## 1 Introduction  
Nanomedicine for cancer therapy has become a promising therapeutic approach to overcome the various limitations of conventional small molecule chemotherapeutics by improving drug internalization and selective intracellular accumulation in cancer cells, easing the toxicity to normal tissues [1, 2]. Polymeric nanoparticles possess remarkable properties when compared to other colloidal systems such as (i) higher stability, particularly in body fluids; (ii) a larger contact area between the nanoparticle and the biological target; and (iii) a rapid adsorption rate and accumulation in the tumor cellular interstices due to the enhanced permeability and retention (EPR) effect [3, 4]. Moreover, polymeric nanoparticle-drug conjugates present advantages when compared to polymer-drug conjugates, such as tunability and high and predefined drug loading based on efficient conjugation of the active agents to polymeric nanocarriers [5]. One of the main advantages offered by nanoparticles (NPs) is their ability to release drugs in a controlled manner [6]. This controlled release can be achieved by implementing a stimulus-sensitive approach involving a two-step process: first, the nanosystem is preferentially accumulated at the target site through the EPR effect; then, the drug-loaded nanoparticles are directly activated by an external (light, temperature, etc.) or internal (pH, enzymatic, redox, etc.) stimulus to produce the local release of the drug [7,8]. In particular, pH has been used for a long time as a critical feature for the differentiation between healthy tissues and abnormal tissues. Although fluctuations may occur, the pH in most solid tumors is between 6 and 7 [9]. This pH difference opened a new pathway for the release of tumor-specific drugs in tumors and simultaneously reduces undesirable effects in healthy tissues. Several examples of pH-sensitive nanodevices such as amorphous calcium carbonate-silica nanoparticles (core/shell), N- (2-hydroxypropyl) ethacrylamide (HPMA), dendrimers, and gold nanoparticles have been reported [10, 11, 12, 13, 14]. The chemotherapeutic drug doxorubicin (DOX) has been widely used in clinic settings for the treatment of different types of cancer. However, its toxicity to healthy tissue with effects such as cardiotoxicity and the development of resistance to multiple drugs during prolonged treatment have limited its therapeutic use [15]. Doxil(r), the first nanopharmaceutical approved by the U.S. Food and Drug Administration (FDA) in 1995, takes advantage of the EPR effect and moves passively to the tumors where the encapsulated doxorubicin is released [16]. Recently, many nanotechnology-based drug delivery systems have been reported for the selective release of doxorubicin [17, 18, 19]. However, there is still room for improvement in terms of the therapeutic efficiency, as compared with free doxorubicin. Most of these nanodevices are based on drug encapsulation, which can lead to undesired drug leakage, causing loss of efficiency and systemic toxicity. This drawback can be overcome by covalent conjugation of the drug to the nanoparticle. We have previously reported the use of polystyrene-based nanoparticles for the efficient conjugation of bioactive molecules of different types, such as sensors, proteins, and nucleic acids. In addition, polystyrene nanoparticles have been implemented for imaging, biosensing, tracking cellular proliferation using fluorescent nanoparticles, metallofluorescent nanoparticles for multimodal applications, and in cellulo proteomics using drug-loaded fluorescent nanoparticles [20, 21, 22]. These polymeric particles are inherently attractive as a delivery system due to certain advantages, such as being easy to handle and robust, with a defined drug loading capacity, tunebility, and lack of toxicity. These nanosystems can achieve efficient delivery through a passive but rapid mechanism, without significant alterations involving cellular gene profiling or proteomics [23, 24].