Development of Micellar and Nanoparticle Structures based on Polyester Diblock Copolymer Platform for the Treatment of Metastatic Tumors

Poor aqueous solubility of a large number of newly discovered chemical entities is posing a significant challenge for the formulation industry and is delaying their drug development. The number of formulation techniques available to solubilize these poorly soluble molecules is very limited. In addition to that, traditional formulation methods involve the use of surfactants such as Cremophor EL and polysorbate 80 that trigger unwanted toxicities and the lack of proper targeting moieties is further hampering their in vivo efficacy. The search for alternate drug delivery systems that overcome these limitations and toxicity issues has therefore led to the use of polyester based diblock copolymers. Polyester based diblock copolymers have garnered tremendous interest in the past two decades for their applications in drug delivery. These block copolymers comprise of a hydrophilic and hydrophobic segments and they readily self-assemble into micellar and nanoparticle structures in aqueous solvents. The ability to modify their surface properties by mixing different copolymers along with their capability to load multiple poorly soluble drug entities into their hydrophobic cores have made them highly sought after in the formulation industry. The polyesters are biodegradable and are approved by the FDA for use in drug delivery purposes. This work encompasses the development of a micellar and a nanoparticle formulation using polyester based diblock copolymers for the delivery of multiple chemotherapeutic agents and imaging applications. The lack of a delivery system that can achieve substantial lymphatic accumulation has motivated us in developing a poly (ethylene glycol)-block-poly (ε-caprolactone) [PEG-b-PCL] nanoparticle system that can simultaneously load three drugs at therapeutically relevant concentrations and also achieve significant lymphatic accumulation, courtesy of its modified surface properties. The efficacy of the developed nanoparticle system was evaluated in its ability to reduce the proliferation of melanocytes in metastatic melanoma mice models. We were able to develop locally acting and centrally acting drug loaded nanoparticles that effectively reduced melanocyte proliferation. We then wanted to demonstrate the diagnostic applications of these nanostructures and therefore developed a methoxy poly (ethylene glycol)-block-poly (lactic acid) mPEG-b-PLA micelle formulation that encapsulates a nerve specific fluorophore BMB. The micellar formulation of BMB achieved significantly higher nerve specific accumulation and fluorescence intensity when compared to its traditional formulation in DMSO and also prevented the unwanted side effects occurring from the formulation excipients. The micellar BMB formulation was a first of its kind as no previous nerve visualization techniques were clinically approved. Finally, we also developed a mPEG-b-PLA micellar formulation that encapsulates two drugs that target the major pathways involved in ovarian cancer and prevent tumor progression by exhibiting synergistic effects. The combination therapy proved more beneficial in reducing the tumor burden in animal models compared to the individual drugs and also reduced the development of drug resistance by inhibiting multiple pathways. We have thus effectively demonstrated the therapeutic and diagnostic applications of micellar and nanoparticle platforms developed from polyester based diblock copolymers in treating metastatic diseased state

Naphthalocyanine-Based Biodegradable Polymeric Nanoparticles for Image-Guided Combinatorial Phototherapy

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 10⁵ M⁻¹cm⁻¹ and efficiently convert the absorbed energy into fluorescence emission (Φ[subscript F] = 11.8%), heat (ΔT ~ 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 lesion-to-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/cm²) 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.This is the author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society and can be found at: https://doi.org/10.1021/acs.chemmater.5b0312

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

Naphthalocyanine-Based Biodegradable Polymeric Nanoparticles for Image-Guided Combinatorial Phototherapy

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 a NIR fluorescence imaging and phototherapeutic agent and (2) a copolymer, poly­(ethylene glycol)-<i>block</i>-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 × 10⁵ M^–1 cm^–1 and efficiently convert the absorbed energy into fluorescence emission (Φ_F = 11.8%), heat (Δ<i>T</i> ∼ 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 lesion-to-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/cm²) 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