**2. Results**

*2.1. Copolymerization of Lactide with a Functionalized Lactide for the Preparation of PLA Graft Copolymers*

To the best of our knowledge, according to the first method mentioned above, few functionalized lactides are described in the literature, and only a small proportion of these substituted lactides has been copolymerized with lactide to yield functionalized

PLA backbones [11–14]. For example, some lactides functionalized with benzyl, allyl and propargyl groups have also been prepared and copolymerized with lactide, but no polymer chains were subsequently grafted onto the PLA backbone [15].

Yu et al. prepared an alkyne-functionalized lactide that was copolymerized with lactide to give an alkyne-functionalized PLA. An azide-paclitaxel-PEG was then reacted with the alkyne-functionalized PLA via a Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click reaction to give a novel graft polymer–drug conjugate (GPDC): PLA-*g*-Paclitaxel-PEG (Figure 2) targeting sustained release of Paclitaxel [16]. Zhang et al. prepared and (co)polymerized a dipropargyloxylactide by ring opening polymerization (ROP) in the presence of Sn(Oct)2 and TBBA (tertiobutylbenzyl alcohol). An azido-PEG (PEG-N3) was then grafted via CuAAC click chemistry (Figure 3) [17]. Turbidity, dynamic light scattering and NMR results suggested that these grafted copolymers exhibit a reversible thermoresponsive property, with LCST ranging from 22 to 69 ◦C depending on the molecular weight of the PEG.

**Figure 2.** Reaction scheme for the synthesis of PLA-*g*-Paclitaxel-PEG (adapted from Yu et al. [16], Copyright American Chemical Society, reproduced with permission).

**Figure 3.** Reaction scheme for the synthesis of dipropargyloxymethyl PLA and the grafting of PEG via click a reaction (adapted from Zhang et al. [17], Copyright Royal Society of Chemistry, reproduced with permission).

In another synthetic method, Castillo et al. prepared a spirolactide–heptene monomer that yielded a PEG-grafted lactide after reaction with an azido-PEG (Figure 4) [18]. This PEG-grafted lactide was then polymerized with molecular weights above 10kDa. Typically, polymerization was carried out in anhydrous CH2Cl2 with 1,5,7-triazabicyclo [4.4.0]dec-5- ene (TBD)/benzyl alcohol as the catalyst/initiator system. Preliminary biological studies showed that PLA-*g*-PEG reduced non-specific protein adsorption and cell adhesion compared to the original PLA.

**Figure 4.** Reaction scheme for the preparation of PLA-*g*-PEG (from Castillo et al. [18], copyright American Chemical Society, reproduced with permission).

This limited number of examples illustrates that this approach based on functionallactides is time-consuming, requires many steps and often gives low yields. For example, the global yields of the syntheses are 20% for dipropargyloxylactide [17] and 10% for PLA-*g*-Paclitaxel-PEG [16]. These copolymers are therefore expensive, and while this is not a fundamental problem for biomedical applications, it is a real drawback for environmental applications that use much larger amounts of product. Therefore, the second method, chemical modification of a preformed PLA chain, is the most widely used to obtain a functionalized PLA backbone allowing for the grafting of a second polymer.

#### *2.2. Direct Functionalization of PLA Backbone: Towards PLA-Based Graft Copolymers*

PLA is an aliphatic polyester known for being highly sensitive to chain breakings, especially in acid or alkaline environments. As a result, unlike poly ε-caprolactone, for which a general method of chain modification in anionic media is described [19], almost all substitution reactions on the PLA backbone are carried out under free radical conditions. In most cases, a functional small molecule is grafted on the PLA backbone to give it functionality and, in a second step, a polymer chain is grafted through this small molecule. This grafting can be carried out by polymerization of a monomer from this functional group ("grafting from") or by the direct grafting of a polymer chain through its reactive chain end ("grafting onto"). From an experimental point of view, the functionalization is carried out in blenders or extruders in the presence of a radical precursor. Very frequently, the modification of the PLA chain aims to obtain a compatibilizing agen<sup>t</sup> for blends of PLA and another polymer in order to improve the mechanical properties of the blends. Zeng et al. described the main basic strategies for the compatibilization of the PLA blends, among them functionalization of the PLA backbone with a reactive compound [20].

## 2.2.1. PLA-*g*-Maleic Anhydride (PLA-*g*-MA)

The most widely used reagen<sup>t</sup> for functionalizing the PLA chain is maleic anhydride (MA) due to its good chemical reactivity, low toxicity and good stability to the experimental synthesis conditions [21–23]. The grafting of MA onto the PLA backbone results in a reactive compatibilizer due to the presence of the anhydride function. PLA graft copolymers are therefore obtained by a reaction of the anhydride group with some reactive functions of the blended polymer.

Functionalization with MA is typically carried out between 120 ◦C and 200 ◦C with stirring at 50–200 rpm in an extruder in the presence of a radical initiators, such as dicumyl peroxide (DCP) or benzyl peroxide (BPO). A typical reaction scheme is shown in Figure 5 [21]. The role of different reaction parameters (MA concentration, nature of the initiator, temperature, molar mass of PLA) on the percentage of grafting is also described [23]. It was found that the molecular weights of PLA decreased during the reaction due to chain scissions. The grafting percentage of low-molecular-weight PLA is greater than that of the high-molecular-weight PLA because of steric hindrance (Table 1). It should be noted that the grafting percentage of MA increased with the initial concentration of MA, but remained low (<1.25%) regardless of the different parameters of the reaction, which shows the low efficiency of these radical reactions [23]. If one wishes to graft at least two molecules of anhydride per PLA chain, the molar mass of the latter must be higher than 14,500 g.mole−<sup>1</sup> if substitution degree = 1%, which is not always the case. Nevertheless, the results obtained for the compatibility of various PLA-based blends are significant. Examples of variations in mechanical properties are shown in Table 2 in blends of PLA/cellulose nanofibers (CNF) [24].

**Figure 5.** Reaction scheme for the grafting of MA on PLA (from González-López et al. [21], copyright Taylor and Francis, reproduced with permission).


**Table 1.** Variations in molecular weight and grafting percentage during functionalization of PLA by MA (extract of data from Muenprasat et al. [23]).

**Table 2.** Mechanical properties of PLA, PLA/CNF and PLA/CNF/PLA-*g*-MA (extract of data from Ghasemi et al. [24]).


The following paragraphs show the main PLA graft copolymers obtained from PLA-*g*-MA with their principal properties and applications.
