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Utilizing the diverse features of biocompatible polymers to target drugs into the tumor/s has been a research hotspot since last decade. Such polymeric conjugates of anti-cancer drugs have proven their potential in providing sustained release of drugs with reduced systemic toxicity and improved tumor retention. Polymers like polyethylene glycol (PEG), N-(2-Hydroxypropyl) methacrylamide (HPMA), Polylactic-co-glycolic acid (PLGA), Polyamidoamine (PAMAM), and others remain exploited for their specific as well as shared characteristics in the rational delivery of anti-cancer agents. Variable nano size, attachment with tumor-specific proteins, responsiveness to stimuli and ability to deliver a wide range of molecules like drugs, antibodies and peptides are some of the achievements of polymeric nano-conjugates so far. Many such conjugates have shown potential clinically which has attracted the researchers and promoted further advancements of the technique. Apart from achievements the polymeric conjugates suffer from shortcomings like poor drug loading and chances of potential chronic-systemic toxicities. The review highlights key findings of research in recent time and advancements taking place in the field of polymeric conjugates of anti-cancer drugs along with the limitations. We have also emphasized on newer and relatively less explored applications of tumor-targeted polymeric conjugates which can add new dimensions to this technique. [ABSTRACT FROM AUTHOR]

• Poor aqueous solubility of bortezomib: major drawback in formulation development. • Bortezomib encapsulation in PEGylated PAMAM dendrimers. • Cytotoxicity assay against A549 and MCF-7 cancer cells. • In vivo pharmacokinetic studies co-relating the in vitro results. Poor aqueous solubility of anticancer drug bortezomib (BTZ) still remains a major challenge in the development of a successful formulation. The dendrimeric platform can provide a better opportunity to deliver BTZ with improved solubility. BTZ encapsulated in PEGylated PAMAM dendrimers (BTZ-PEG-PAMAM) was characterized and evaluated comparatively with encapsulated and conjugated dendritic formulations. The particle size of BTZ-PEG-PAMAM was 188.6 ± 4.17 nm, with entrapment efficiency of 78.61 ± 2.91% and drug loading of 39.30 ± 1.98%. The aqueous solubility of BTZ in PAMAM-PEG conjugate was enhanced by 68.11 folds in comparison to pure drug. In vitro drug release profile was found to be sustained up to 72 h. A comparative colorimetric MTT assay against A549 and MCF-7 cancer cells resulted in maximum efficacy from BTZ-PEG-PAMAM with IC 50 value 333.14 ± 15.42 and 152.60 ± 24.56 nM, respectively. Significantly higher cellular internalization was observed in FITC tagged BTZ-PEG-PAMAM. In vivo pharmacokinetic study performed on Sprague Dawley rats resulted in 8.63 folds increase in bioavailability for BTZ-PEG-PAMAM than pure drug. Pharmacokinetic parameters of BTZ-PEG-PAMAM were better and improved over BTZ and other dendritic formulations. In conclusion, the prepared formulation of BTZ-PEG-PAMAM has given significant outcome and this strategy may be further explored for better delivery of BTZ in future. [ABSTRACT FROM AUTHOR]

• Synthesis and evaluation of conjugates; HPMA-Biotin, HPMA-PLA, HPMA-PLA-Biotin. • Effect of biotin as a targeting ligand on breast cancer cells. • Two folds reduction in IC 50 values of HPLA-BT PNPs than pure BTZ. • Cellular uptake interactions of PNPs in breast cancer cells. • In vivo data (bioavailability, t1/2, v d) supported in vitro results. Bortezomib (BTZ) is a proteasome inhibitor as approved by US FDA for the treatment of multiple myeloma. It exhibits significant anti-cancer properties, against solid tumors; but lacks aqueous solubility, chemical stability which hinders its successful formulation development. The present study is an attempt to deliver BTZ using N-(2-hydroxypropyl) methacrylamide (HPMA) based copolymeric conjugates and biotinylated PNPs in an effective manner. Study describes a systematic synthetic pathway to synthesize functional polymeric conjugates such as HPMA-Biotin (HP-BT) HPMA-Polylactic acid (HPLA) and HPMA-PLA-Biotin (HPLA-BT) followed by exhaustive characterization both spectroscopically and microscopically. Our strategy yielded polymeric nanoparticles (PNPs) of narrow size range of 199.7 ± 1.32 nm. Release studies were performed at pH 7.4 and 5.6. PNPs were 2-folds less hemolytic (p < 0.0001) than pure drug. BTZ loaded PNPs of HPLA-BT demonstrated significant anti-cancer activity against MCF-7 cells. IC 50 value of these PNPs was 56.06 ± 0.12 nM, which was approximately two folds less than BTZ (p < 0.0001). Cellular uptake study confirmed that higher uptake of formulations might be an outcome of biotin surface tethering characteristics that enhanced selectivity and targeting of formulations efficiently. In vivo pharmacokinetics evidenced increased bioavailability (AUC 0 t-∞) of DL-HPLA-BT PNPs (drug loaded) than BTZ with an improved half-life. Overall the developed PNPs led to the improved and effective BTZ delivery. [ABSTRACT FROM AUTHOR]