Skip to main content

Advertisement

SpringerLink
Log in

Layer-by-layer microcapsules for pH-controlled delivery of small molecules

  • Research Article
  • Published:
Journal of Pharmaceutical Investigation Aims and scope Submit manuscript

Abstract

The aim of this study is to investigate the influence of pH on the encapsulation and release behavior of charged and neutral small molecules in layer-by-layer microcapsules (LbL-MC). Alternative layers of polystyrene sulfonate and polyallylamine hydrochloride polyelectrolytes were adsorbed onto calcium carbonate sacrificial templates. Six model small molecules including ascorbic acid, indomethacin, imatinib mesylate, rhodamine, 5-fluorouracil and estradiol were studied for their encapsulation in LbL-MC. Encapsulation efficiency was optimized for solute concentration, pH, incubation time and NaCl concentration. In vitro release studies were performed using dialysis membrane method at pH 4, 7.4 and 9. Optical microscopy and zetasizer results showed particles of 3.1 ± 0.2 μm diameter and 1.67 ± 0.87 mV potential. FTIR and differential scanning calorimeter studies confirmed the encapsulation of small molecules in LbL-MC. Encapsulation efficiency (%) of model molecules in LbL-MC increased with increase in solute concentration and increase in pH from 2 to 6. Interestingly, encapsulation efficiency was significantly greater for charged small molecules compared to neutral molecules. Extended release of charged molecules was achieved at pH 9. Kinetic modelling of release studies showed Fickian and non-Fickian diffusion of small molecules. In conclusion, LbL-MC can be developed as a potential carrier for small molecules depending on their physical and chemical properties.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Bart G, Heleen D, Stefaan CDS, Ine L (2012) Crucial factors and emerging concepts in ultrasound-triggered drug delivery. J Control Release 164:248–255

    Article  Google Scholar 

  • Benjamin MW, Johan FJE (2012) Responsive layer-by-layer materials for drug delivery. J Control Release 158:2–14

    Article  Google Scholar 

  • Cai S, Thati S, Bagby TR, Diab HM, Davies NM, Cohen MS, Forrest ML (2010) Localized doxorubicin chemotherapy with a biopolymeric nanocarrier improves survival and reduces toxicity in xenografts of human breast cancer. J Control Release 146:212–218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 5:786–795

    Article  CAS  PubMed  Google Scholar 

  • Chunhong Y, Olga S, Rossella C, Irina D, David LK, Vladimir VT (2011) Robust and responsive silk ionomer microcapsules. Biomacromolecules 12:4319–4325

    Article  Google Scholar 

  • Chunyin L, Bin M, Peng L (2011) Stimuli-responsive multilayer chitosan hollow microspheres via layer-by-layer assembly. Colloid Surf B 83:254–259

    Article  Google Scholar 

  • Clark SL, Hammond PT (2000) The role of secondary interactions in selective electrostatic multilayer deposition. Langmuir 16:10206–10214

    Article  CAS  Google Scholar 

  • Fukumura D, Jain RK (2007) Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 101:937–949

    Article  CAS  PubMed  Google Scholar 

  • Gan Q, Lu X, Dong W, Yuan Y, Qian J, Li Y, Shi J, Liu C (2012) Endosomal pH activatable magnetic nanoparticle-capped mesoporous silica for intracellular controlled release. J Mater Chem 22:15960–15968

    Article  CAS  Google Scholar 

  • Gao Z, Fain HD, Rapoport N (2004) Ultrasound-enhanced tumor targeting of polymeric micellar drug carriers. Mol Pharm 1:317–330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Han B, Shen B, Wang Z, Shi M, Li H, Peng C, Zhao Q, Gao C (2008) Layered microcapsules for daunorubicin loading and release as well as in vitro and in vivo studies. Polym Adv Technol 19:36–46

    Article  CAS  Google Scholar 

  • Jia X, Yin J, He D, He X, Wang K, Chen M, Li Y (2013) Polyacrylic acid modified upconversion nanoparticles for simultaneous pH-triggered drug delivery and release imaging. J Biomed Nanotechnol 9:2063–2072

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Li Y, Kim MS, Kang SW, Jeong JH, Lee DS (2012) Synthesis and evaluation of biotin-conjugated pH-responsive polymeric micelles as drug carriers. Int J Pharm 427:435–442

    Article  CAS  PubMed  Google Scholar 

  • Kong SD, Sartor M, Hu CJ, Zhang W, Zhang L, Jin S (2013) Magnetic field activated lipid–polymer hybrid nanoparticles for stimuli-responsive drug release. Acta Biomater 9:5447–5452

    Article  PubMed Central  PubMed  Google Scholar 

  • Kotov NA (1999) Layer-by-layer self-assembly: the contribution of hydrophobic interactions. Nano Struct Mater 12:789–796

    Article  Google Scholar 

  • Labala S, Mandapalli PK, Bhatnagar S, Venuganti VV (2014) Encapsulation of albumin in self-assembled layer-by-layer microcapsules: comparison of co-precipitation and adsorption techniques. Drug Dev Ind Pharm. doi:10.3109/03639045.2014.947509

    PubMed  Google Scholar 

  • Liu J, Zhang Y, Wang C, Ruizhi X, Zhongping C, Ning G (2010) Magnetically sensitive alginate templated polyelectrolyte multilayer microcapsules for controlled release of doxorubicin. J Phys Chem C 114:7673–7679

    Article  CAS  Google Scholar 

  • Liu J, Pang Y, Huang W, Zhu Z, Zhu X, Zhou Y, Yan D (2011) Redox-responsive polyphosphate nanosized assemblies: a smart drug delivery platform for cancer therapy. Biomacromolecules 12:2407–2415

    Article  CAS  PubMed  Google Scholar 

  • Mak WC, Cheung KY, Trau D (2008) Influence of different polyelectrolytes on layer-by-layer microcapsule properties: encapsulation efficiency and colloidal and temperature stability. Chem Mater 20:5475–5484

    Article  CAS  Google Scholar 

  • Manchun S, Dass CR, Sriamornsak P (2012) Targeted therapy for cancer using pH-responsive nanocarrier systems. Life Sci 90:381–387

    Article  CAS  PubMed  Google Scholar 

  • Mandapalli PK, Labala S, Vanamala D, Koranglekar MP, Sakimalla LA, Venuganti VVK (2013) Influence of charge on encapsulation and release behavior of small molecules in self-assembled layer-by-layer microcapsules. Drug Deliv. doi:10.3109/10717544.2013.867381

    PubMed  Google Scholar 

  • Manju S, Sreenivasan K (2011) Hollow microcapsules built by layer by layer assembly for the encapsulation and sustained release of curcumin. Colloid Surf B 82:588–593

    Article  CAS  Google Scholar 

  • Manna U, Patil S (2009) Dual drug delivery microcapsules via layer-by-layer self-assembly. Langmuir 25:10515–10522

    Article  CAS  PubMed  Google Scholar 

  • Mao Z, Ma L, Gao C, Shen J (2005) Preformed microcapsules for loading and sustained release of ciprofloxacin hydrochloride. J Control Release 104:193–202

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto NM, Prabhakaran P, Rome LH, Maynard HD (2013) Smart vaults: thermally-responsive protein nanocapsules. ACS Nano 7:867–874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mihaela D, Helmuth M, Andre GS (2011) Stimuli-responsive LbL capsules and nanoshells for drug delivery. Adv Drug Deliv Rev 63:730–747

    Article  Google Scholar 

  • Peng L (2014) Stabilization of layer-by-layer engineered multi-layered hollow microspheres. Adv Colloid Interface Sci 207:178–188

    Article  Google Scholar 

  • Poon Z, Chang D, Zhao X, Hammond PT (2011) Layer-by-layer nanoparticles with a pH-sheddable layer for in vivo targeting of tumor hypoxia. ACS Nano 5:4284–4292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Qinghe Z, Bingyun L (2008) pH-controlled drug loading and release from biodegradable microcapsules. Nanomedicine 4:302–310

    Article  Google Scholar 

  • Rao W, Zhang W, Poventud-Fuentes I, Wang Y, Lei Y, Agarwal P, Weekes B, Li C, Lu X, Yu J, He X (2014) Thermally responsive nanoparticle-encapsulated curcumin and its combination with mild hyperthermia for enhanced cancer cell destruction. Acta Biomater 10:831–842

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rodrigues PCA, Beyer U, Schumacher P, Roth T, Fiebig HH, Unger C, Messori L, Orioli P, Paper DH, Mulhaupt R, Kratz F (1999) Acid-sensitive polyethylene glycol conjugates of doxorubicin: preparation, in vitro efficacy and intracellular distribution. Bioorg Med Chem 7:2517–2524

    Article  CAS  PubMed  Google Scholar 

  • Santos JL, Nouri Fernandes T, Rodrigues J, Tomas H (2012) Gene delivery using biodegradable polyelectrolyte microcapsules prepared through the layer-by-layer technique. Biotechnol Prog 28:1088–1094

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Sano M (2005) van der Waals layer-by-layer construction of a carbon nanotube 2D network. Langmuir 21:11490–11494

    Article  CAS  PubMed  Google Scholar 

  • Su X, Kim BS, Kim SR, Hammond PT, Irvine DJ (2009) Layer-by-layer assembled multilayer films for transcutaneous drug and vaccine delivery. ACS Nano 3:3719–3729

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Su J, Chen F, Cryns VL, Messersmith PB (2011) Catechol polymers for pH-responsive, targeted drug delivery to cancer cells. J Am Chem Soc 133:11850–11853

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tao X, Chen H, Sun XJ, Chen JF, Roa WH (2007) Formulation and cytotoxicity of doxorubicin loaded in self-assembled bio-polyelectrolyte microshells. Int J Pharm 336:376–381

    Article  CAS  PubMed  Google Scholar 

  • Veronika K, Eugenia K, Irina D, Derek C, Vladimir VT (2010) Responsive microcapsule reactors based on hydrogen-bonded tannic acid layer-by-layer assemblies. Soft Matter 6:3596–3608

    Article  Google Scholar 

  • Wang YC, Wang F, Sun TM, Wang J (2011) Redox-responsive nanoparticles from the single disulfide bond-bridged block copolymer as drug carriers for overcoming multidrug resistance in cancer cells. Bioconjug Chem 22:1939–1945

    Article  CAS  PubMed  Google Scholar 

  • Weijun T, Changyou G, Helmuth M (2008) pH-responsive protein microcapsules fabricated via glutaraldehyde mediated covalent layer-by-layer assembly. Colloid Polym Sci 286:1103–1109

    Article  Google Scholar 

  • Yan S, Zhu J, Wang Z, Yin J, Zheng Y, Chen X (2011) Layer-by-layer assembly of poly (l-glutamic acid)/chitosan microcapsules for high loading and sustained release of 5-fluorouracil. Eur J Pharm Biopharm 78:336–345

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Grailer JJ, Pilla S, Steeber DA, Gong S (2010) Tumor-targeting, pH-responsive, and stable unimolecular micelles as drug nanocarriers for targeted cancer therapy. Bioconjug Chem 21:496–504

    Article  CAS  PubMed  Google Scholar 

  • Yu F, Shilong B, Shuxun C, Dengli Q, Zhiqiang W, Xi Z (2002) Hydrogen-bonding directed layer by layer multilayer assembly: reconfirmation yielding microporous films. Macromolecules 35:9451–9458

    Article  Google Scholar 

  • Zhang XX, Eden HS, Chen X (2012) Peptides in cancer nanomedicine: drug carriers, targeting ligands and protease substrates. J Control Release 159:2–13

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu L, Kate P, Torchilin VP (2012) Matrix metalloprotease-2 responsive multifunctional liposomal nanocarrier for enhanced tumor targeting. ACS Nano 6:3491–3498

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This article does not contain any studies with human and animal subjects performed by any of the authors. All authors (P.K. Mandapalli and V.V.K. Venuganti) declare that they have no conflict of interest. This work is financially supported by Department of Science and Technology, Science and Engineering Research Board-young scientist award (SERB/F/1260/2012–13). PK Mandapalli received CSIR-senior research fellowship for his doctoral studies.

Author information

Authors and Affiliations

  1. Department of Pharmacy, BITS Pilani, Hyderabad Campus, Shameerpet, Hyderabad, 500078, India

    Praveen Kumar Mandapalli & Venkata Vamsi Krishna Venuganti

Authors
  1. Praveen Kumar Mandapalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Venkata Vamsi Krishna Venuganti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Venkata Vamsi Krishna Venuganti.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mandapalli, P.K., Venuganti, V.V.K. Layer-by-layer microcapsules for pH-controlled delivery of small molecules. Journal of Pharmaceutical Investigation 45, 131–141 (2015). https://doi.org/10.1007/s40005-014-0153-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40005-014-0153-0

Keywords

Search

Navigation