Conjugated polymer nano-systems for hyperthermia, imaging and drug delivery

Abstract

Hyperthermia has shown tremendous therapeutic efficiency in the treatment of cancer due to its controllability, minimal invasiveness and limited side effects compared to the conventional treatment techniques like surgery, radiotherapy and chemotherapy. To improve the precision of hyperthermia specifically to a tumor location, near infra-red (NIR) light activatable inorganic metal nanoparticles have served as effective photothermal therapy materials, but toxicity and non-biodegradability have limited their clinical applications. Conjugated polymer nanoparticles have overcome these limitations and are emerging as superior photothermal materials owing to their excellent light harvesting nature, biocompatibility and tunable absorption properties. In this review we focus on the development of organic conjugated polymers (polyaniline, polypyrrole, polydopamine etc.) and their nanoparticles, which have broad NIR absorption. Such materials elicit photothermal effects upon NIR stimulation and may also serve as carriers for delivery of therapeutic and contrast agents for combined therapy. Subsequently, the emergence of donor-acceptor based semiconducting polymer nanoparticles with strong absorbance that is tunable across the NIR have been shown to eradicate tumors by either hyperthermia alone or combined with other therapies. The design of multifunctional polymer nanoparticles that absorb near- or mid- infrared light for heat generation, as well as their diagnostic abilities for precise biomedical applications are highlighted.

Introduction

Despite enormous scientific efforts and economical investments in cancer research, each year millions of lives are affected by this deadly disease [1,2]. Clinical treatment of cancer involves surgery, radiotherapy and chemotherapy, which can benefit many patients, but they suffer from limitations such as multi-drug resistance, lack of specificity, acute side effects and metastatic disease detection [3,4]. The search for specific and non-invasive therapeutic strategies to treat cancer has led to the development of new hyperthermia based techniques involving nanoparticles [5].

Hyperthermia, involving the generation of heat by external stimuli has recently shown great promise as an adjuvant technique in fighting cancer [6,7]. In principle, hyperthermia elevates the temperature of the cellular environment and subsequently disrupts cell membranes and nuclear processes, as well as inducing DNA strand breakage, and increases vascular permeability. The effect of hyperthermia on these processes can sensitize tumors to chemotherapy or radiation, leading to enhanced treatment efficacy [8,9]. Specific delivery of hyperthermia to the tumor cells is of the utmost importance to prevent damage to normal cells. Integration of nanotechnology and biomedical science has addressed this problem by generating photothermal agents (PTAs) of nanometer dimensions that generate heat by external stimulation [10,11]. Nanomaterials manifested several advantages over small molecules in biomedical applications due to their excellent structural features [12]. They have the ability to passively accumulate at the tumor location due to the leaky vasculature of tumor tissues, i.e., the enhanced permeability and retention (EPR) effect [13]. Nanomaterials can be functionalized easily by biocompatible polymers, proteins and peptides to prevent their nonspecific uptake by reticuloendothelial system or can serve as carriers of therapeutic molecules that can be efficiently loaded onto nanoparticles [14,15].

Near infra-red (NIR) light (650–1350 nm), utilized to instigate thermal energy from photothermal agents (PTAs), is called the ‘tissue transparent biological window’ due to its high tissue penetration ability and low scattering [[16], [17], [18]]. With improved specificity and minimal invasiveness photothermal therapy has evolved as a flourishing modality with the development of new PTAs to harvest light and produce thermal energy to destroy cancer cells [19]. The benefit of photothermal therapy (PTT) lies in the ability to remotely control the temperature of the tumor environment by either varying the concentration of PTAs or tuning the intensity of laser irradiation. Therefore, characteristics of an ideal PTA include (i) strong NIR absorbance, (ii) a high mass absorption coefficient, (iii) high photothermal conversion efficiency (PCE), (iv) photostability, and (v) biocompatibility.

Several inorganic and organic photothermal agents have been reported for photothermal therapy and combination therapy, having their own pros and cons. PTAs such as gold nanostructures [[20], [22], [21]], palladium nanoparticles [23], carbon dots [24], copper sulfide nanoparticles [25], and graphene oxide [26], etc., have been found to exhibit excellent efficiency for ablating of tumor cells upon NIR irradiation. Among noble metals, silver, along with palladium, have also been explored for PTT, but their low photostability and metal ion induced toxicity has limited their applications [16,27]. Gold nanostructures are the most explored among inorganic PTAs due to their strong surface plasmon resonance and NIR absorbance [27,28]. However, gold nanoparticles cannot be degraded in vivo, and some formulations exhibit shape changes/melting associated aggregation upon NIR stimulation which in turn alters their optical properties and renders them ineffective for subsequent NIR stimulation (heat/cool cycles) [[29], [30], [31]].

In this respect, small molecule organic chromophores e.g. cyanine, BODIPY, thiocyanine etc. have been demonstrated as PTAs, with advantages like the ability to tune their absorbance and improved biocompatibility compared to metal nanoparticles [32]. However, their low photothermal conversion efficiency (PCE), photo-bleaching and issue of aqueous solubility has labeled them as poor PTAs. To overcome these disadvantages conjugated polymers (CPs) have emerged as promising photothermal materials due to their delocalized electronic structures and long π-conjugated backbones. CPs were first developed to satisfy the need for polymers with longer absorption wavelengths for increasing energy generation in photovoltaic and optoelectronic devices [[33], [34], [35], [36], [37], [38]]. Their exceptional light harvesting nature, photostability and high brightness have made them promising fluorescent probes [[39], [40], [41], [42]]. Within the past decade methods for converting CPs into water soluble conjugated polymer nanoparticles (CPNPs) for biological applications have been developed. It has been demonstrated that CPs' high absorption capability is retained, and sometimes improved upon in nanoparticle versus polymer form. They are biocompatible, photostable, and have tunable optical absorption dependent upon the molecular weight and polymer chain interactions. Their many benefits, in addition to their ease of functionalization for adding molecules to target disease, and their flexibility of design have made CPNPs an exciting new class of PTAs [43,44]. Organic polymers (e.g. polyaniline, polydopamine, polypyrrole, and poly-ethylenedioxythiophene: polystyrene (PEDOT: PSS)) with broad NIR absorbance have been well explored as potential PTAs [45]. More recently, donor-acceptor (D-A) conjugated polymers, which were initially designed for solar applications, exhibit sharp and tunable NIR absorbance, and have begun to be explored for photothermal treatment of cancer in in vitro and in vivo. [[46], [47], [48]]

In addition to their utility to serve as fluorescent imaging agents, CPNPs are being investigated to continue to improve their effectiveness, specifically the evolution of CPNPs with NIR-II (950–1350 nm) light absorption, since longer wavelengths have higher tissue penetration than those in the NIR-I window (650–950 nm) [49]. A high PCE is always desired for CPNPs so that the lowest intensity of light is able to generate hyperthermia with minimum damage to adjacent tissues around the tumor. PCEs of polymers can be improved by obtaining a planar structure with greater electron delocalization. Also strengthening of the electron donors and acceptors can improve PCE. Third, although CPNPs may accumulate in the tumor microenvironment through the enhanced permeability and retention effect (EPR); their functionalization with target receptors may improve the specificity of the photothermal treatment. Although CPNPs are being explored for PTT of cancer, sometimes the complexity and heterogeneity of tumors can result in incomplete ablation with the risk of tumor recurrence. Therefore, pre-clinical research has begun exploring their applications as a combination therapy, including coupling with chemotherapy, since combination with hyperthermia has been shown to be augmentative [[50], [51], [52]]. Here NIR light not only produces hyperthermia by exciting PTAs but also triggers the release of chemotherapeutic agents [53]. Hyperthermia assists internalization of the drug in the tumor cells by increasing the permeability of the cell membranes. Therefore, as a combination therapy, chemo-photothermal therapy has displayed great potential with reduced risk of tumor recurrence, inhibition of multi-drug resistance and minimum side effects compared to monotherapy [54].

The aim of this review is to summarize the evolution of conjugated polymers for photothermal therapy, imaging and drug delivery, followed by recent developments in D-A based semiconducting polymers for improved optical properties and more efficient nanoparticles. The conversion process of the polymers to their nanoparticles, PCEs, PTT properties and in vitro/in vivo applications are discussed. The effect of polymer design, laser intensity, and dosage of PTAs for eliciting photothermal effects is also explained. Finally, this review evaluates the synergistic impact of polymer based hyperthermia and NIR/hyperthermia triggered drug release.