ABSTRACT
Leptin is released in response to increased triglyceride storage in adipocytes and impacts body weight, but has drawbacks such as poor therapeutic effect and side effects when delivered systemically. Leptin also modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. Here, light-triggered degradation of hydrogels was used to improve accuracy and effectiveness for sustained and controllable release. In our approach, leptin was entrapped within methylcellulose (MC)-based hydrogels, with incorporation of gold nanoparticles (NP). The incorporation of gold NP into MC hydrogels led to a tunable light irradiation response that dictated the hydrogel release rate of leptin. This manuscript demonstrates feasibility in designing tunable thermosensitive hydrogels for loading multimodality therapeutic agents to enhance the bioactivity of leptin for obesity therapy.
Subject(s)
Adipocytes/drug effects , Hydrogels/chemistry , Leptin/pharmacokinetics , Metal Nanoparticles/chemistry , 3T3-L1 Cells , Adipocytes/metabolism , Animals , Gold/chemistry , Lasers , Leptin/administration & dosage , Leptin/chemistry , Light , Metal Nanoparticles/administration & dosage , Methylcellulose/chemistry , Mice , Obesity/drug therapy , Obesity/metabolismABSTRACT
Chemotherapy represents a conventional treatment for many cancers at different stages and is either solely prescribed or concomitant to surgery, radiotherapy, or both. However, treatment is tempered in instances of acquired drug resistance in response to either chemotherapy or targeted therapy, leading to therapeutic failure. To overcome this challenge, many studies focus on how cancer cells manipulate their genomes and metabolism to prevent drug influx and facilitate the efflux of accumulated chemotherapy drugs. Herein, we demonstrate magnetic adeno-associated virus serotype 2 (ironized AAV2) has an ability to be magnetically guided and transduce the photosensitive KillerRed protein to enable photodynamic therapy irrespective of drug resistance.
Subject(s)
Breast Neoplasms/pathology , Photochemotherapy/methods , Transduction, Genetic/methods , Adenoviridae/genetics , Cell Line, Tumor , Drug Resistance, Multiple/radiation effects , Female , Humans , MagneticsABSTRACT
Clinical virotherapy has been successfully approved for use in cancer treatment by the U.S. Food and Drug Administration; however, a number of improvements are still sought to more broadly develop virotherapy. A particular challenge is to administer viral therapy systemically and overcome limitations in intratumoral injection, especially for complex tumors within sensitive organs. To achieve this, however, a technique is required that delivers the virus to the tumor before the body's natural self-defense eradicates the virus prematurely. Here we show that recombinant adeno-associated virus serotype 2 (AAV2) chemically conjugated with iron oxide nanoparticles (â¼5 nm) has a remarkable ability to be remotely guided under a magnetic field. Transduction is achieved with microscale precision. Furthermore, a gene for production of the photosensitive protein KillerRed was introduced into the AAV2 genome to enable photodynamic therapy (PDT), or light-triggered virotherapy. In vivo experiments revealed that magnetic guidance of "ironized" AAV2-KillerRed injected by tail vein in conjunction with PDT significantly decreases the tumor growth via apoptosis. This proof-of-principle demonstrates guided and highly localized microscale, light-triggered virotherapy.
