Incidence rate of osteonecrosis of jaw after cancer treated with bisphosphonates and denosumab: A systematic review and meta-analysis.

OBJECTIVES: This study aimed to assess the overall incidence of osteonecrosis of the jaw (ONJ) caused by bisphosphonates and denosumab when used for controlling bone cancer metastasis or as adjuvant therapy. SUBJECTS AND METHODS: A systematic search of the PubMed, Embase, and Cochrane Library databases and major meetings' proceedings as of July 30, 2022, identified randomized controlled trials (RCTs) and observational trials that evaluated ONJ caused by denosumab or bisphosphonates. The total incidence and risk ratio (RR) for ONJ were calculated using a random-effects model. RESULTS: A total of 42 003 patients with various solid tumors reported in 23 RCTs were included. The overall ONJ incidence in cancer patients receiving denosumab or bisphosphonates was 2.08% (95% CI 1.37-2.91; p < .01; I2  = 94.99%). Patients receiving denosumab had a higher ONJ incidence than those receiving bisphosphonates (RR 1.64, 95% CI 1.10-2.44; p < .05; I2  = 65.4%). Subgroup analyses showed that prostate cancer patients receiving denosumab and receiving zoledronic acid had the highest ONJ incidences, 5.0% and 3.0%, respectively. The incidence of ONJ induced by different doses was also different. CONCLUSIONS: The incidence of ONJ caused by denosumab and bisphosphonates is low, the dose of the drug and the type of cancer have certain influence on ONJ. Therefore, clinicians should use the drug reasonably to improve the quality of life of patients.

Synthesis and characterization of multifunctional poly(glycidyl methacrylate) microspheres and their use in cell separation.

Multifunctional poly(glycidyl methacrylate) (PGMA) microspheres containing magnetic, fluorescent, and cancer cell-specific moieties were prepared in four steps: (i) preparation of parent PGMA microspheres by dispersion polymerization and their reaction with ethylenediamine to obtain amino groups, (ii) precipitation of iron ions (Fe(2+) and Fe(3+)) to form Fe(3)O(4) nanoparticles within the microspheres, (iii) consecutive reactions of folic acid with the amino groups on PGMA, and (iv) incorporation of fluorescein isothiocyanate into the microspheres. The microspheres were superparamagnetic, highly monodispersive, intensively fluorescent, and capable of recognizing and binding cancer cells that overexpress folic acid receptors. It was demonstrated that with these microspheres, HeLa cells could be captured from their suspension and easily moved in the direction of the externally applied magnetic field.

Anti-tumor activity of folate targeted biodegradable polymer-paclitaxel conjugate micelles on EMT-6 breast cancer model.

BACKGROUND: Paclitaxel (PTX) is a first line chemotherapy drug for breast cancer. There have been few studies reported concerning the therapeutic efficacy of paclitaxel-conjugated polymeric micelles in breast cancer in vivo. METHODS: Two kinds of PTX conjugate micelles, one of which (M(PTX)) contained 25 wt.% of PTX and the other (M(FA/PTX)) contained 22.5 wt.% of PTX and 1.4 wt.% of folate (FA), were prepared for cell apoptosis and anti-tumor activity evaluation on EMT-6 mice breast cancer models in comparison with 0.9 wt.% saline (control) and equivalent PTX. Cell apoptosis was analyzed by flow cytometry. Breast tumors were examined histologically with H&E staining and immunohistochemically by examining Bax and Bcl-2 expression. The survival status of tumor-bearing mice with different treatments was also examined. RESULTS: On day 5 of the drug administration, the average tumor masses were 0.49, 0.33, 0.22, and 0.18 g for the control, PTX, M(PTX) and M(FA/PTX) groups, respectively. The inhibition rates of tumor growth calculated for the three drug groups were 32.6%, 51.6% and 62.3%, respectively. The percentage of cell apoptosis based on flow cytometry was 1.0%, 36.6%, 55.9% and 66.1%, respectively, which showed statistically significant differences (p<0.05) between three drug groups and the control group. Bcl-2 expression of PTX and M(FA/PTX) groups was lower than control group (p<0.05). Bax expression of drug groups was higher than control group (p<0.05). At an equivalent paclitaxel dose of 26.7 mg/kg, the average survival time was 33 days, 31 days, 34 days and 42 days, respectively (p<0.05). CONCLUSION: The M(FA/PTX) have better anti-tumor activity and are promising in treatment of human breast cancers.

A complex of cyclohexane-1,2-diaminoplatinum with an amphiphilic biodegradable polymer with pendant carboxyl groups.

A biodegradable and amphiphilic copolymer, MPEG-b-P(LA-co-MCC), which contains pendant carboxyl groups, was chosen as a drug carrier for the active anticancer part (DACH-Pt) of oxaliplatin to form an MPEG-b-P(LA-co-MCC/Pt) complex. It was able to self-assemble into micelles with a mean diameter of 30-40 nm, and a surface potential near -10 mV. The typical platinum content was 10 wt.%. The micelles showed acid-responsive drug release kinetics, which is beneficial for drug release in the intracellular environment. The Pt(II) species were released mainly in the form of DACH-Pt-Cl(2) in 150 mM NaCl solution and DACH-Pt(2+)-(H(2)O)(2) in pure water according to the results obtained by high-performance liquid chromatography coupled with inductively coupled plasma mass spectrometry and X-ray photoelectron spectroscopy. In vitro evaluation showed that the micelles displayed the same or higher cytotoxicities against SKOV-3, HeLa, and EC-109 cancer cells compared with oxaliplatin. The enhanced cytotoxicity against SKOV-3 cells is attributed to effective internalization of the micelles by the cells via endocytosis and the sensitivity of SKOV-3 cells to platinum drugs. This novel biodegradable and amphiphilic copolymer-based platinum drug will have great potential application in clinical use.

Delivery of active DACH-Pt anticancer species by biodegradable amphiphilic polymers using thiol-ene radical addition.

A biodegradable and amphiphilic copolymer, mPEG-b-P(LA-co-MAC/TMA) that contains pendant 1,2-bidentate carboxyl groups is synthesized by thiol-ene radical addition and is further used to chelate with the active anticancer species (DACH-Pt) of oxaliplatin to form an mPEG-b-P(LA-co-MAC/TMA-Pt-DACH) complex. The polymer platinum complex can self-assemble into micelles. In vitro studies show that the DACH-Pt micelles display enhanced or comparable cytotoxicity against SKOV-3 and MCF-7 cancer cells, while they show reduced toxicity to HeLa cells compared with oxaliplatin.

Co-delivery of daunomycin and oxaliplatin by biodegradable polymers for safer and more efficacious combination therapy.

An oxaliplatin pro-drug (Oxa(IV)-COOH) with an axial carboxyl group was synthesized and conjugated to biodegradable polymers with pendant hydroxyl groups to prepare polymer-Oxa(IV) conjugates. A hydrophobic anthracycline-based drug, daunorubicin (DRB) was conjugated to similar biodegradable polymers with carboxyl groups to synthesize polymer-DRB conjugates. The two drug conjugates have the similar polymer backbone and are amphiphilic; thus, they can co-assemble into composite micelles. In the composite micelles, the polymer-Oxa(IV) conjugates can release clinically widely used water soluble anticancer drug oxaliplatin (Oxa(II)) upon reduction, while polymer-DRB conjugate is thought to release DRB via acid hydrolysis in the cancer cells. In this way, combination of the hydrophilic platinum drug Oxa(II) and hydrophobic drug DRB can be realized by delivering them in one platform. Moreover, the composite micelles showed reduced systematic toxicity and greater synergistic effect than combination of small molecules of the two anticancer drugs both in vitro and in vivo; thus, this polymer based combination therapy can be useful in future clinic application.

A prodrug strategy to deliver cisplatin(IV) and paclitaxel in nanomicelles to improve efficacy and tolerance.

A strategy of preparing composite micelles containing both cisplatin(IV) prodrug and paclitaxel was developed, i.e., synthesizing a cisplatin(IV) conjugate and a paclitaxel conjugate starting with the same biodegradable and amphiphilic block copolymer, and co-assembling the two conjugates. The composite micelles could release effective anticancer drug cisplatin(II) upon cellular reduction and PTX via acid hydrolysis once they came into the cancerous cells. Moreover, the composite micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo.

Anti-tumor activity of biodegradable polymer-paclitaxel conjugate micelles on Lewis lung cancer mice models.

Two kinds of paclitaxel (PTX) conjugate nanomicelles were prepared for cell apoptosis and anti-tumor activity evaluation on Lewis lung cancer mice models. One (PTX micelles) was prepared by self-assembling the PTX-conjugate co-polymer, poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2-carboxyl-propylene carbonate/PTX), and the other (FA-PTX micelles) was by co-assembling a mixture of the folic acid (FA)-carrying co-polymer poly(ethylene glycol)-b-poly(L-lactide-co-2,2-dihydroxylmethyl-propylene carbonate/FA) (PEG-b-P(LA-co-DHP/FA)), and the PTX-conjugate co-polymer. At 7 and 14 days after tail intravenous injection, the mice were killed. The inhibition rates of tumor growth for PTX and FA-PTX micelles were 50 and 90%, respectively, on the day 7, and 33 and 71%, respectively, on the day 14 after drug injection. Flow cytometry analysis showed that the cell apoptosis rates were 43, 54 and 72% for the control group, PTX micelles group and FA-PTX micelles group, respectively, on the day 7, and 16, 25 and 42 on the day 14. With the TUNEL assay, the grey values of PTX micelles and FA-PTX micelles groups were determined to be 61-62% and 43-44%, of that of the control group, on day 7 or day 14, respectively. Therefore, the PTX micelles and the FA-PTX composite micelles significantly inhibited the subcutaneously inoculated Lewis lung cancer and effectively induced the cell apoptosis, and the FA-PTX composite micelles displayed a better efficacy than the PTX-micelles, implying the contribution of the folate-mediated targeting and endocytosis effect.

Biodegradable polymer - cisplatin(IV) conjugate as a pro-drug of cisplatin(II).

A Pt(IV) complex was covalently conjugated to a new biodegradable amphiphilic tri-block copolymer, MPEG-b-PCL-b-PLL, which contains pendant amino groups, to form a polymeric pro-drug of cisplatin(II), MPEG-b-PCL-b-PLL/Pt(IV). The conjugate was assembled into nano-micelles. The Pt(IV) complex, the polymer carrier and the conjugate were characterized systematically. In vitro release experiments showed that drug release from the polymer-Pt(IV) micelles follows an acid responsive and oxidation-reduction sensitive kinetics. HPLC-ICP-MS analysis revealed that cisplatin(II) can be released from the conjugate under an acidic plus a reductive condition which is available inside a cancerous cell. In vitro MTT assay demonstrated that the polymer-Pt(IV) micelles display higher cytotoxicity against SKOV-3 tumor cells than both cisplatin(II) and Pt(IV) complex. This enhanced cytotoxicity is attributed to effective internalization of the micelles by the cells via endocytosis mechanism, which was observed by fluorescence imaging and by direct determination of the platinum uptake by the cells. This polymer-Pt(IV) conjugate is a promising polymeric pro-drug of cisplatin in micellar form. It can protect the Pt(IV) complex against blood clearance. It can enter cancerous cells via endocytosis mechanism and then cisplatin(II) can be released. Therefore, this polymeric pro-drug of cisplatin is expected to find clinical applications in the future.

Synthesis, self-assembly in water, and cytotoxicity of MPEG-block-PLLA/DX conjugates.

Docetaxel (DX) is one of the most effective antineoplastic drugs. Its current clinical administration is limited because of its hydrophobicity and serious side effects. A polymer/DX conjugate is designed and successfully prepared to solve these problems. It is monomethoxy-poly(ethylene glycol)-block-poly(L-lactide)/DX (MPEG-PLLA/DX). It was synthesized by reacting DX with carboxyl-terminated copolymer MPEG-PLLA, which was prepared by reacting succinic anhydride with hydroxyl-terminated copolymer monomethoxy-poly(ethylene glycol)-block-poly(L-lactide) (MPEG-PLLA). Its structure and molecular weight was confirmed by (1)H NMR and GPC. The MPEG-PLLA/DX micelles in aqueous solution were prepared using a solvent displacement method and characterized by dynamic light scattering for size and size distribution, and by transmission electron microscopy for surface morphology. Its antitumor activity against HeLa cancer cells evaluated by MTT assay showed that it had a similar antitumor activity to pure DX at the same drug content.