The Application Of Therapeutic Nanoreactors And Novel Treatment Strategies To Overcome Multi-Drug Resistance In Cancer Therapy

Cancer disease persists to dramatically increase in humankind and sophisticated therapeutic strategies are urgently needed to achieve efficacious therapeutic effect than ever before.This thesis entitled "the application of therapeutic nanoreactors as in vivo nanoplatforms and novel treatment strategies to overcome multi-drug resistance in cancer therapy" is composed of four chapters based on individual and yet related works that mainly focus on the engineering of therapeutic nanoreactors that can be used in cancer treatment and development of different treatment strategies to reverse drug resistance in cancer therapy.The following is the abstract of work presented in each chapter:Chapter ?Cancer is a growing burden to mankind and ranked the second among serious diseases leading to major deaths worldwide annually.Although chemotherapy is the main treatment option for most of cancer types,its successful application in clinics is critically limited by less effectiveness mostly due to multidrug resistance and severe side effects.Among various current approaches reported to achieve enhanced cancer treatment effect with mitigated side effects,the application of therapeutic nanoreactor suggested promising strategies for cancer treatment which also allow the application of exogenous therapeutic enzymes.Nevertheless,further efforts are required to address several limitations in that field such as the complex engineering procedures,intrinsic membrane permeability,off-target activation of the nanoreactors,required multiple steps required to apply therapeutic nanoreactors and so on.In this chapter,we highlighted the general background about the current progress and limitations of therapeutic nanoreactors designed for cancer treatment and diagnosis by also showing some of the proposed approaches to address these limitations towards the development of ideal therapeutic nanoreactors.Furthermore,we presented two more proposed strategies to overcome multidrug resistance often encountered in the conventional chemotherapy.In overall,the study conducted in this thesis is expected to contribute a lot to the existing literature especially through the inspiring the next generation of researchers to develop advanced therapeutic nanoreactor and with novel treatment approaches to achieve enhanced therapeutic effect and with remarkably minimized adverse effect as well as to overcome multi-drug resistance and ready for clinical translation in cancer therapy.Chapter ?Therapeutic nanoreactors are currently emerging as promising nanoplatforms to in situ transform inert prodrugs into active drugs.Nevertheless,it is still challenging to engineer a nanoreactor with balanced key features of tunable selective membrane permeability and structural stability for prodrug delivery and activation in diseased tissues.Herein,we present a facile strategy to engineer a polymersome nanoreactor with tumor-specific tunable membrane permeability to load both hydrophobic phenylboronic ester-caged anticancer prodrugs(e.g.,camptothecin or paclitaxel prodrug)and hydrophilic glucose oxidase(GOD)in the membranes and cavities,respectively.The nanoreactors maintain inactive during blood circulation and in normal tissues.Upon accumulation in tumors,the mild acidic microenvironment triggers selective membrane permeability to allow small molecules(glucose and O2)to diffuse across the membrane and react under the catalysis of GOD.The massively generated H2O2 triggers in situ transformation of innocuous prodrugs into toxic parental drugs through cleavage of the self-immolative degradable caging groups.The developed system showed significantly enhanced antitumor efficacy by H2O2 production and prodrug activation via combined oxidation-chemotherapy.The well-devised polymersome nanoreactors with tumor-pH-tunable membrane permeability to coload H2O2-responsive prodrug and GOD represent a novel strategy to realize prodrug delivery and activation for enhanced therapeutic efficacy with low side toxicity.Chapter ?Drug resistance of cisplatin significantly limited its therapeutic efficacy in clinical applications against a variety of cancers.In addition to DNA damage and mitochondria apoptosis,oxidative stress is deemed to play a pivotal role in underlying mechanisms of cisplatin-induced cytotoxicity.Herein,we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells(A549R)under amplified oxidative stress by a vesicular nanoreactor for cisplatin delivery and H2O2 generation.We engineered the nanoreactors from self-assembly of the amphiphilic diblock copolymers consisting of poly(ethylene glycol)and a copolymerized segment of benzyl methacrylate and 2-(piperidin-l-yl)ethyl methacrylate,which co-deliver both glucose oxidase(GOD)and cisplatin(Cis)and were denoted as Cis/GOD@Bz-V.Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation until it reaches tumor parenchyma where the mild acidity(pH 6.5-6.8)can activate its molecular-weight selective membrane permeability and release cisplatin locally.The subsequent diffusion of small molecules such as oxygen and glucose across the membrane can induce the in-situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize cisplatin-resistant cells A549R via activation of pro-apoptotic pathways.The results showed that Cis/GOD@Bz-V nanoreactors can effectively kill A549R cells and significantly inhibits the growth of A549R xenograft tumors.Accordingly,the tumor acidity-activable nanoreactors show great potentials as drug delivery nanocarriers of cisplatin to enhance the therapeutic efficacy of cisplatin-resistant cancers.Chapter ?Multidrug resistance(MDR)continues to become one of the major menaces that obstruct chemotherapy success in clinics.In addition to the reported many factors that induce MDR in cancer therapy,the role of mitochondria mediated pathways that generate cancer cell survival mechanisms under various stress is obvious.Therefore,targeting mitochondria can be an ideal strategy to overcome MDR.Herein,we report a rationally designed dual targeting polymer prodrug nanoparticle that can simultaneously target cancer cell and mitochondria by folic acid(FA)and tetraphenylphosphonium(TPP)targeting species,respectively,to overcome MDR through amplification of mitochondrial oxidative stress and DNA damage.Briefly,a diblock copolymer containing cinnamaldehyde(CNM)and doxorubicin(DOX)drug moieties denoted as FA&TPP-PEOGMA18-b-P(CNM17-co-DOX15)was synthesized and used to prepare nanoparticles mentioned as PCD.Upon the accumulation of PCD nanoparticles in cancer cells,the endosomal acidity(?pH 5-6.5)can trigger the release of CNM in the cytoplasm followed by amplification of mitochondria ROS production that can subsequently enhance oxidative stress and trigger the release of DOX in the mitochondria for DNA damage.This treatment strategy showed enhanced potential to kill and inhibit DOX resistant MCF-7 ADR tumor cells both in vitro and in vivo without observable side effect.