Abstract and Introduction
Abstract
Aim: The development of chemoradiation – the concurrent administration of chemotherapy and radiotherapy – has led to significant improvements in local tumor control and survival. However, it is limited by its high toxicity. In this study, we report the development of a novel NP (nanoparticle) therapeutic, ChemoRad NP, which can deliver biologically targeted chemoradiation.
Method: A biodegradable and biocompatible lipid–polymer hybrid NP that is capable of delivering both chemotherapy and radiotherapy was formulated.
Results: Using docetaxel, indium111 and yttrium90 as model drugs, we demonstrated that the ChemoRad NP can encapsulate chemotherapeutics (up to 9% of NP weight) and radiotherapeutics (100 mCi of radioisotope per gram of NP) efficiently and deliver both effectively. Using prostate cancer as a disease model, we demonstrated the targeted delivery of ChemoRad NPs and the higher therapeutic efficacy of ChemoRad NPs.
Conclusion: We believe that the ChemoRad NP represents a new class of therapeutics that holds great potential to improve cancer treatment.
Introduction
The advent of concurrent administration of chemotherapy and radiotherapy (chemoradiation) has significantly improved cancer care. Currently, it is the standard of treatment for many cancers, including esophageal, gastric, head and neck, and rectal cancers.[1] However, chemoradiation is limited by its higher (potentially life-threatening) toxicity, thereby precluding patients with poor general health from undergoing treatment. One potential strategy to improve chemoradiation utilizes advancements in drug delivery technology to improve efficacy and lower toxicity of the treatment. In particular, advances in nanotechnology have led to the development of nanoparticle (NP) drug-delivery vehicles, which can potentially improve the codelivery of chemoradiation. NPs are particularly well suited for cancer applications as they passively accumulate in tumors through the enhanced permeability and retention effect.[2] The proof-of-principle was observed in liposomal formulations of chemotherapeutics, such as Doxil, which demonstrated lower toxicity than their small molecular counterparts.[3] Our group and other investigators have demonstrated that the combination of biological targeting and NP delivery result in a higher concentration of chemotherapeutics within cancer cells.[4–12] Considering the many favorable characteristics of targeted NPs, we became interested in developing a targeted NP platform that is capable of delivering both chemotherapy and radiotherapy. We hypothesized that such an NP may improve efficacy and lower toxicity of chemoradiotherapy.
In this study, we report the development of what we believe to be the first multifunctional NP platform intended for the codelivery of chemotherapeutics and therapeutic radioisotopes (ChemoRad NP). Although previous studies have incorporated radioisotopes into NPs for biodistribution and pharmacokinetics, none have utilized the NPs for the delivery of chemoradiation.[13] The main challenge for engineering a ChemoRad NP lies in incorporating therapeutic doses of radioisotopes into NPs without affecting NP characteristics, including size, surface charge, stability and drug delivery profile. Potential compartments for radioisotope incorporation include the NP surface, the NP core, or a combination of the two. However, incorporating radioisotopes onto the NP surface would likely change the surface charge and size of the NP.[14] Furthermore, adding the radioisotopes into the core can change the drug encapsulation and drug release. Therefore, we chose to add radioisotopes into a layer between the outer NP surface and core. To accomplish this, we chose to utilize a lipid–polymer hybrid NP platform where such a layer is possible. The following design criteria were also used in the engineering of the ChemoRad NP:[15]
The NP platform is comprised of natural or biocompatible and biodegradable/bioeliminable materials to facilitate potential clinical translation;
The NPs should have minimal release of radioisotopes prior to reaching the tumor to minimize potential toxicity;
The NPs should have size range of 50–100 nm, which has been shown to be optimal for tumor accumulation/targeting.
Based on these criteria, we developed the ChemoRad NP using a biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer and biocompatible lipids. We systematically examined the structural morphology, size, stability, drug release profile and radioisotope chelation properties of the ChemoRad NP, followed by evaluating its targeting ability and therapeutic effectiveness using prostate cancer as a disease model.
Nanomedicine. 2010;5(3):361-368. © 2010 Future Medicine Ltd.
Cite this: ChemoRad Nanoparticles: A Novel Multifunctional Nanoparticle Platform for Targeted Delivery of Concurrent Chemoradiation - Medscape - Apr 01, 2010.
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