Development of iodine based sustained release antimicrobial coatings for polyurethane voice prostheses.

Voice prostheses are known to fail in few weeks to several months of implantation due to the clogging mainly caused by microbial biofilm formation, which is a cause of concern. Iodine is a known broad-spectrum biocide and is reported to easily form complexes with various polymers. For long term device disinfection, strong iodine complexation that offers sustained iodine release for a prolonged period is essential. The present research work deals with the synthesis of a poly(methyl methacrylate-n-butyl acrylate-N-vinyl-2-pyrrolidone) (poly[MMA-BA-NVP]) tercopolymer through free radical polymerization for surface coating thermoplastic polyurethane (TPU) based voice prostheses. The NVP content in the tercopolymer was varied from 20% to 50% to optimise iodine loading and subsequent release. Base TPU coated with the tercopolymer was treated with 4% aqueous iodine solution at room temperature (28 ± 3 °C) for two hours. It was observed that the tercopolymer containing 35% N-vinyl-2-pyrrolidone (NVP), 32.5% methyl methacrylate (MMA) and 32.5% butyl acrylate (nBA) gave a stable coating on TPUs together with sustained iodine release for a prolonged period. Furthermore, the tercopolymer coated and iodine loaded TPUs exhibited excellent antimicrobial activity against Candida albicans, Staphylococcus aureus and Escherichia coli.

Quatramer™ encapsulation of dual-targeted PI3-Kδ/HDAC6 inhibitor, HSB-510, suppresses growth of breast cancer.

Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual-targeted inhibitors of phosphoinositide 3-kinase (PI3-K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3-Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid-methoxy polyethylene glycol; polylactic acid-polyethylene glycol-polypropylene glycol-polyethylene glycol-polylactic acid) (HSB-510) as a delivery system to target PI3-Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB-510 showed an average diameter of 96 ± 3 nm, a zeta potential of -17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3-Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB-510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA-MB-468, SUM-149, MCF-7, and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho-AKT, phospho-ERK, and c-Myc levels. Importantly, bi-weekly treatment of Balb/c wild-type mice harboring EAC cells with HSB-510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB-510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3-Kδ/HDAC6 dual inhibitor (HSB-510) represents an approach for the successful targeting of breast cancer and potentially other cancer types.

Polylactic acid based biodegradable hybrid block copolymeric nanoparticle mediated co-delivery of salinomycin and doxorubicin for cancer therapy.

Existence of cancer stem cells (CSCs) are primarily responsible for chemoresistance, cancer reoccurrence and treatment failure in cancer patients. Eliminating CSCs along with bulk tumor is a necessity to achieve complete cancer inhibition. Salinomycin (SAL) has potential to specifically target and kill CSCs through blocking their multiple pathways simultaneously. SAL has also been reported to improve anti-cancer efficacy of numerous chemo-based drugs when used in combination therapy. However, clinical use of SAL is restricted due to its high off targeted toxicity. Herein, we have developed a PLA based hybrid block copolymer for concomitant delivery of SAL and doxorubicin (DOX) with an aim to reduce their adverse side effects and enhance the therapeutic efficacy of the treatment. Designed PLA based nanoplatform showed high encapsulation and sustained release profile for both the drugs. Cytotoxicity evaluation on cancer cell lines confirmed the synergistic effect of SAL:DOX co-loaded NPs. Additionally, prepared SAL NPs were also found to be highly effective against chemo-resistant cancer cells and CSCs derived from cancer patient. Most importantly, encapsulation of SAL in PLA NPs improved its pharmacokinetics and biodistribution profile. Consequently, undesired toxicity with SAL NPs was significantly reduced which in-turn increased the dose tolerability in mice as compared to free SAL. Treatment of EAC tumor bearing mice with SAL:DOX co-loaded NPs resulted in excellent tumor regression and complete inhibition of cancer reoccurrence. These results conclude that concomitant delivery of SAL and DOX using PLA based block copolymeric nano-carrier have a strong potential for cancer therapy.

Polylactic acid based polymeric nanoparticle mediated co-delivery of navitoclax and decitabine for cancer therapy.

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.

Co-encapsulation of PI3-Kδ/HDAC6 dual inhibitor and Navitoclax in Quatramer™ nanoparticles for synergistic effect in ER+ breast cancer.

Progression and metastasis of ER+ breast cancer depend on multiple signaling cascades. The available conventional treatment options have limited efficacy in ER+ breast cancer due to overexpression of AKT, c-Myc and BCL-2 proteins. Simultaneous targeting and inhibition of these targets in ER+ cancer may result in effective therapeutic outcomes. However, combining two or more free drug molecules to treat cancer leads to unsynchronised pharmacokinetics, toxicity, and eventual resistance development. To overcome these limitations, a novel nanoformulation of PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax is developed using Pluronic modified PLA based hybrid block copolymer. The prepared dual drug loaded PI3-Kδ/HDAC6-NAV-NPs (1:3-NPs) have shown high encapsulation efficiency, hydrodynamic size, and polydispersity of âˆ¼ 93 %, 159 ± 2.6 nm, and 0.19 ± 0.03, respectively. These PI3-Kδ/HDAC6-NAV-NPs exhibit slow and sustained release profiles of PI3-Kδ/HDAC6 inhibitor and NAV in phosphate buffer saline (PBS, pH 7.4). The in-vitro cytotoxicity studies done with PI3-Kδ/HDAC6-NAV-NPs in ER+ breast cancer cell lines have shown a synergistic effect with lower IC50 values compared to individual NAV-NPs and PI3-Kδ/HDAC6-NPs. The PI3-Kδ/HDAC6-NAV-NPs treatment (4 mg/kg, I.V., twice a week for three weeks) of ER+ breast cancer syngeneic mice tumor model resulted in complete tumor eradication without any overt toxicity. These results demonstrate that a unique formulation of a novel PI3-Kδ/HDAC6 dual inhibitor in combination with Navitoclax represents an approach for an efficient treatment option for ER+ breast cancer.

Development and evaluation of PLA based hybrid block copolymeric nanoparticles for systemic delivery of pirarubicin as an anti-cancer agent.

Pirarubicin (PIRA) is a semi-synthetic anthracycline derivative that is reported to have lesser toxicity and better clinical outcomes as compared to its parental form doxorubicin (DOX). However, long term use of PIRA causes bone marrow suppression and severe cardiotoxicity to the recipients. Herein, we have developed a biodegradable polymeric nano platform consisting of amphiphilic di-block copolymer methoxy polyethylene glycol-polylactic acid and a hydrophobic penta-block copolymer polylactic acid-pluronic L-61-polylactic acid as a hybrid system to prepare PIRA (& DOX) encapsulated nanoparticles (NPs) with an aim to reduce its off targeted toxicity and enhance therapeutic efficacy for cancer therapy. Prepared PIRA/DOX NPs showed uniform particle size distribution, high encapsulation efficiency and sustained drug release profile. Cytotoxicity evaluation of PIRA NPs against TNBC cells and mammospheres showed its superior anti-cancer activity over DOX NPs. Anti-cancer efficacy of PIRA/DOX NPs was found significantly enhanced in presence of penta-block copolymer which confirmed chemo-sensitising ability of pluronic L-61. Most importantly, encapsulation of PIRA/DOX in the NPs reduced their off targeted toxicity and increased the maximum tolerated dose in BALB/c mice. Moreover, treatment of EAC tumor harbouring mice with PIRA NPs resulted in higher tumor regression as compared with the groups treated with free PIRA, free DOX or DOX NPs. Altogether, the results conclude that prepared PIRA NPs exhibits an excellent anti-cancer therapeutic efficacy and has a strong potential for cancer therapy.