerating bone, offering a potential clinically relevant approach for treating osteosarcoma. Lu (Lu et al., 2021) developed a composite scaffold coated with polydopamine, consisting of lamellar hydroxyapatite loaded with DOX and PLGA, to inhibit tumors and repair bones (Figure 10). The scaffold significantly inhibited tumor cell growth, followed by enhanced osteoblast adhesion and proliferation. Improved bone growth around the scaffold was also demonstrated in vivo (Lu et al., 2021). The dual-function scaffold holds significant potential for the therapy of bone tumors.