Current clinical and preclinical anticancer formulations are limited by their use of toxic excipients and stability issues upon combining different drug formulations. We have found that poly(ethylene glycol)-block-poly(d,l lactic acid) (PEG-b-PLA) micelles can deliver multiple poorly water-soluble drugs at clinically relevant doses. Paclitaxel (PTX), etoposide (ETO), docetaxel (DCTX) and 17-AAG were solubilized individually in PEG-b-PLA micelles. Combinations of PTX/17-AAG, ETO/ 17-AAG, DCTX/17-AAG and PTX/ETO/17-AAG were also solubilized in PEG-b-PLA micelles. PEG-b-PLA micelles were characterized in terms of drug loading, size, stability and drug release. All anticancer agents in all combinations were all solubilized at the level of mg/mL and were stable for 24 hours in the 2 and 3 drug combination PEG-b-PLA micelles. The stability of the 2 and 3 drug combination PEG-b-PLA micelles was due to the presence of 17-AAG. In vitro, t 1/2 values for 2 and 3 drug combination PEG-b-PLA micelles spanned 1-5 hrs. PEG-b-PLA micelles offer a promising alternative for combination drug therapy without formulation related side effects.

Non-ionic surfactant vesicles, simply known as niosomes are synthetic vesicles with potential technological applications. Niosomes have the same potential advantages of phospholipid vesicles (liposomes) of being able to accommodate both water soluble and lipid soluble drug molecules control their release and as such serve as versatile drug delivery devices of numerous applications. Additionally, niosomes can be considered as more economically, chemically, and occasionally physically stable alternatives to liposomes. Niosomes can be fabricated using simple methods of preparations and from widely used surfactants in pharmaceutical technology. Many reports have discussed niosomes in terms of physicochemical properties and their applications as drug delivery systems. In this report, a brief and simplified summary of different theories of self-assembly will be given. Furthermore manufacturing methods, physical characterization techniques, bilayer membrane additives, unconventional niosomes (discomes, proniosomes, elastic and polyhedral niosomes), their recent applications as drug delivery systems, limitations and directions for future research will be discussed.

Poly(ethylene glycol)-block-poly(d,l lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel dose in clinical trials. We show that PEG-b-PLA micelles act as a 3-in-1 nanocontainer for paclitaxel, 17-allylamino-17-desmethoxygeldanamycin (17-AAG), and rapamycin for multiple drug solubilization. 3-in-1 PEG-b-PLA micelles were ca. 40 nm in diameter; dissolved paclitaxel, 17-AAG, and rapamycin in water at 9.0 mg/mL; and were stable for 24 hrs at 25°C. The half-life for in vitro drug release (t1/2) for 3-in-1 PEG-b-PLA micelles was 1-15 hrs under sink conditions and increased in the order of 17-AAG, paclitaxel, and rapamycin. The t1/2 values correlated with log Po/w values, implicating a diffusion-controlled mechanism for drug release. The IC50 value of 3-in-1 PEG-b-PLA micelles for MCF-7 and 4T1 breast cancer cell lines was 114 ± 10 and 25 ± 1 nM, respectively; combination index (CI) analysis showed that 3-in-1 PEG-b-PLA micelles exert strong synergy in MCF-7 and 4T1 breast cancer cell lines. Notably, concurrent intravenous (IV) injection of paclitaxel, 17-AAG, and rapamycin using 3-in-1 PEG-b-PLA micelles was well-tolerated by FVB albino mice. Collectively, these results suggest that PEG-b-PLA micelles carrying paclitaxel, 17-AAG, and rapamycin will provide a simple yet safe and an efficacious 3-in-1 nanomedicine for cancer therapy.

The purpose of this work is to evaluate biodegradable drug carriers with defined size, hydrophobicity, and surface charge density for preferential lymphatic uptake and retention for sustained regional drug delivery. PLGA–PMA:PLA-PEG (PP) nanoparticles of defined size and relative hydrophobicity were prepared by nanoprecipitation method. These were compared with PS particles of similar sizes and higher hydrophobicity. PLGA–PMA:PLGA-COOH (PC) particles at 80:20, 50:50, and 20:80 ratios were prepared by nanoprecipitation for the charge study. Particle size and zeta potential were characterized by dynamic light scattering and laser doppler anemometry, respectively. Particles were administered in vivo to rats subcutaneously. Systemic and lymph node uptake was evaluated by marker recovery. Lymphatic uptake and node retention of PP nanoparticles was shown to be inversely related to size. Lymphatic uptake and node retention of PP particles, as compared to PS particles, was shown to be inversely related to hydrophobicity. Lastly, lymphatic uptake and node retention of PC nanoparticles were directly related to the anionic charge on the particles. In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases.

words)Image-guided phototherapy is extensively considered as a promising therapy for cancer treatment. To enhance translational potential of this modality, we developed a single agent-based biocompatible nanoplatform that provides both real time near-infrared (NIR) fluorescence imaging and combinatorial phototherapy with dual photothermal and photodynamic therapeutic mechanisms. The developed theranostic nanoplatform consists of two building blocks: (1) silicon naphthalocyanine (SiNc) as NIR fluorescence imaging and phototherapeutic agent and (2) a copolymer, poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) as the biodegradable SiNc carrier. Our simple, highly reproducible and robust approach results in preparation of spherical, monodisperse SiNc-loaded PEG-PCL polymeric nanoparticles (SiNc-PNP) with a hydrodynamic size of 37.66 ± 0.26 nm (polydispersity index = 0.06) and surface charge of -2.76 ± 1.83 mV. The SiNc-loaded nanoparticles exhibit a strong NIR light absorption with an extinction coefficient of 2.8 x 10 5 M -1 cm -1 and efficiently convert the absorbed energy into fluorescence emission (Φ F = 11.8%), heat (∆T ~ 25 °C) and reactive oxygen species. Moreover, the SiNc-PNP are characterized by superior photostability under extensive photoirradiation and structure integrity during storage at room temperature over a period of 30 days. Following intravenous injection, the SiNc-PNP accumulated selectively in tumors and provided high lesionto-normal tissue contrast for sensitive fluorescence detection. Finally, Adriamycin-resistant tumors treated with a single intravenous dose of SiNc-PNP (1.5 mg/kg) combined with 10 min of a 785 nm light irradiation (1.3 W/cm 2 ) were completely eradicated from the mice without cancer recurrence or side effects. The reported characteristics make the developed SiNc-PNP a promising platform for future clinical application.